Eduard BILD

Lucian MIRON

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ONCOLOGY
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Basic Concepts for Students

SECTION 1
CANCER DEFINITIONS, TERMINOLOGY, MALIGNANT PHENOTYP AND
EPIDEMIOLOGY
Oncology is the study of neoplasic disease in generally referred to as the cancer
problem.
There are many definitions of the word cancer, but none is universally accepted.
The cancer is best defined by four characteristics:
1. Clonality: cancer originates from a single cell, which proliferate to form a clone of
malignant cells.
2. Autonomy: growth is no properly regulated.
3. Anaplasia: is a lack of normal cell differentiation.
4. Metastasis: the capacity for discontinous growth and dissemination to other parts of
the body.
Peyton Rous, a Nobel laureate for his pionnering work on viral oncology wrote:
Tumor destroy man an unique an appaling way, as flesh of his own flesh, wich had
somehow been rendered proliferative, rampant predatory and ungovernable 1911.
A good working definition is that cancer is a group of diseases characterized by
uncontrolled cellular growth with local tissue invasion and/or systemic metastasis.
Perhaps, the best definition available of neoplasm is that of Willis (1952) as an
abnormal mass of tissue, the growth of witch exceeds and is uncoordinated with that of
the normal tissue an persists in the same excessive manner after cessation of the stimuli
with invoked the change.
Robbins added: abnormal mass is purposeless, preys on the host and is virtually
autonomous (1984).
The word tumor is derived from latin word tumore = to swell.
At one time the word was used to indicate any type of swelling (traumatic,
inflammatory or neoplasia).
Today, its meaning is often used synonymously with the term neoplasm.
Composed of two terms neo and plasma (lat. new growth), the word neoplasm
refers to an abnormal growth of tissues whose cells usually have rapid growth.
The term cancer is from latin word Kankrum.
A tumor can be either benign or malign.
Information about cancer is increasing rapidly. There are several reasons for this:
- because is not one but over 200 separated diseases;
- since in many countries, but not all, many infections diseases witch used to be the
major causes of death for large fraction of population;
- discoveries in the basic sciences, particularly in genetics.
Cancer can be defined as a disorder of growth and is caused by accumulation of
somatic changes that can interfere with the normal growth process.
History
Cancer is not a modern disease but clearly existed for many centuries, although it is a
more common phenomen in human today than in the past. Human neoplasia appears to be
as old as mankind.

The Egyptians wrote about cancer in papyrus. In one form or another, cancer was
known in perhaps all of the ancient civilizations. The medical papyri of Edwin Smith
dating from about 2500 B.C. are devoted to surgical case histories and number 45
describes a tumor of the breast.
It is untenable that the pregrecian ancient laid the foundation of oncology as a modern
scientific discipline! However the documented to important features of the human disease:
its antiquity and special difficulties in its management.
The Hippocrates writers classified tumors in two: carcinos (Karkinas) and carcinoma
(Karcinomas). They distinguish these from: phyomas, oedemas and other kind of growth
and swelling. Galen of Pergamus (129-199) classified tumors in 2-3 majors groups.
Both the hipocratic and galenic views of cancer treatment were Primum non
nocere(first do not harm !). The aphorisms of Hippocrates contain a variety of references
to malignan disease: Every cancer not only corrupts the part it has seised but spreads
future.
Islamic science in Middle Age keep the elements of Greek, Indian and Persian cancer
medicine alive when Cristian West was fighting desperately with barbarism. The greatest
figure of middle age was Ibn Sina (Avicenna) (980-1037) that write The Canon that
describe many internal cancers of many types.
The cultural Renaissance begin in Italy 1450 and thence spread to most part of
Europe. With Beniveni Antonio begin at Padova, Italy, the longest continues line of
eminent anatomist the world has ever know. This line includes: Andreea Vesalius (15141564), Morgani, Eustachio, Fallopio.
Claude Deshais Gendrom (1663-1750) wrote a little book at 1700: Recherches sur la
Nature et la Guerison des Cancers he proposed that cancers were not due to fluxed
humours or ferments or to corrosive acid whose very existence he had come doubt.
R.Virchow celebrate aphorism every cell from a cell placed the cell at the dead
center of all biological process normal or pathologic.
Little progress or mention was made of cancer until 18th century when Bernard
Peyrihle proposed a viral theory of cancer. John Hunter gave a long account of surgery for
cancers of the female breast, uterus, lips and stomach and advised that many tumors may
be hereditary and that palpation of the mass should be gentle in case rough handling spread
the disease.
In 1775, Percival Pott describbed the occupation cancer of the scrotum that occurred
in chimney sweps. In 1761, John Hill suggested that snuff was responsible for nasal cancer
and polyps. Prior to this, Ramazzini has reported an excess of breast cancer in nuns in
Padua, Italy.
Treatment advances came in the 19th century. In 1881, Billroth performed a succesful
gastrectomy for stomach cancer and in 1884, Godlee removed a brain tumor. William
Marsden founded his Cancer Hospice in 1851 with two aims: care of the cancer patients
and cancer reserch. The century closed with the discoveries of Rentgen and family Curie
wich led to the radiologic diagnosis and radiotherapy and the work of Beatson on
hormonal manipulation in breast cancer.
Different forms of cancer have been recognised and treated for centuries, but it is
advances in civilisation and asociated improvement in life expentancy that have
contributed to making cancer such a common disease worlwide. In United Kingdom in
1880 approximately half of the population die before 40 years of age; in the population

reached the age of 70 and in 1990 the corresponding figure was acceleration of the decline
of premature mortality and an increase in life expentancy and, inadvertently, of cancer.
More and more men and women today live to ages at wich cancer is most common than
ever before, a phenomenon that not restricted to a hanful developed countries.
Cancer is not over 200 separated disease, each with its own causes, natural history and
selections of treatments, each of these cancers are studied individually.
Discoveries in the basic sciences, particularly in genetics, have proved new ways to
study the molecular and cellular biology of cancer. With these tools has come new
understanding of how cancers begin and develop.
CLASSIFICATION NOMENCLATURE
Anaplasia, dysplasia and hyperplasia
Anaplasia, dysplasia and hyperplasia are three words commonly used in refference to
malignancies. The suffix plasia means formation. The prefixes ana, dys and
hyper give these words their unique meanings.
Anaplasia is the loss of structural organisation and useful function of a cell.
Generally, cancer cells resemble undifferentiated or primitive cells that have not developed
the specilised cell structure typical of their tissue of origin. In other words, instead of
developing into nerve cells or muscle cells, they remains in an undifferenciated primitive
state. The degree of anaplasia varis; sometimes the tumors are so undifferentiated, it is
literally impossible to determine the tissue of origin.
Dysplasia is a disturbance in the size, shape and organisation of the cells and
tissues. Dysplasia is abnormal - but not yet cancerous - tissue development. The
epidermitis and mucosal surfaces (linings of the mouth, nose, intestine, cervix) that
normally and constantly undergo cellular multplication, differentiation, organisation and
death are common sites of dysplasia. Dysplasia also is comon in chronic inflammatory and
proliferative lesions and is recognised as part of a developmental phase of many
neoplasms.
Hyperplasia is an increase in the number of cells in a tissue or organ causing an
increase in the bulk of an organ. It should not be confused with hypertrophy, wich an
increase in the size of the constituent cell. Nor is hyperplasia a synonym for tumor growth.
Hiperplasia is induced by known stimuli and is a controlled process inasmuch as it stops
when the stimulushas cessed. In addition, hyperplasia may serve a useful purpose, such as
preparing breast tissue for lactation or reconstituting the liver with structurally normal cells
after partial hepatectomy. Tumor growth obeys none of these rules or purpses. However,
cancerous changes may eventually occur in hyperplastic tissue.
Because hyperplasia and dysplasia often precede the development of many tumors by
months or even years, recognition and proper treatment at this stage in the development
process may help to prevent malignancies. For exemple, the Papanicolau Smear (or Pap
Smear) permits differentiation among normal, dysplasic or cancerous cells, a tehnique that
allows early detection of cervical cancer. The Pap Smear has greatly reduced the morbidity
and mortality of cervical cancer.

Benign tumors
The word benign means non-malignant and suggests that such tumors are harmless. In
many cases this is true. But a benign tumor can lead to death if it grows in critical area of
the body, such as the brain. Also, over a period of time, some benign tumor du becomes
malignant. The ability to distingue between benign and malignant tumors is crucial in
determining the appropriate treatment and prognosis of patients.
The distinguishing features of benign tumors are (table 1.1):
- the benign tumor usually is encapsulated by a well-define fibrous cover (like the skin
of an orange) separating the mass from surrounded tissue.
- malignant tumors invade and destroy adjacent normal tissue.
Indices

Benign

Growth rate
slow
Infiltration
no
Metastasis
no
Survival after treatment high

Low grade malignant

(bordeline)
Variable
Locally
Low
Local recurrence

Malignant
rapid
infiltrate
metastasizing
local recurrence
distant metastases

Table 1.1. Comparative biologic behaviors of neoplasms

Benign tumors may push normal tissue and become life threatening if they press on
nerves or blood vessels or if they secrete biologically active substances, such as hormones
that alter normal homeostatic mechanism.
- a benign tumor neither invades surrounded tissue nor metastasizes (spreads via the
blood and lymphatic systems), but remains within the site of origin. Malignant tumors
metastasized through the lymphatic channels or blood vessels to lymph nodes and other
tissues in the body. Benign tumor remains localized and does not metastasized.
- benign tumor cells exhibit a lesser degree of anaplasia (the loss of structural
organization and useful function of cell). Therefore benign tumor cells resemble normal
cells, they are said to be typical of the cells or tissue of origin.
Malignant tumors cells tend to be anaplasic or less well differentiated than normal
cells of the tissue in witch they arise.
At first, some malignant neoplasic cells resemble the normal tissue in witch they arise,
both structurally and functionally. Later, as the malignancies progress invades surrounding
tissue and metastasized, the malignant cells may look less like the normal cell of origin.
The development of a less well differentiated malignant cell in a population of
differentiated normal cells is some times called dedifferentiation. This term is probably a
misnomer for the process, because it implies that a differentiated cell goes backward in its
development after carcinogenic insult.
Many malignant neoplasm particularly the most rapidly growing and invasive one,
only vaguely resemble their normal counterpart tissue structurally and functionally. They
are thus said to be undifferentiated or poorly differentiated.
- benign tumors usually grow slowly.

Malignant tumors usually, but not always, grow more rapidly then benign tumors.
Once, they rich a clinically detectable stage, malignant tumors generally show evidence of
significant growth with evolvement of surrounding tissue over weeks or months, whereas
benign tumors often grows slowly over several years.
Malignant tumors continue to grow even in the phase of starvation of the host; they
press on and invade surrounding tissue often interrupting vital functions; they metastasized
to vital organs for example: brain, spine, and bone marrow compromising their functions
and they invade blood vessels causing bleeding. The most common effects on the patients
are: cachexia (extreme body wasting), hemorrhage and infections. About 50% of terminal
patients died from infections.
Malignant cells exhibit a unique trait called autonomy. Autonomy is the ability of
tumor cells to grow in an essentially unrestraint manner in the host. In other words,
malignant cells ignore the normal rule of cell reproduction they function outside the
limits of growth of normal cell and are not responsive to normal control on cell numbers.
- in malignant tumors unlike benign tumors, recurrence is more common after surgical
removal because cell have invaded surrounding tissue or have metastasized and are not
removed or destroyed by treatment.
Such local invasions and metastasis may be microscopic and not detected at the time
of treatment.
The disease can be defined as a disorder of growth and is caused by accumulation of
somatic changes that can interfere with intricate growth control processes of the cell.
In summary, a malignant tumor invades surrounding tissue, usually produced
metastasis, and is likely to recur after removal and in most cases causes death unless
adequately treated.
Epidemiology
The dimension of cancer in the world. Present situations and projections
Biological, demographical and medical bases of the present dimension and the future
trends of cancer epidemiology:
1. Cancer is one of the three cell destinies:
1.1. Homeostasis as morphology, function and kinetic proliferation;
1.2. To die;
1.3. To be transformed - malignant phenotype:
- invasion;
- metastasis formation.
2. The principal roads to cancer (Liu T. E.):
2.1. Aberrations of signaling patways;
2.2. Blok in cell death;
2.3. Release of suppression.
3. Cancer origin and genesis depend on:
3.1. The degree of endogenous (genetic) defects leading to cell unstableness;
3.2. Carcinogenic exogenous environmental exposure;
3.3. Aging as the length of time;
3.4. Molecular points of origin are oncogenes.

4. Increase of world population and aging;

5. The present limits of cancer control;
6. Trends:
6.1. Decline in stomach and uterine cancers;
6.2. Increase in lung cancer, melanoma, non Hodgkins lymphoma, pancreatic,
colorectal cancers and brain tumors.
7. Cancer can be preventable; factors related to the risk of cancer are known:
7.1. Smoking cessation and smoking prevention;
7.2. Moderation of alcohol intake;
7.3. Diet and nutrition: low fat, increase in dietary fiber, micronutrients;
7.4. Reduction in exposures to environmental carcinogens burden:
7.4.1. Radiation;
7.4.2. Occupational (industrial) chemicals;
7.4.3. Infections viral agents (HBV, EBV, HIV);
7.4.4. Drugs; hormons.
7.5. Genetic screening in genetic susceptibility.
Epidemiology is the study the distribution and determinants of disease in human
population. Worldwide, one person in three will develop cancer.
This proves remarkably information about patterns and causes of cancer in different
populations around the world. There is now a reasonable clear description of the burden of
disease and death caused by cancer and extends of variation in cancer rates around the
world by age and sex.
Incidence and mortality
Statistical investigations of neoplasic disease are usually based on incidence newly
diagnosed cases and mortality statistics.
Sites
Lung
Colon-rectum
Breast (female)
Prostate
Urinary
- Kidney
- Bladder
Uterus and cervix
Oral
Lymphoma
Leukemia
Pancreas
Skin
Ovary

New cases (0/0000)

170000
152000
182000
165000

Deaths
159000
57000
46000
35000

27700
52300
445000
298000
509000
29300
27700
32000
22000

109000
9900
10200
7700
22000
18600
25000
6800
13300

Table 1.2. Estimated incidence and deaths for majors sites of cancer (USA, 1996)

Incidence the best measure of the frequency of cancer occurrence is the number of
new (incident) cases arising in the population expressed as a rate (number of cases per
100.000 persons per year).
Cancer registries are designed to provide this information, for a defined population by
accurately recording a standard set of data for every new case of cancer diagnosed in
persons living in territory covered by registry.
Mortality - figures are derived from death certificates.
Mortality rate is expressed as the number of deaths per 100.000 population per year.
In developed countries heart diseases and cancer are the first and second most common
causes of death respectively, a pattern now in increasingly seen in developing countries.
Cancer death for all age groups ranks either first or second among the leading
causes for mortality. In developed countries cancer mortality rate for all cancer site
combined are usually higher in males then in females. In men there is a higher incidence of
cancers of low-curability (lung, stomach, oesophagus, prostate), whereas in women the
commoner have a better prognosis (breast, uterus) - table 1.3.
The mortality data are presented in the World Health Statistics Annual in tabular form.
Cancer occurrence in developing countries is published by International Agency for
Research in Cancer (D.M.Parkin 1986).
Male
Lung 25%
Skin 15%
Prostate 11%
Stomach 7%
Colon 7%
Rectum, anus 5%
Pancreas 3%
Oesophagus 3%
Kidney 2%
Others 3%

Female
Breast 22%
Skin 12%
Lung 10%
Colon 8%
Ovary 4%
Cervix 4%
Rectum 4%
Stomach 4%
Endometrium 3%
Pancreas 3%

Table 1.3. The ten most common cancers according to the sex
(A.J.Neal P.J.Hoskin 1997)
Prevalence
Prevalence is the estimated number of persons with cancers (all sites or site specific)
who are alive at any point in time (point prevalence) or at sometime during a definite
period (period prevalence).
Prevalence is usually implied to describe the burden to the disease in a community. It
can be expressed as a number of cases per 100000, if referring to the population in general
or as a percentage, if referring to the number of cases within a given hospital.
The prevalence increases with a incidence (new cases arising in the community) and
with a duration of the disease and decrease with mortality and the cure rates.
Differences in the incidence in the specific cancers between populations or between
individuals in-groups defined by sex ethnic group or religion have often provided valuable
clues for research on the causes of disease.

Age
Is the most important determinant of cancer risk. For most epithelial cancer incidence
rates increase steadily through out life such that a graph of age vs. incidence rate using
logarithmic scales is roughly a straight line.
Incidence rates for older persons often increase less rapidly than earlier age and these
patterns may differ between countries, as with breast cancer, where postmenopausal
incidence varies from continuing increase (USA) to decrease (Japan).
Cancer incidence is so closely related to age and population.
Sex
One of the most striking and consistent features of cancer is that age-specific
incidence rates at nearly all-anatomic sites are higher in males than in females.
A part from breast cancers the exception of these observation comprise a rather
interesting group of cancer: those of the gall bladder and thyroid witch are generally more
common in females and malignant melanoma of the skin and cancer of the eye, salivary
gland and proximal colon, for witch the risk is approximately equal in both senses. Since
few of these differences are explicable in terms of different exposure to carcinogenes, one
must conclude that they represent differences in susceptibility. What means that in
biological terms is still obscure!
Geographic variations
Every tumor type has its own peculiar geographic distribution. Some cancers are fairly
uniformly distributed throughout the world while others show clear patterns of high
incidence in some areas in low others. Lung cancer is very high for Americans blacks and
very low in Bombay.
Stomach cancer is high in Japan (79.6) and again very low in Bombay.
Female breast cancer is high among white women in USA and Denmark and low in
Japan.
Unfortunately, the pattern of cancer occurrence in some areas of the world, notably in
developing countries, remains to be clearly established.
Studies of variation in cancer risk by ethnic origin inevitably rise questions as weather
any of the observed difference are the results of genetic differences in susceptibility to
environmental cancinogens or of differences in life style between the different groups.
One approach to resolving this problem is to study migrannt population and to
compare their risk of cancer with that of persons of the same genetic background living in
the place of the migrants, and with that of persons living in the new host country, with
whom they share a common external environment.
Distribution of disease occurrence in different geographical location, population
groups and over time, suggest that at least 80% of cancer cases can be related to
environmental factors other than to genetic differences (Doll - Peto).

The global cancer burden

Estimates of the global cancer burden have been made for 1975, 1980 and 1985.
These estimates are for all forms of cancer but specifically enclude nonmelanoma skin
cancer, wich is poorly registred on incidence staistics and only infrequently fatal. In men
there were an estimated 3,1 milion cases in 1985. The most common form of cancer is lung
cance, wich an estimated 667.000 cases in 1985.
The estimated number of cases of lung cancer has increased by 44% over the 10-year
period covered by these estimates. Other forms of cancer that have increased notably are
colo-rectal cancer, prostate cancer, bladder cancer, melanoma and lymphoma particularly
non-Hodgkin lymphoma. Although some these increases could be due to better precission
in estimation methodology, there is also likely to be a real etiologic component to these
increases.
In women, it was estimated that there were 3,8 milion cases in 1985. Breast cancer is
the most common form of cancer, with an estimated 719.000 new cases. This is a large
increase over the estimated 541.200 cases in 1975: an increase of 33% in 10 years. A
similar increase has taken place in oral cavity and colo-rectal cancer and lymphoma. The
largest relative increase of cancer in women has been in lung cancer, which increased from
129,700 in 975 to 219,000 in 1985, an increase of 73%. This can most entirily be
explaineted by changes in smoking patterns in women parts of the world.
The estimated number of new cases of cancer woldwide increased from 5,9 millions in
1975, through 6,4 million in 1980, to 7,6 million in 1985. Assuming that age-specific rates
remain constant at the 1985 levels, it was estimatedthat there were 8,4 million new cases in
1990 and would be 10,3 million new cases in the year 2000. It could be deduced that the
number of new cases of cancer worldwide would have doubled between 1970 and 2000.
Beyond 2000, the absolute numbers of cases of cancer will, the absolute numbers of cases
of cancer will likely increase as the post-World War II baby boom generation reaches
ages at wich the age-specific raes of cancer start to increase.
This is important implication for public health as well as other health services around
the world. There will be a need for medical, nursing and related staff to treat these patients;
there will need to be more hospitalsand treatment facilities avaible and this will be a major
expense for the near future as well as major logistical problem. The implications for
planning are that cancer control activities will need to increase to help reduce the mortality
burden that oderwise likely to materialise.
Summary
Descriptive epidemiology has progressed enormously in recent years and very large
good-quality data banks are currently being developed to provide reliable basic statistics on
cancer. Intersting clues for research have been generated by such observations, for
exemple, the studies on migrants, the maps and atlases of the geographic variation of
cancer, detailed analysis of time trends, correlation studies between the incidence of certain
cancers and the prevalence of suspected risk factors, as well as more precisely targeted
epidemiologic studies that attemt to explain the reasons for the existence of such
variations.

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SECTION 2
CANCER ETIOLOGY, CARCINOGENESIS
The etiology of cancer
The current strategies against cancer are to eradicate the disease after detection. The
ideal strategies are prevention but this is not possible in most cases because the exact cause
of cancer or causes of most cancers are unknown. The major exceptions to this is lung
cancer, in witch there is no doubt that cigarette smoking is the major contributing factor.
Thus lung cancer is largely a preventable cancer.
Medical doctors, oncologists, and general practitioners must know no legible about
the risk factors that may predispose individuals and family members to certain types of
cancer. This knowledge will allow participation in screening programs and appropriate
education and counseling.
Epidemiologists J.Higginson and Sir Richard Doll have estimated that 80-90% of
human cancers results from enviromental factors. This estimate based on the comparison
of an individual's average risk for the developemnt of cancer to that obtained by summing
up the lowest observed cancer rate for each organ side. In the contxt of this estimate, the
enviroment is broadly defined and include the direct induction of cancer by exposure to
specific chemicals or viruses as well as the moodification of cancer risk by dietary factors
or reproductive patterns. Exposure to carcinogenic chemicals may results from social
habits such as tobacco usage, the ingestion of some naturally occuring toxins, or work in
certain industries.
The proportions of cancer deaths attributable to various causes are (table 2.1):
Factor or Class of Factor
Tobacco
Alcohol
Diet
Food additives
Reproductive/sexual behavior
Occupation
General pollution
Industrial products
Medicines/medical procedures
Geophysical factors
Infections

Best Estimate
30
3
35
<1
7
4
2
<1
1
3
10?

Range of Estimates
25-40
2- 4
10-70
-5-2
1-13
2-8
1-5
<1-2
0.5-3
2-4
1-?

Table 2.1. Proportion of cancer deaths attributed to various risk factors (R.Doll, R.Peto)
The life style account for about 80% of all malignant cancer: about 30% of all cancers
are related to the smoking, 3% to alchool consumption 35% the diet, 7% to sexual and
reproductive pattern, 5% industrial productions.

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Environmental factors
The english physician Percivall Pott demonstrated the role of these factors in human
cancer more than 200 years ago who recognized a relationship between prolonged
exposure to the irritant of chimney soot ad the subsequent development of scrotal cancer in
these young boys. Since than evidence documenting environmental factors in the etiology
of cancer has continued to accumulate.
Today it is estimated that environmental factors may be involved in a significant
percentage of cancers.
The epidemiological evidence for the etiology of cancers falls in two major categories:
- the first is derived from interpretation of observed differences in: sex, age, socialeconomic and geographic pattern;
- the second pattern category of evidence comes from analytical studies specifically
designed to test hypothesis suggested by the first category.
The risk factors are divided into 3 categories: occupational, medical and social.
Cigarette smoking
Epidemiologists have attributed as many as 25-40% of all cancer death to tabacco use,
primary smoking.
The most direct correlation is between cigarette smoking and lung cancer, tabacco use
has also been implicated in cancers of the mouth, pharynx, larynx, esophagus, urinary
bladder, pancreas and kidney.
Smoking of pipes or cigars has been implicated in the occurrence of cancers of the
mouth, pharynx and esophagus, but this form of tabacco use is generally considered much
less dangerous because the smoke is usually not inhale.
A number of studies have also suggested a correlation between passive smoking and
other cigarettes at home or work place and lung cancer.
An enormous amount of research on the relationship of tabacco smoking and cancer
has been carried out in recent years. The vast majority of these studies indict cigarette
smoking as a major cause of lung cancer.
The data that support the strong relationship tabacco-lung cancer are summarized:
- the strong relationship between smoking and lung cancer mortality in men is supported
by the risk of 11-22 times whose of non-smokers;
- a dose response relationship between cigarette consumption and risk of development of
lung cancer in males and females;
- cessation of smoking results in lowered risk or mortality from lung cancer in
comparison with continuation of smoking;
- results from autopsies studies show that changes in the bronchial mucosa that are
thought to precede development of bronchogenic carcinoma are more common in smokers
than in non-smokers and there is a dose response relationship for these changes;
- chronic inhalation of cigarette smoke or the intratraheal instillation of varies fractions
of tabacco smoke produce lung cancer in such experimental animals as dogs and hamsters;
- cell culture studies show that various constituent found in tabacco smoke condesate
produce malignant transformation in cells.

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Alcohol
Is thought to interact with smoking in the causation of certain cancers, particularly
oral and esophageal cancers.
Appears to be synergic with tabacco in causing cancer of the mouth, pharynx, larynx
and esophagus but not of the lung.
In the case of liver cancers, there is good evidence that alcohol consumption is
sufficient to cause cirrhosis that increase the incidence of liver cancers, perhaps secondary
to chronic damage of the liver caused by alcohol abuse.
A small positive association between alcohol and breast cancer risk has been seen in
some, but not all epidemiological studies. In some studies, even moderate consumption (<3
drinks per week) was associated with increased risk. However, a clear relation between
alcohol consumption and breast cancer has not established.
The industrial environment
Some occupations have been implicated in the etiology of cancers. For examples,
worker in the aniline dye industries has an increase risk of developing bladder cancer.
Lung cancer is more prevalent among those who mine or work with chromate or
uranium areas, especially if they also smoke cigarettes.
Workers in nickel refining plants are more likely to develop cancer of the nasal
sinuses than are average individuals. Exposure to certain solvent e.g. benzene has been
associated with an incidence of leukemia.
Asbestos workers may develop mesotheliomas of the pleural of peritoneal cavities.
Diet
There is suggestive evidence that diet is associated with several types of human
cancers.
Cancers of stomach, colon, pancreas, breast, ovary, uterine endometrum and prostate
appear to fail into this category. This hypothesis stems largely from the observed incidence
of cancers in various of the world.
Stomach cancers are more prevalent in Japan, western-south America and parts of
northern and eastern Europe than in USA.
On the other hand cancer of the colon, pancreas, breast, ovary, endometrum and
prostate are more common in the USA, Western Europe, Australia.
Based on epidemiological data, a high dietary intake of fate, protein and beef as well
as dietary deficiencies of fiber have been implicated in colon cancer.
The cooking of foods may also generate potential carcinogenic substance.
Benzpyrene and other policiclic hydrocarbons can be produced pyrolises when meet is
boiled or smoked or when food is fried in fats that have been used repeatedly.
Diet also seems to be related to high incidence of liver cancer among certain groups of
black Africans living in Africa compared to Americans blacks.
The high incidence among black Africans in Africa correlates with eating of foods
(especially peanuts) contaminated with a fungus known as Aspergillus flavus. This fungus
produces a highly carcinogenic substance known as aflatoxin B.

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On the other hand chronic hepatitis is known to predispose to the development of the
liver cancer and chronic hepatitis is very common in Africa and Asia.
The recommendation of American Cancer Society has recently developed:
- avoid obesity; individuals who are 40% more over weight increase their risk for
certain types of cancer;
- reduce total fat consumption; a high fat diet may be a factor in the development of
particular cancer;
- eat more high fiber foods: whole grain cereals, fruits, vegetables.
Studies suggest that a high fiber diet may help to reduce the risk of colon cancer.
- include foods rich in vitamins A and C, daily.
Vitamin A dark green, deep yellow vegetables and fruits: spinach, carrots, apricots.
Vitamin C oranges, grapefruit, strawberries, green and red bell peppers.
- include cruciferous, vegetables regularly.
Vegetables in cruciferous family include cabbage, broccoli.
Minimized consumption of smoked, salt-cured and nitrit-cured foods.
- keep alcohol consumption moderate.
The ideal should not smoke or drink; should eat a diet low in fat, rich in fibers and
yellow vegetables; should protect himself from hazardous chemicals in work place and
home; should minimized the drug in take and avoid X rays and excessive exposure at sun
light. Ideal women should all these and in addiction have at least one child early and
avoid multiple sex parteners.
Other environmental factors
Parasites
Smoking is also implicated in the risk of developing bladder cancer. The exact
mechanism in unknown, but statistics show that is a correlation between smoking and an
increased of bladder cancer.
Alcohol is thought to be a carcinogen or cocarcinogen (along with cigarette smoke)
for cancers of the head, neck and esophagus. It may also play a rate in the etiology of liver
cancer. Women who become sexually active at an early age and who have multiple
partners are at greater than normal risk of developing cervical cancers.
Drugs and cancer
A number of drugs in clinical use have also been rarely associated with cancer. The
majority of the high implicated agents are immunosuppressive agents principally the
antimetabolites and glucocorticoides.
The most highly implicated carcinogenic drugs are anticancerous agents and the
majors cancers produced are leukemias and lymphomas.
Acute myelocitic leukemia is an unfortunate and rare complication of alkylating
agents such as Melphalan, Cyclofosfamide.
Of interested, the incidence of alkylating agent induce cancer is highest with
prolonged chronic drugs administration schedules.
These agents are associated with unusually lymphomas of the skin or central nerves
system in transplant patients receiving prolonged immunosuppressive therapy.

14

Hormones and cancer

Some hormones are thought to posses carcinogenic potential and this is important in
cancers like:
- Breast cancers - large doses of estrogens when given continuously can cause breast
cancer in susceptible strains of mice. Animal studies also show that estrogen is a
cocarcinogen when administrated experimentally along with another cancer causing agent
such as X-rays or the chemical metylcholanthrene. The animal data have raised concern
that women taking birth control pills or who received estrogen supplements at menopause
might incur an increased risk of cancer. Most of the large studies suggest that exogenous
estrogen probably is not a significant factor in human breast cancer although some experts
still feel that the safety of estrogen has not been.
Women who undergo menopause before 30 have a two-fold reduction in breast cancer
risk when compared to women who undergo menopause after 55 years.
- Endometrial cancer - many physicians suspect that estrogens increase the hazard of
developing cancer of the uterine endometrium. This is based upon several of de case
control studies report an increase risk of malignancy in women receiving estrogen
supplements; though other studies report no such increases and still other studies find an
actual decrease in the risk.
- Vaginal adenocarcinoma: in 1947 it was thought that synthetic estrogen such as DES
were tolerated in pregnancy but the daughters of DES treated mother had an increased
incidence in vaginal dysplasia and carcinoma.
- Ovarian cancer - several analyses have documented that women with a history of
low parity or involuntary infertility are at increased risk for ovarian cancer.
The treatment with ovulatory induced drugs involuntary infertility is increased risk for
ovarian cancer.
Several large control studies have documented a marked protective effect of oral
contraceptive have approximately half the risk of ovarian cancer as do non-users and the
protective effect appears to persists for years after their discontinuation.
Carcinogenesis
The term carcinogenesis is defined as a process wherein the normal physiologic
function of living cells is altered, resulting in abnormal and uncontrolled growth of a
particular organ or tissue.
Two observation derived from human studies of cancer development provide the keys
to understanding mecanisms of carcinogenesis. First, studies of the expression of X-linked
markers genes in tumors obtained from females heterozygous for these loci have
demonstrated that most neoplasms appear to arrise from a single cell, that is, they are
clonal in origin.
Second, epidemiological studies indicate that there is a long latent period in the
development of a tumor.
As shown, epidemiologic studies indicate that a majority of human cancers occur as a
result of exposure to environment factors. Environmental factors includs: smoking, diet,
cultural and sexual behavior, occupational factors, exposure to agents or substances in air,
water and soil.

15

Human carcinogenesis can be divided into three main categories:

1. physical carcinogens;
2. biologic carcinogens;
3. chemical carcinogens.
Physical carcinogens
Physical carcinogens include radiation, films and fibers and chronic irritation. One of
the must widely studied physical carcinogens is ultraviolet (UV) light. Skin cancers, such
as squamous cell carcinoma (SCC), basal cell carcinoma (BSC) and malignant melanoma
(mm) are all correlated with increased UV exposure. In particular, the incidence of skin
cancers is higher in sunny regions of the world, among out door workers in general, in
people with fair complexions and on most sun exposure areas of the human body.
Episodes of sunburn exposure in childhood or in early adolescence may contribute to
an increase in skin cancers incidence. Ionizing radiation induced by exposure to
electromagnetic particles such as -rays, X-rays, or photons is also known to cause cancers
in humans or photons is also known to cause cancer in humans. Examples of occupations
in which exposure to ionizing radiation resulted in bone marrow cancers include watch dial
painters exposed to 224Ra and underground mine workers exposed to radon. Exposure to
asbestoses fibers in humans leads to induction of malignant mezothelioma appears to be
dependent more on the size and structure of the fiber as opposed to its composion. Chronic
irritation or trauma resulting from long-lasting wound or sore is considered a potential
cause of cancer although a direct involvement in human cancer incidence is not shown
unequivocally. Examples of chronic irritation are: lip cancer in pipe smokers, moles in
locations on the body subjects to chronic irritation such as the belt region or the back of the
neck, oral cancers in betel nut or tobacco chewers, and lung cancer in foundry or quarry
workers or people exposed to other types of fiber such as silica fiber. However, in many of
these latter cases, additional exposure to other potential carcinogenetic agents may
confound the establishment of direct associations.
Radiation
Ultraviolet light it was been known for a long time that exposure to ultraviolet (UV)
irradiation can cause cancer in humans.
The association between skin cancer and exposure to the sunlight was observed more
than 100 years ago.
UV in low energy emission and does not penetrate deeply. The evidence for the
association of the skin cancer and UV in compelling and can summarized as follows:
- skin cancers occurs primarily an exposed areas: head, neck, arms, hands, legs in
women as well as upper torso in men.
Skin cancers is relative rare in dark skinned race, in whom pigment filters out UV
whereas in common in fair skinned people.
The incidence of sin cancer and the amount of exposure to sunlight are related.
Skin cancer can be induced in laboratory animals by repeated exposure to UV.
- the inability to repair DNA damage by UV is associated with skin cancer. Thus
individuals xeroderma pigmentosum almost always developed skin cancer.

16

Ionizing radiation
The carcinogenetic effects of ionizing radiation were discovered from the studies of
pioneers radiation workers who were occupationally exposed individuals who were
exposed to diagnostics or therapeutic radiation and atomic bomb survivors.
There is a wealth of experience concerning cancers and leukemia induced in human
population by radiation witch could be briefly summarized:
lung cancer is pitch blander minor and in uranium main;
bone tumors were observed in radium dial pointers who painted luminous dials
on clocks and watches;
excess incidence of liver cancer was reported in patients in whom the contrast
material Thorotrast was used the survivals of atomic bombs attacks on
Hiroshima and Nagasaki represent the most important single group with
leukemias and cancers;
thyroid cancer has been reported in children irradiated for a enlarged thymus or
epilated with X rays.
There is an excess incidence of breast cancer in patient receiving radiotherapy for past
14 months. The 2-3 % increased of cancers in persons in area of Chernobyl.
Biological carcinogenesis
Certain biologic agents have been shown to be associated with specific human
cancers, including viruses, parasites and bacteria. Viral carcinogenesis (figure 2.1) include
activation or derepression of specific DNA sequences called oncogene.
The mechanisms of activation are:
Single point mutation of the protooncogene;
Chromosomal translocation to an active part of the genom;
Amplification (production of multiple copies of the c-onc);
Insertion of an oncogenic virus at an adjacent site;
Deletion/loss of a gene, chromosomal segment or of a whole chromosome;
Derepresion/loss of suppressor gene control.
For exemple Epstein-Barr viruses (EBV) are associated with Burkitt's lymphoma and
is also associated with Hodgkin's lymphoma. Chronic infection with hepatitis B virus has
been linked to the liver cancer in some parts of Asia and Africa. Papilloma virus infection
has been implicated in cervical cancer.
The parasite Schistostoma Haematobium common in some parts of the world such as
Egypt can cause bladder cancer.
The parasite enters the body through the skin as workers stand in infested water.
Then it may migrate to the bladder. Long term infestation is associated with an
increased incidence of bladder cancer. Clonorchis sinensis and Opistorchis felineus have
been associated with gastric cancer in humans.
Among bacteria, infection with Helicobacter pylori has been associated with gastric
cancer in humans.
The relationship between these latter.
Infectious agents cancer may not be direct and they may not be acting more like a
cocarcinogenic and/or tumor promoting stimulus.

17

Figure 2.1. Protooncogene activation mechanism

Chemical carcinogenesis
The majority of human cancers are associated with exposure to chemicals in diet,
tobacco smoke, pollution, medical agents, industrial products, etc.
Based on studies in experimental animals as well as exposed human populations,
chemical carcinogens may be divided into three major classes:
a. organic chemicals;
b. inorganic chemicals;
c. hormones.
In a spite of the variety of chemicals that have been shown to be carcinogenic, it is
important to note that only a small fraction of natural or industrial compounds have been
carcinogenic activity. The most important discovery of the last 30 years in the field of
chemical carcinogenesis was made by James and Elisabeth Miller who provided a basis for
understanding the underling similarity of chemical carcinogens. Their work demonstrated
that most chemical carcinogens require metabolism by the organism to derivates that are
able to react covalently with the DNA, RNA and protein of cells.
Many xenobiotics (non-nutritive chemicals) taken into the body, including chemical
carcinogens are poor soluble in water and cannot be eliminated directly by the kidney.
The efficient excretion of these chemicals depends on their metabolism, often in two
or more steps to more soluble forms. The first metabolic steps, the so-called Phase I
reactions are oxidants performed by membrane bound enzymes presented in reticulum.
The oxidations include the hydroxilation include the hidroxilation of primary and
secondary amines or alifatic carbon atoms, the epoxidation of isoladed double bonds, and
the hydroxylation of aromatic rings. Phase II metabolism of these oxidized derivates
results in the production of glucuronide sulfate or mercaptopuric acid conjugates that are
ready eliminated. Although the liver is the primary organ for xenobiotic metabolism, a
variety of tissues contain lower levels of many of these enzymatic activities. The levels of
the enzymes in the liver or other tissues may be increased by prior exposure to some
xenobiotics including phenobarbital, policyclic hydrocarbons and halogenated aromatic
compounds. The distribution of cancers among different organs reflects booths the levels
of these enzymes in the tissues and the route of exposure to the carcinogen.

18

Carcinogens, by virtue of their ability to form DNA adducts can induce a spectrum of
mutations. The spectrum of mutations induced by chemical carcinogens includes: point
mutations, frameshift mutation (e.g. deletions/insertions), chromosomal aberrations,
aneuploidy and polyploidy with varying degrees of specificity that are usually dose
dependent.
Multistage carcinogenesis
Experimental studies of the skin carcinogenesis in mice have demonstrated that
chemical carcinogenesis can be divided into two stages: initiation and promotion, based on
the responses of the animals to independent or sequential treatments with various agents.
Repetitive treatments of mouse skin with a carcinogen, such as benzpyrene results in a
high yeld of tumors, while a single application of the carcinogen is ineffective. However,
when this simple initiating treatment with a carcinogen is followed by repetitive
application of a noncarcinogenic tumor promoter, a high yeld of tumor is obtained.
The initiation represents an irreversible step and consistent with induction of a
mutation or heritable genetic alteration in one or another critical genes within the target
cell.
The initiation is silent, cumulative and irreversible.
Promotion is a more prolonged process consequent to repeated or continuous
exposure to a substance, which not be carcinogenic or capable of initiating the process.
The tumor promotion phase of multistage carcinogenesis involves the clonal
expansion of initiated cells. By definition and observation, tumor promoting agents are not
mutagenic like carcinogens but rather causean alteration of expression of genes whose
products are associated with hiperproliferation, tissue remodeling and inflamation.
Promoter agents alter the expression of genetic information in the cell; this is associated
with an increase in DNA replication. Tumor promoting stimuli are very diverse in this
model system and include various chemicals such as the phorbol esters, organic peroxides
(figure 2.2).

Figure 2.2. Experiments demonstrating the 2 stages:

initiation and promoting of carcinogenesis in mice (C.H.Pitot)

19

Progression is now generally recognized as separate stage of carcinogenesis. The

most characteristic feature of progression is the occurrence of a measurable change in
karyotipe. This change is directly associated with other features of progression: increasing
growth rate, increasing autonomy of cell, invasiveness and metastatic capability. The
hallmark of tumor progression in the mouse skin model is accumulation of additional
genetic changes in cells that comprise premalignant papillomas.
Natural history of cancer
The carcinogenesis has two main features:
- is a multistage process;
- has a natural history.
The natural history of cancer is a sequence of changes, which develops over time.
The stages of the process of development of cancer are initiation, promotion and
progression (figure 2.3). Progression is an irreversible stage characterized by the malignant
transformation of cells.

Figure 2.3. Genetic changes and progression in colon carcinoma (Fearon-Vogelstein, 1990)
Neoplastic cells undergo replication in cell cycle rate of growth varies. Some
neoplasms grow slowly, some rapidly. The malignancy correlates with the rate of growth.
The doubling time of average human cancer is 50-60 days with a wide range.
Individual tumors can have different doubling times at different times in their natural
history. The growth curve of cancer cells is exponential initially and declines as the tumor
grows because the blood supply.
The growth curve of a tumor of cancer cells is exponential initially, and declines as the
tumor grows larger because the blood supply (figure 2.4).

20

Figure 2.4. The growth curve of a tumor (R. R. Love)

It was necessary about 30-40 doubling of volume take plan before it reach 107 cells, a
diagnostic able size of 1cm, thus the cancer is visible late (years) in its natural history.
The assessment of growth rate of neoplasms can be made:
- clinical and imaging approach;
- flow cytometry: percentage of cells in the S and G2 phases of cell cycle.
Genes of cancer
Oncogenes
Certain normal genes termed proto-oncogenes appear to be target genes for chemical
carcinogens and their alteration is strongly associated with tumor formation and
carcinogenesis. Proto-oncogenes function in a tightly regulated manner to control normal
cellular proliferation and differentiation. However, when these genes are altered by
mutation, sequence deletion, virus integration, chromosome translocation, gene
amplification or promoter insertion, they have the ability to transform cells in vitro. The
altered forms of these genes are called oncogenes (figure 2.5).

Figure 2.5. Identification of the c-ras gene from human bladder carcinoma

21

Proto-oncogenes can be activated to oncogenes either qualitatively or quantitatively.

Qualitative changes includes alteration in the codding region of the gene such as point
mutation. The best examples of oncogenes that are activated by such a mechanism is the
ras family of genes. A large number of cellular oncogenes (>50) have been identified.
Most oncogene proteine products appear to function in one way or another in cellular
signal transduction pathways. Signal transduction pathways are used by the cells to receive
and process information and ultimately to effect a biologic response. Note that oncogenes
fall into six main categories all of which are molecules involved in signal transduction,
including:
a) growth factors : EGF, FGF, PDGF, IGF etc.
b) growth factor receptors: Her-2/neu= EGF receptor;
c) non receptor tyrosine kinases;
d) serine-threonine kinases;
e) G proteins/GTP-ases;
f) nuclear proteins : myc, myb, neu (table 2.2.).
Function
Growth factors
Receptor tyrosine kinases
Kinases
Nonreceptor
Tyrosine kinases
Membrane
G proteins
Transcription factors
Apoptosis bloking factors

Oncogene
sis
hst
erB-1, -2, -3, -4
fms
src, yes
fgr, fps
H-ras, K-ras
N-ras
fos, jun
myc
bcl-2

Oncoprotein
PDGF B
FGF related factor
EGFR and variants
Mutant CSF-1 receptor
Signal transducers
Signal transducers
Gene expression
Control
Bloks myc-induced apoptosis

Table 2.2. Functional clases of oncogenes

Tumor suppresor genes
Tumor suppresor genes and the proteins they encode function as negative regulators of
cell growth. Their function is in direct contrast to dominate transforming oncogenes, which
act as positive regulators of cell growth. Accordingly, tumor suppressor genes have been
termed anti-oncogenes, recessive oncogenes and growth suppressor genes. When tumor
suppressor genes are lost by deletion or inactivated by point mutation they are not longer
capable of negatively cellular growth. Generally, if one copy of the tumor of the tumor
suppressor genes is inactivated, the cell is normal but if both copies are inactivated, loss of
growth control can occur and cancer can develop. The concept that loss of genetic material
is involved in carcinogenesis comes from somatic cell fusion experiments.
Additional evidence has come from the work of Knudson who postulated that two
mutational events are necessary for development of retinoblastoma (a common malignant
tumor in children). This work led to the identification of retionoblastoma gene and the
discovery that both copies of the gene (two mutational events) are inactivated and/or
deleted in retinoblastoma tumors.

22

This deletion involves a specific locus termed RB (figure 2.6).

Figure 2.6. The two-hit mutation model with LOH

(Loss of Heterozigozity, Knudson, 1971)
Tumor suppressor
Gene involved
P53

Condition

Human Cancer

Li-Fraumeni syndrome
(hereditary)
Non hereditary

Sarcomas, leukemia, breast and

brain cancers
Lung, breast, colon, esophagus,
liver, bladder, ovary, sarcoma,
brain, all solid tumors,
lymphomas, leukemias
Nephroblastoma
Adenomas and adenocarcinoma
in the right and transverse colon
Large bowel adenomas and
adenocarcinomas
Neurofibroma
Retinoblastoma
Breast cancer
Pancreatic endocrine tumors,
and pituitary adenomas
Adematous polyps in colon

WT-1, U'
MSH-2, PMS-2

Wilm's tumor
Hereditary nonpolyposis

APC, MCC

Familial adenomatous
Polyposis ( FAP)
Neurofibromatosis
Retinoblastoma
Familial breast carcinoma
Multiple endocrine
neoplasia type 1
Deleted in colon carcinoma

NF-1
RB-1
BRCA-1
MEN 1
DCC

Table 2.3. Human tumor suppressor genes

A number of other tumor suppressor genes have been identified through the analysis
of families with inherited cancer syndromes, including: APC, BRCA1, BRCA2, NF2,
WT1 and WHL; but the most notable being p53 in Li-Fraumeni syndrome. The RB and

23

p53 are usual tumor suppressor genes in that they directly influence the cell-cycle
machinery. RB expression inhibits cell cycle progression by binding to E2F-1 and bloking
transcription of genes necessary for entry into the S-fase of cellular cycle. P53 inhibits cellprogression by inducting the transcriptional activation of CK1; p21 which in turn inhibits
activation of cdk (cycline dependent kinase) such that cannot phosporylate substrate such
as RB (table 2.3.).
The actual data support the hypothesis that the p53 gene may be an important target
for human chemical carcinogenes. The extent to which other tumor suppressor genes might
be targets for chemical carcinogens remains to be determinated.
Cancer - a genetic disease
Cancer is a genetic disease. Progression from normal tissue to invasive cancer takes
place over 5 to 20 years and is influenced by hereditary genetic factors as well as somatic
genetic changes.
Cancer progression is driven by a series of accumulating genetic changes. Some
genetic oncogenic changes contribute to uncontrolled growth or loss of senescence.
Some oncogene cause uncontrolled growth by altering critical nodes in the cell cycle.
Uncontrolled growth can be caused by deregulation at the level of DNA transcription
factors. Separate genetic changes (beyond those causing uncontrolled growth) are required
for tumor invasion and metastasis. Invasion and metastasis from a multistep cascade
involving positive and negative regulatory pathway. Cancer invasion and angiogenesis are
an uncontrolled version of physiologic invasion.
Genetic instability may predispose the premalignant cell to generate malignant
offspring. Instability can take place at the macro level (chromosome kariotype), as well as
the micro level (DNA sequence copy fidelity repair). Chromosomal rearrangement can
activate silent oncogenes or delete regions containing suppressor genes. Loss of
heterosygosity is a hallmark of suppressor gene inactivation in cancer progression.
Telomerase defects may affect growth control as well as genetic instability.
Mutations in cellular DNA can activate oncogenes or inactivate suppressor genes.
Defects in DNA repair mechanisms contribute to the accumulation of genetic defects
fueling cancer progression. Genetic defects causing an inhibition of cell death pathways
are an important mechanism in tumorigenesis.
Family history
There are cancer families with a high incidence of cancers.

Syndromes with an autosomal dominant inheritance includes: familial polyposis coli,

multiple endocrine neoplasia (MEN), neurofibromatosis, Wilmss tumor, neuroblastoma,
retinoblastoma, and basal-cell nevus syndrome. Family cancer syndrome (Li Fraumeni
syndrome) is characterized by cancer of the breast, colorectal, endometrium and soft tissue
sarcomas.
Diseases associated with increased risk of neoplasia:

Some non-neoplastic or preneoplastic conditions are associated with increased risk of

neoplasia:
xeroderma pigmentosum with squamous cancer of skin;
Barretts oesophagus with adenocarcinoma of esophagus;

24

Plummer-Vinson syndrome with esophageal cancer;

cirrhosis with hepatocellular carcinoma;
ulcerative colitis with colon cancer;
Pagets disease of bone with osteosarcoma;
mongolism (trisomy 21) with acute myeloid leukemia.
Summary
During the past two decades, rapidly advancing knowledge of natural histories of
cancers and specific characteristics of their stage have developed from biologic, cellular
and molecular levels of investigation and integration of these three levels of
comprehension. These new understanding have provide more specific methods designed to
prevent cancer formation in the preclinical phase and to enhance management of these
disease in patients in clinical phase.
The concept of ireversibility of action by initiating agents has led to major efforts to
limit human exposure to these agents (e.g. limiting radiation exposure from diagnostic
radiology procedure; limitation of ultraviolet light from sunlight; and limitation of
exposures to known human chemical carcinogens in the workplace, in pharmaceutical
products and and in dietary sources).
Additional effort at removing exposure to promotion agents has lead to limit exposure
to cigarette smoke, use of smokless tobaco and reduction of excess dietary fat. A search for
agents designed to modify the stage of promotion has led to the new science of cancer
chemoprevention exemplified by the use of vitamin A and chemicals analogs (e.g. 13-cisretinoic acid and inhibition of continued development of upper airway cancers).
An understanding of karyotypic instability present in the stage of progression and its
relationship in some circumstances to actions by oncogenic viruses has led to development
immunization methods (e.g. hepatitis B vaccination and attempts to prevent hepatic
cancers).
New knowledge concerning the natural histories of how cancers evolve should enable
design of novel approaches to cancer control.

25

SECTION 3
INVASION AND METASTASES
The early stages of natural history are initiation, promotion and progression.
The process of invasion and metastasis can be considered part of progression or as the
separate and last stage.
The potential biological mechanisms of tumour invasion can be classified into three
categories:
1. increased mechanical pressure caused by rapid cell proliferation;
2. increased motility of malignant cells;
3. lytic enzymatic activity of malignant cells.
Initiation is a rapid and irreversible process caused by exposure to a carcinogen agent
(chemical, radiation or viral).
Promotion is a more prolonged process consequent to repeated or continuous
exposure to a substance, which not be carcinogenic or capable of initiating the process.
The promotion is characterized by an alteration in gene expression. If cancers arise
consequent to relatively rare event affecting singles cells, then they should exhibit in some
fashion this single cell or clonal origin.
For some specific cancers there is very suggestive evidence supporting a monoclonal
origin. For example, in 90% of cases of chronic myelogeneous leukemia (LMC), the
leukemic cells all passes a distinct kariotypic abnormality, usually a chromosome 9 to12
translocation, called Philadelphia chromosome.
In multiple myeloma, excess production of a single immunoglobulin is usually found.
In support of the general case that tumors are monoclonal in origin, the best evidence
comes from the studies of G-GTP, which is controlled by sex chromosome X.
Progression
If tumors progress beyond the promotion stage, they develop new and unique
characteristics, which justify recognition as belonging to a distinct stage-progression.
The most characteristic feature of progression is the occurrence of a measurable
change in kariotype.
This change is directly associated with other feature of progression: increasing growth
rate, increasing autonomy of the cell, invasiveness and metastic capability.
It has been only recently, with improved laboratory techniques, that this essentially
universal characteristic of human malignant neoplasms has been recognized.
The malignant phenotype development is consequence of activation of several types
of protooncogenes in oncogenes.
Activation of c-oncogenes can take place by means of all the mechanisms that
include:
Point mutation gene;
Gene rearrangement;
Gene amplification;
Increase transcription;
Chromosomal alteration.

26

The critical kariotype instability leads to the malignant change notes above, but also
most significantly to activation of proto-oncogenes.
The two best-studied human malignancies are chronic myelogenous leukemia (CML)
and Burkitt lymphoma.
As mentioned earlier, in CML is a well-described translocation of part of chromosome
9 to 22 is usually seen. This translocation brings a proto-oncogene named c-abl to
chromosome 22 where a chimeric gene is formed, which production of a new fusion
protein.
In Burkitt's lymphoma, the usual translocation is between chromosome 8 and 14,
which translocation of c-myc proto-oncogene to chromosome 14, where it is often placed
adjacent to the promoter-enhancer region of immunoglobulin genes. Thus, results in
increased expression of the c-myc gene.
Other mechanisms of proto-oncogene activation besides chromosomal translocation
have been described: base mutations in coding sequences, deletions in noncoding
sequences, altered promotion for RNA polymerase, increase or substitution with repetitive
DNA elements and gene amplification.
In some human tumors, measured gene amplification has been related to poor
prognosis.
Cell cycle, cellular replication
Karyotypic instability is the cardinal characteristic of progression and the absence of
cellular replication which distinguished malignancy and which makes cancers lethal.
The events of cell division have been described as a sequence called the cell cycle,
which has 4 components and a 5th phase G0, in which cells are in resting phase.
The dividing cell cycle is the series of changes that the cell goes through from the time
it is first formed until it divides into 2 daughter cells.
The time required to complete this cycle is called the generation time. The cycle
begins at the end of the mitosis (the M phase) in a phase called G1. Following G1 is S
phase, the period of time required for DNA doubling.
After S phase is a second gap, G2. This is followed by mitosis.
The duration of S, M and G2 are relative constant in different tissue.
The duration of G1 is quite variable between tissues and it determines the length of
cell cycle. G0 is a quiescent phase. Importantly, most stem cells in normal tissue are in G0
and are not committed to division. The tissue spend in each phase of cell cycle is shown in
table 3.1.
Phase
G1
S
G2
MITOSIS
G0

Function
Enzyme manufacture
DNA synthesis
Double DNA component
Synthese mitosis proteins
Cell division
Resting (not in cell cycle)

Table 3.1. Phases of cell cycle: time and function

Time
Varies greatly
10 - 20 h
2 - 10 h
30 - 60 h
Varies greatly

27

After mitosis, the daughter cell enters Gs. It remains in G1 until it receives a stimulus
to enter S-phase. An important chemical message to undergo division is the recently
identified protein called cyclin (figure 3.1).
Cyclins act specifically because is synthesized at a discrete stage of the cell cycle:
cyclin D and E in G1 cyclin A in S and G2 and cyclin B in G2 and M.
The G2 phase follows the S phase. It is a short, premitotic phase, during which RNA
and specialized protein are produced, particularly the topoisomerase enzymes, which allow
for proper uncoiling of supercoiled DNA.
These enzymes include topoisomerase II which makes double stranded cuts in DNA
and topoisomerase I enzymes which make single strand cuts in DNA. These enzymes are
targets for drugs such as Etoposide and topotecan (topo I).

Figure 3.1. Cell-Cycle Phases

Metastasis
Once the diagnostic of cancer is established, the next question is: is the disease
localized to the primary site or has it already spread to regional lymph nodes and distant
organs?

28

A metastasis is defined as one or more neoplastic cells growing at some finite distance
from the original primary growth of the tumor.
The ability of cells of a cancer to disseminate and form new foci of growth of noncontiguous site represents its most malignant characteristic and is responsable for the
majority of cancer deaths.
Metastases are the spread of cancer cells from a primary tumor to the vital organs
and distant sites in the cancer patient's body. Metastatic disease is the hallmark of
malignant cancer.
Tumor invasion and metastasis is the major cause of treatment failure for cancer
patients. About 30% of patients with newly diagnosed solid tumors already have clinically
detectable metastases. Of those of 70% of cancer patients who are clinically free of
metastasis, about half can be cured by local tumor therapy alone. The remaining patients
have clinically occult micrometastases that ultimately become manifest. Thus, 60% of
patients have microscopic or clinically evident metastases at the time of primary tumor
treatment.
Most patients suffer from multiple metastases. The formation of metastatic colonies is
a continuous process commencing early in the growth of the primary tumor and increasing
in frequency with tumor duration and tumor burden.
The patient with metastatic disease succumbs to the direct anatomic compromise
caused by the metastasis or to complications associated with anti-metastatic therapy.
For many common epithelial tumors, the onset of tumor-cell dissemination occurs
soon after primary vascularization. It was calculated that most metastases from breast
carcinomas are initiated when the primary is less than 0,125cm3.
During the last years, neoplasms have become widely recognized as biologically
heterogeneous. At the time of diagnosis, most neoplasms consist of different populations
of cells with divers biologic characteristics. Subpopulations of tumor cells differ in
immunogenity, growth rate, karyotipe, pigment production, hormone production, receptor
content and susceptibility to cytotoxic drugs. The formation of metastatic foci is a
continuous process that can begin early in the growth of the primary tumor and increases in
frequency with tumor duration and tumor burden
FIDLER and HART have emphasized that neoplasms can be heterogeneous for the
propensity to invade and metastasize and that the aggressive subpopulations may be
selected out in the formation of metastasis. They discovered that preexisting
subpopulations growing in the same tumor exhibit heterogeneous metastatic potential.
The process of metastasis is not random. Instead, it is a cascade of liked sequential
steps that must be traversed by tumor cells if a metastasis is to develop. To be successful, a
metastatic tumor cell must leave the primary tumor and invade local host tissue. It must
then enter the circulation, survive in circulation, arrest (stopping) at the distant vascular
bed, extravasate into the organ interstitium and parenchyma, and multiply to initiate a
metastatic colony.
Interruption of the metastatic process cascade at any of these steps can prevent the
production of clinically symptomatic metastasis. A large foundation of experimental work
suggests that during each stage of metastasis the rules of survival of the filtest apply.
Metastasis is thus the results of a high selective competition favoring the survival of a
minor subpopulation of metastatic cells that preexist within the primary neoplasm.

29

The metastatic cascade

A metastatic colony is the result of a complicated series of tumor - host interactions.
The phases of metastatic process are (table 3.2):
Metastatic Cascade Event

Potential Mechanisms

1. Tumor initiation

Carcinogenic insult, oncogene activation or

derepression, chromosome rearrangement

2. Promotion and progression

Karyotypic, genetic, and epigenetic instability;

gene amplification: promotion associated genes
and hormones

3. Uncontrolled proliferation

Autocrine growth factors or their receptors,

receptors for host hormones such as estrogen

4. Angiogenesis

Multiple angiogenesis factors including known

growth factors

5. Invasion of local tissues, blood and

lymphatic vessels

Serum chemoattractants, autocrine motility factors,

attachment receptors, degradative enzymes
Tumor cell homotypic or heterotypic aggregation

6. Circulating tumor cell arrest and

extravasation
a. adherence to endothelium
b. retraction of endothelium
c. adhesion to basement membrane
d. dissolution of basement
membrane
e. locomotion

Tumor cell interaction with fibrin, platelets, and

clotting factors; adhesion to RGD-type receptors
Platelet factors, tumor cell factors
Laminin receptor, thrombo-spondin receptor
Degradative proteases, type IV collagenase,
heparinase, cathepsins
Autocrine motility factors, chemotaxis factors
Receptors for local tissue growth factors,
angiogenesis factors

7. Colony formation at secondary site

8. Evasion of host defenses and
resistance to therapy

Resistance to killing by host macrophages, natural

killer cells, and activated T-cells; failure to express,
or blocking of, tumor-specific antigens;
amplification of drug resistance genes

Table 3.2. Tumor - Host Interactions During the Multiple Cascade (L.A.Liotta)
Oncogenesis
Oncogenesis (tumorigenesis) - after the initial neoplastic transformation the tumor
cells undergo progressive proliferation that accompanied by further genetic changes and
development of a heterogeneous tumor cell population with varying degrees of metastatic
potential. The initial growth of the primary tumor is supported by the surrounding tissue
microenvironment, which eventually becomes rare limiting for further growth.
The progressive alteration in cellular oncogenes and inactivation of tumor suppressor
genes that results in uncontrolled growth and loss of contact-dependent cell growth has
been well documented in many tumor types.

30

Local invasion
Continued genetic alteration in the tumor cell population results in selection of tumor
cell clones with distinct growth advantage and acquisition of an invazive phenotype.
During the tumor progression a great number of tumoral cells are localized on surface
of basement membrane (carcinoma in situ). In human, the earliest detectable malignant
lesions are often referred to as in situ cancer. These are small tumors that are localized in
tissue.
The mammalian organism is compared of a series of tissue compartments separated
from each other by two type of extracelullar matrix: basement membrane (MB) and
interstitial stroma.
The matrix determines tissue architecture, has important biologic functions and series
as mechanical barrier to invasion.
During the transition from in situ to invasive carcinoma, tumor cells penetrate the
epithelial basement membrane and enter the underlying interstitial stroma (microinvasive
cancer).
The MB has trilaminar structure: on electronic microscope: lamina lucida externa,
lamina densa and lamina lucida interna.
The MB is formed by colagenic components (fiber of colagen) and non-colagenic
elements: fibronectina, laminina and proteoglicani.
A three-step process has been proposed to describe the sequence of biological events
during tumor-cells invasion of extracellular matrix:
1. Attachment
2. Local proteolysis
3. Migration
1. The first step is tumor-cell attachment to MB. This attachment may be mediated
through specific glicoproteins such: laminin, fibronectin receptors (cadherine - a cell
surface glicoprotein have been described that mediate intercelular adesion).
2. After attachment, the tumor cells secretes hydrolytic enzymes (or induce host cells to
secrete enzymes) that can locally degrade the matrix. A positive association with tumor
aggressiveness has been noted for various classes of degradative-enzymes including
metalloproteinase, serine and heparanases.
Plasminogen activator, specifically urokinase-type plasminogen activator has been
closely linked to the metastatic phenotype.
The matrix lysis most likely takes place in a highly localized region, close to the tumor
cell surface. Where the active enzyme outbalance the natural protease inhibitors present in
the serum and in the matrix.
3. Migration. The third step of local invasion is tumor-cell locomotion into the region, the
region of the matrix modified by proteolysis.
The direction of the locomotion may be influenced by host-derived chemotactic factor
and tumor-cell derived motility factors. The chemotactic factors derived from serum, organ
parenchyma or the matrix itself may influence the organ specificity metastasis. Continued
invasion of the matrix may take place by cyclic repetition of these three steps.
It is important to keep in mind that malignant cells use some of the same tissue
degradative and invasive mechanisms that are utilized by normal processes such as
migration and tissue remodeling in embryonic development, wound healing and
trophoblast invasion of the uterine wall during normal pregnancy.

31

The last of these events can be used as an example.

If a successful implantation of the blastocyst into the uterine wall is to occur in
pregnancy throphoblast cells must cross the basement membranes of the uterine epithelium
and vasculature.
Several lytic enzymes, proteolytic enzyme regulators and growth factors are involved
in this process.
For example the production of protease of the urokinase-type plasminogen activator
(u-PA) by murine throphoblast coincides with the invasion of the mouse blastocyst into the
uterine-wall.
Similarly, human throphoblast express u-PA. Metalloproteinase such as stromelysin
and colagenaze-IV are produced by throphoblast cells, as are tissue inhibitors of
metalloproteinases.
The difference between normal throphoblast invasion of the uterine wall and cancer
cell metastasis is that the former is a tightly regulated process with stringent termination
signals.
The interaction of the tumor cell with the extracellular matrix (ECM), in particular the
basement membrane defines the malignant phenotype and tumor invasion is a paramount
to methastasis. It is now recognized that ECM exerts a profound influence on cell behavior
and that cells direct the assembly and disassembly of the matrix. This concept is know as
dynamic reciprocity and also applies to the interaction of malignant tumors to the ECM.
Angiogenesis
One crucial step for the continuos growth of tumors and the development of
metastasis is the induction of vasculature (angiogenesis). A tumor mass that is less than
0,5mm in diameter can receive oxygen and nutrients by diffusion, but any increase in
tumor mass beyond 0,5mm requires the proliferation and morfogenesis of vascular
endothelial cells.
The formation of new blood vessels, or angiogenesis, permits the expansion of a
tumor mass in three dimensions.
Prevascular tumors may persists thin asimptomatic lesions, restricted by the limits of
oxygen and nutrient diffusion. In contrast, vascularized tumors expand locally and by
metastasis.
Tumors can induce angiogenesis through a variety of soluble factors. Angiogenesis is
not one event, but a cascade of process emanating from microvascular endothelial cells.
The process of angiogenesis consists of multiple, sequential and interdependent steps.
It is begins with local degradation of basement membrane surrounding capillaries,
which is followed by invasion of surrounding stroma by underlying endothelial cells in the
direction of the angiogenetic stimulus. Endothelial cell migration is accompanied by the
proliferation of endothelial cells and their organisation into three-dimensional structures
that joint with other similar structures to form a network of new blood vessels (figure 3.2)
Endothelial cells resting in the parent vessels are stimulated to degrade the endothelial
basement membrane, migrate into the perivascular stroma and initiate a capillary sprout.

32

The angiogenesis is a three step process:

a) Destruction by proteolysis;
b) Proliferation of endothelial cell;
c) Motility by chemotaxis toward the angiogenesis stimuli. Migration of endothelial
cells toward angiogenetic factors;
d) Lying down of a basal lamina around the nascent capillary.
Endothelial proliferation permits extension of the microvascular tubes, which develop
into loops and then into a functioning circulatory network. The existence of endothelial
cells from the parent vessel involves cell migration and degradation of the extracelullar
matrix in a manner that may be functionally indistinguishable from cancer cell invasion of
extracelullar matrix.
The agents that can induce angiogenesis are called angiogenetic factors (described
by Folkmann), such as: vascular endothelial growth factor (VEGF), fibroblastic growth
factor (FGF), TGF beta, PDGF, IGF-1 (TAF).
Angiogenesis is of course also a normal process by which new blood vessels are
formed, for example in development of placenta, in vascularization of developing organs
and in wound healing. Under these conditions however, angiogenesis is high regulated
being turned on for specific period of time and then shut off. Angiogenesis is a balance of
pozitive and negative effectors. Some endogenous inhibitors of angiogenesis are:
angiostatin, endostatin, vasostatin, restin, interferon alpha and beta, angiopoietin-2 and
antithrombin III fragment.
In conclusion, angiogenesis is a dynamic process essential for the growth of primary
and metastatic tumors as well as hematopoietic cancers. Understanding the basic principles
of the biology of angiogenesis has led to the development of new prognostic factors tumor
markers, imaging techniques and therapeutic modalities.

Figure 3.2. Angiogenesis

33

Intravasation
Newly formed tumors vessels are often defective and easily invaded by tumor cells
within the primary mass.
Tumor cells also invade preestablished host blood vessels at the invasion front. The
invasive phenomenon of the vessel wall is similar to this of local invasion: attachment,
local proteolysis and migration.
Early clinical observation led to the impression that carcinomas frequently spread and
growth in the lymphatic system, whereas tumors mesenchimal origin spread more
frequently by means of the bloodstream.
Cancer cells may invade the lymphatics directly or may gain access to them via blood
vessels. Tumor cells can readily pass from blood to lymph nodes and back again,
indicating that venolympathic communication via the interstitial spaces of lymph node and
other tissue exist.
Cancer cells can spread along tissue plans and into various tissue spaces and cavities,
but the two major routes of metastatic spread are via lymphatic vessels or blood vessels.
Indeed, for the purpose of clinical staging, metastases are subdivided into two groups:
those in regional lymph nodes, which are usually regarded as having disseminated via the
lymphatic circulation, and those which arise at more distant sites and organs, which usually
spread via the blood vascular system. It used to be thought that these two routes were
independent options and sarcomas were regarded as most likely to spread via the blood
vascular system, which carcinomas spread initially via lymphatics to lymph inating more
widely. These two circulation systems are widely interconnected, however, such that they
cannot be regarded as independent routes of spread.
Different types of tumors have different patterns of spread.
Tumor of the head and neck for example usually spread initially to regional lymph
nodes and only when more advanced to distant sites; thus, localized therapy that includes
treatment of regional lymph nodes can be effective.
In contrast, tumors of the breast can spread early to distant sites. Involvement of
axillary lymph nodes at the time of primary treatment is later found to have widespread
metastases. Thus, the lack of lymph nodes metastases does not rule out the possibility that
the cancer has disseminated via the via the blood vascular system.
During circulation in the vascular system, tumor cells can undergo a variety of
interactions, including aggregation with platelets, lymphocytes and neutrophiles, leading to
formation of emboli that become lodged in the capillary bed of a distant organ. These
clumps of cells adhere to the capillary endothelium and elicit the formation of a complex
with the matrix that appears to favor the survival of cancer cells.
Circulating tumor cell
Once the tumor cells and tumor cell clumps (emboli) have riched the vascular or
lymphatic compartments, they must survive a variety of hemodinamic and immunologic
challenges. Little is known about how these factors may impact on the inefficiency of the
metastatic process in human cancers.
Circulating tumor cells use a variety of means to arrest in the vessels of the target
organ where they initiate metastatic colonies.

34

About 80% of the circulating tumor cells are in single-cell form and directly attach to
the intact endothelial basement membrane. Clumps of circulating tumor cells or tumor
cells aggregated with host-leukocytes, fibrin or platelets can directly embolize the
precapillary venules by mechanical impaction. Tumor-cells in single-cell or clumps form
adhere to the endothelial luminal surface of arterioles. The fate and time course of the
arrested tumor cells differs depending on the mechanism and location of arterioles. The
vast majority of tumor cells that enter in the circulation are rapidly eliminated. The chance
a tumor cell will survive in the circulation increases if it forms aggregated.
Arrest and extravasation
The arrest of tumor cells in the small blood vessels of organ is often associated with
thrombus formation involving the interaction of the cells with platelets and leukocytes.
Thrombi have been observed around arrested tumor cells, but apparently remain for only a
few hours before being broken down, presumably by fibrinolytic enzymes such as plasmin
produced or activated by the tumor cells.
Such thrombi might provide protection for the cell against mechanical trauma due to
blood flow and against host cells. Adhesion the tumor cells themselves may also involved
in the cell arrest.
The first step in the process of tumor cell-attachment to an invasion through
endothelial cell monolyers and their basement-membrane-like matrix is the attachment to
endothelial cells, mediated by cell adhesion molecules (CAM). The CAM include the
I-CAM and the N-CAM family (cadherines), cell surface lectines and lectin-binding
glicoproteins expressed by the cells.
The next steps are:
Retraction of the endothelium;
Adhesion to the basement membrane;
Locomotion.
Recent studies have demonstrated that endothelial cell, derivated from the small
vessels of different organs, express different levels of such molecules so that adhesion to
endothelial cell monolyers by tumor cells depends on the origin of the endothelial cells as
well as tumor cells.
Following attachment to the endothelial cells the tumor cells extends pseudopodia into
the endothelial cell junctions or induces endothelial cell retraction allowing access to the
basement membrane (MB). Alternatively, the cells may attach directly to regions of
denuded basement membrane.
Adhesion to the basement membrane involves binding to membrane components such
as laminin, fibronectin, vitronectin, collagen IV and proteoglicans.
This binding appears to be mediated by cell-surface receptors, many of which are part
of the integrin family.
The third step of extravasation is digestion of the basement membrane by various
proteolytic enzymes that are produced by the tumor cells.
It appears that a large number (80%) of circulating tumor cells remains viable in the
circulation and extravasate up to 3 days after their introduction in circulation. However,
only a small subset of cells (1 to 40) grow to form micrometastases and fewer (1 to 100)
continue to grow, forming macroscopic tumors. Almost 40% of injected tumor cells
remained as dormant solitary cancer cells. Metastasis formation is an inefficient process.

35

Locomotion and establishement of a new growth

The extravasation of tumor cells permits them access to the tissue interstitial space,
where they can divide and grow if conditions are appropriate.
Clinical observations have indicated that metastases from certain types of tumors tend to
occur in specific target organs.
Because lungs, liver, lymph nodes, bone and brain are the most common sites of
spread the lesser, more specific sites led Stephan Paget (1889) to propose the soil and
seeds theory, in which he postulated that differential tumor-cell host organ interactions
can occur, which are more or less favorable for metastatic development.
Theoretic mechanisms for organ tropism include the following:
a) Tumor-cells disseminate equally in all organs, but preferentially grow only in specific
organs. Preferential growth may be induced by local growth factors or hormones
present in the target organ for metastases.
b) Circulating tumor-cells may adhere preferentially to the endothelial luminal surface
only in the target organ for metastases. This hypothesis predicts organ-specific
endothelial determinants.
c) Circulating tumor-cells may respond to soluble factors diffusing locally out of the
target organ. Such factors could in a chemotactic fashion to attract the tumor-cells to
extravasate. They could cause the circulating tumor-cells to aggregate and therefore
embolize in the target organ.
In 1929, James Ewing challenged Paged seed and soil theory and suggested that
metastatic dissemination occur by purely mechanical factor that is a result of the
anatomical structure of vascular system (hemodynamic theory).
Both hyphotesis are correct because common regional metastastatic involvements
could be attributed to anatomical or mechanical consideration, such as efferent venous
circulation or lymphatic drainage to regional lymph nodes, but that distant organ
colonization by metastatic cells from numerous types of cancers established their own
patterns of site specificity.
The growth in secondary sites
The final step in metastasis is tumor cells proliferation. During the interaction of
metastatic cells with host tissues, signals from autocrine, paracrine or endocrine pathway,
alone or in combination, stimulate or inhibit tumor cells proliferation, with the eventual
outcome dependent on the net balance of positive and negative regulators.
Only a few of these organ-derived growth factors have been isolated and purified to
homogeneity. A potent growth-stimulatory factor was isolated from tumors conditioned
medium and stromal cells like TGF-alfa, FGF-alfa, hepatocyte growth factor.
Conversely, a number of tissue-specific had been isolated and purified, including
TGF-alfa, mammastatin and amphiregulin. Autocrine or paracrine host growth factors that
control organ repair and regeneration may also affect the proliferation of malignant cells.
Recent data indicate that the process of metastasis is selective for cells that succeed in
producing angiogenesis, mobility, invasion, embolisation, survival in the circulation, arrest
in a distant capillary bed and extravasation into and multiplication within organ
parenchyma.

36

Tumor cells can reach the microvasculature of many organs into the organ
parenchyma and growth occurs only in some organs.
Ability of metastatic tumor cells to escape the host immune response
Tumor specific antigens (TSA) might be present on the surface of malignant cells, and
these antigens are may be recognized by the immune system. This poses the paradox of
why, in the presence of a competent immune system not always function to protect the host
from tumor growth, individuals thus who succumbing to neoplastic disease, and why,
when malignant tumors occurs in individuals, do tumours bearing TSA's not provide an
efficient immune response to rejects them ?
Cell surface antigens representing the major histocompatibility complex (MHC),
antigens of the mouse (H-2 genes) and human (HLA genes) play a role in immune
surveillance, tumorogenicity and metastatic potential in both mouse and human cancer.
Cytolityc lymphocytes recognize cell surface alterations of neoplastic cells associated
with MHC antigens.
Experiments in mice have demonstrated that metastatic properties of certain mouse
tumors are correlated with the expression of class I MHC antigens.
Using cloned cell lines of differing metastatic capability derived from the 3-methyl
cholontrene-induced fibrosarcoma of mice, a correlation was observed between the in
vivo metastatic potential and expression of the H-2D and H-2K antigens. Metastatic
clones expressed only H-2D and H-2K expression of the H-2D and H-2K antigens, but
locked H-2D and H-2K expression.
Non-metastatic clones had H-2D on their cell surface but not H-2D, suggesting that
the DK antigen contributes to the metastatic potential of these clones. Furthermore, when
genes coding for the H-2K region were transfected into metastatic clones T10 cells, these
cells expressed Kb and KR antigens on their surface and lost their metastatic ability in vivo,
even though they remained locally tumorigenic. These results strongly imply that the MHC
system is involved in immune surveillance that limits the mobility of circulating,
metastatically potent tumor cells.
This contention is supported by the fact that the H-2K gene transfected cells where
more immunogenic and more susceptible to killing by cytolytic lymphocytes than their
H-2K-negative counterparts.
Somewhat paradoxically, the presence of immune lymphocytes that recognize tumor
cells may enhance the colonization of metastatic sites. The ability of cancer cells to take
advantage of the hosts own inflammatory response mechanisms and at the same avoid
distructions by the hosts immunologic defense system, gives the cancer cells tremendous
selective advantage.
A great effort has been made to induce an improve specific and non-specific immune
response, and great progress also has been made field, although immunotherapy has still
not become a conventional method in cancer management. One of these reasons may be
that immunosupression in cancer patients contributes to this failure.
There are another several mechanisms of tumors escape from immunologic
destruction. These are presented in the table 3.3:

37

I. Tumor related
1. Failure of the tumor to produce a suitable target (defective immunosensibility):
a. lack of antigen epitope;
b. lack of MHC class I molecule;
c. deficient antigen processing by tumor cell;
d. antigen modulation;
e. antigen masking of the tumor;
f. resistance of tumor cell to tumoricidal effector pathway.
2. Failure of the tumor to induce an effective immune response (defective
immunogenicity):
a. lack of antigen epitope;
b. decreased MHC or antigen exppression by the tumor;
c. lack of costimmulatory signal;
d. production of inhibiting substances (e.g. cytokines) by the tumor;
e. standing of antigen and tolerance induction;
f. induction of apoptosis in T- cell by expression of Fas ligant by cancer cells;
g. induction of T-cell signaling defects by tumor burden.
3. establishment of paracrine stimulatory loop.
II Host related
1. failure of the host to respond to an tumor antigen:
a. immune suppression of deficiency of host including apoptosis and signaling
defects of T-cell due to carcinogen (phisical, chemical) infection or age;
b. deficient presentation of tumor antigens by host antigen-presenting cells;
c. failure of host effectors to reach the tumor (e.g. stromal barrier).
2. failure of host to kill variant tumoral cells because of immunodominant antigens on
parenteral tumor cells.
Table 3.3. Mecanisms of tumor escape from immunologic destruction
Types of hematogenous metastatic spread
Walther established that there are 4 types of hematogenous metastatic dissemination:
a) Lung type = primary tumor in lung left heart lung;
b) Hepatic type = primary tumor in liver superior cave vein lung;
c) Caves veins systems left heart great vessels;
d) Portal veins system port system.
Batson describe a particularly dissemination system paravertebral plexous way in
prostate cancer.
Tumor cells can spread by direct extension into body cavity such as pleural and
peritoneal space or cerebro-spinal fluid. In these cases, tumor cells released into the body
space can seed out into tissue surfaces and develop new growths after they become
embedded.

38

Figure 3.3. Clinical forms of metastasizing

Examples of cancer that spread in this way are lung cancer that spread to pleural
cavities, ovarian cancer that enter peritoneal cavity and brain tumors that send cells into the
cerebro-spinal fluid.
Tumor cells metastases by invading blood vessels or lymphatic channels.
Breast axillary lymph nodes, opposite breast, lung, pleura, liver, bones, adrenal and
spleen, ovary.
Colon lymph nodes, liver, lung, stomach.
Kidney lung, liver, bone.
Lung pleura, liver, bone, kidney, adrenal, thyroid and spleen.
Prostate bones of spine and pelvis, regional lymph nodes.
Ovary peritoneum, regional lymph nodes, lung and liver.
Stomach regional lymph nodes, liver, lung and bone.
Testis regional lymph nodes.
Summary
Metastasis is the major cause deaths due to cancer and it occurs primarily by
dissemination of tumor cells through the lymphatic and blood vessels. In humans there is
evidence for organ-site specificity in the development of metastases from particular types
of primary tumors, and cells that have specific organ-site preferences for metastatic
development have been from tumors in animals.

39

Isolation of cloned cell population from rodent tumors has demonstrated wide
heterogeneity in metastatic potential between clonal population.
These are several major steps involved in the process of metastasis that include: the
ability to invade into and out of blood vessels, to survive in the circulation and to arrest
and grow at a new site.
The development of metastatic potential may be viewed as one of the late stages of the
process of tumor progression.
Primary tumors are heterogenous for a large number of properties including invasion
and metastasis.
The process of metastasis is sequential and the growth of metastases represents the
endpoint of many lethal events that only a few tumor cells can survive (inefficient
process).
The outcome of metastasis is determinate by interaction of metastatic cells with
various homeostatic factors. The successful metastatic cell (the decathlon champion)
succeeds by usurping homeostatic mechanisms. Hence, insight into the molecular
mechanisms that regulate the pathobiology of cancer metastasis as well as a better
understanding of the interaction between the metastatic cell and the host environment can
provide a foundation for new therapeutic approaches.

40

SECTION 4
CANCER DIAGNOSIS
Cancer diagnosis
History taking, physical examination, hypothesis forming, laboratory examinations,
cancer localization, pathologic diagnosis, staging and evaluation of prognostic factors, and
pretherapeutical examinations comprise steps in the diagnostic process in oncology.
Awareness of cancer etiology, paraneoplastic symptoms, means of tumor localization, and
histologic analysis guide cancer diagnosis. Understanding of clinical and pathologic
prognostic factors on the one hand, and risk assessment on the other, are crucial in the
decision making process.
A diagnosis of cancer depends on the patient's consulting a physician. This in turn
depends on the patient's knowledge of health problems. At one extreme a patient may
know that if he has pain or bleeding, he should see a physician; or at the other extreme he
may know he has the best chance of being cured of cancer if he has periodic health
examinations. Thus the prompt diagnosis of cancer is directly related to the educational
level of lie public. In order to ensure timely diagnosis of cancers, all physicians should
contribute to public education about cancer in their communities.
Once a patient presents himself, there are certain things the physician must do to
establish a diagnosis. We must be familiar with the first and cardinal symptoms produced
by different types of malignant disease. The first physician to see the patient has the grave
responsibility of facilitating a prompt diagnosis so that the patient may have the best
chance of cure.
Although there have been significant advances in tumor imaging over the past
decade, many procedures are more useful in evaluation of the extent of the disease than as
procedures for detecting small tumors. Although several of the newer techniques can
diagnose as small as 0.5-1.0cm, practical considerations usually prevent diagnosis of such
small tumors. With the exception of cervical cytology (the Pap test) mammography, both
of which can be used to screen asymptomatic woman the indications for the use of most
imaging and other diagnostic procedures are the presence of signs and symptoms, findings
which are often not present in patients with small tumors.
History taking
A standard history covering acute symptoms, evaluation of the differing organ systems, and general physical condition is required. Assessment of cancer risk factors must be
thorough. In many instances, history taking in the absence of physical examination can
provide vital clues in the diagnosis of cancer.
Important diagnostic clues might be obtained if conditions predisposing to cancer
development are found such as immunosuppression (iatrogenic in transplant patients or
autoimmune diseases; infectious as in HIV); chronic infections (hepatitis, papillomata,
schistosomiasis); or autoimmune disease (ulcerativ colitis, Hashimoto thyroiditis).
The drug history can reveal risk factors for specific cancer types (e.g. diethyl
stilbestrol and vaginal/cervical cancer) as well as known carcinogens (e.g. cigarette smoke)
and thus help in making the diagnosis.

41

A positive family history of cancer can lead to the identification of hereditary cancer
syndromes. As a result of such information, careful attention can be directed in the
physical examination to specific organs. Recent developments in genetic alteration in
breast cancer, with risk determined by the strength of the familial situation underpin the
increasing importance of a well-taken, in-depth family history.
Occupational (eg, dioxin) and environmental (eg, sunlight) exposures to carcinogens
need to be elucidated and suspected or established causal relationship (eg, asbestos and
pleuromesothelioma) clearly defined in the history.
A history of autoimmune disease can provide useful clues as to potential site of
cancer. Such conditions include autoimmunegastritis (stomach cancer), Hashimotos
thyroiditis (thyroid cancer), myasthenia gravis (thymoma), primary biliary cirrhosis
(hepatoma, bile duct neoplasms), and ulcerative colitis (rectal cancer). A history of specific
infections can also point to individual cancers. Well-known associations include hepatitis
B/C and liver cancer, human papilloma virus and cervical/larynx cancer, Epstein-Barr virus
(EBV) and Burkitt's lymphoma, HTLVl and leukemia, Hellicobacter pylori and gastric
cancer, schistosomiasis and bladder cancer, liver flukes and bile duct carcinoma, etc.
Finally, neoplasms linked to drugs include anabolic steroids (hepatic neoplasm
phenacetine abuse (urothelial cancers) as well as chemotherapeutic agents themselves such
as busulfan (bone marrow neoplasms) melphalan (bladder cancer) etc.
A careful history should be taken from the patient. The physician should train himself
to listen to the patient's story. Unfortunately, patients are not trained historians and often
the important stories are hidden within other information. It is the rare patient, however,
who does not reveal the critical story to the intelligent listener. In the queries made while
taking a history, one should be careful to inquire into the family history for, while
predisposition to cancer is not often heritable, it is obviously so in some families.
The social history is important because certain souci-economic groups have a higher
incidence of cancer than others. For instance, there is a higher rate of cervical cancer in
lower souci-economic groups.
The marital and sex history is important. The number of pregnancies and a history of
lactation have some influence on the incidence of breast cancer, while early age at sexual
intercourse is associated with an increased incidence of cervical cancer.
An individual's habits often help to determine certain high-risk groups. Cigarette smoking increases the incidence of upper respiratory tract, lung, and urinary bladder cancers;
use of chewing tobacco, either plug or snuff, increases the incidence of cancers of the
mouth.
The patient's occupation affects the incidence of certain cancers. The chimney sweeps
of England were probably the first to be so recognised. Watch dial painters, who pointed
their brushes with their lips, transferred radioactive material to them, causing sarcomas of
bone. Workers in uranium mines get more lung cancers. Chemical workers using aniline
dyes may develop bladder cancer, while asbestos workers have an increased incidence of
mesothelioma and lung cancer.
The past history is of great importance. Radiation to the neck or thymus in childhood
may cause thyroid cancer. Radium implantation or other radiation may cause malignant
change in the irradiated areas. A review of systems will often bring out certain factors that
the patient may have overlooked or mistakenly felt was insignificant or irrelevant.

42

The history is the most important part of examination. It should be taken by the
physician and not by a clerk who does not have the background with which to separate the
clues that should be followed up from those that arent essential. The greatest injustice that
can be done to a patient is to overlook an important clue that might have saved his life had
it been noted and appropriate action taken in time.
Although the early part of the growth of a cancer is silent, at some time it causes signs
and symptoms, which can led to diagnosis and treatment. The best opportunity for cure
cancer is early detection followed by appropriate treatment. To this end, The American
Cancer Society has compiled a list of seven early warning signals with which we should be
familiar. To help you remember the seven early warning signals listed below, notice that
together the first letter of each signal spell the word CAUTION.
Of course, each of these signals can be a sign of other diseases in most cases it is; but,
still, in case of cancer, it is better to fail on the side of CAUTION that not !

Change in bowel or bladder habits

A sore that does not heal
Unusual bleeding or discharge
Thickening or lump in breast or elsewhere
Indigestion or difficulty in swallowing
Obvious change in a mole or wart
Nagging cough or hoarseness

Table 4.1. Cancer's seven early warning signals

All of these signals can be associated with specific type of cancers. For example:
Change in the bowel habits may be a sign of colo-rectal cancer. Constipation or
diarrhea- either alone or alternating with each other - and accompanied by abdominal pain
may indicate partial obstruction of the colon. The chief symptom in cancer of the rectum is
the discharge of blood (either visible or occult) along with the bowel movement.
A sore that does not heal or that bleeds easily may be due to cancer. An example is
oral cancer, for which heavy smoking and drinking or use of chewing tobacco are the risk
factors.
Chewing tobacco can cause oral leukoplakia, or white, roughened patches, which
contain preneoplastic (dysplastic) cells.
Unusual bleeding or discharge from the rectum may be a sign of colo-rectal cancer or
from the vagina may bee a warning of uterine cancer; vaginal bleeding is unusual when it
occurs between regular menstrual periods or after menopause. Bladder or kidney cancer
may be manifested by blood in the urine (hematuria) or by difficult or painful urination
(disuria).
Thickening or lump in the breast may be an indication of breast carcinoma, although it
may also indicate nonmalignant cystic masses. Other signs of breast cancer include
retraction of the nipple, nipple discharge or pain and tenderness in the area.
Testis cancer presents as a lump. Enlarged lymph nodes, especially in the neck may be
an early sign of lymphoma.

43

Indigestion or difficulty in shallowing can be a symptom of esophageal cancer is that

food get stuck. Such dysphagia may be due to a physical obstruction, such as a
malignancy, or to a motor disorder.
Obvious change in a mole or wart (or darkening of a previously normal area) is often
a sign of skin cancer. Most skin malignancies are easily curable like basal cell and
squamous cell cancers.
Malignant melanoma, however, can metastasize very quickly, so early detection is
very important. This cancer is associated with a small, black lesion, which may raise and
may not always appear on sun-exposed areas.
Nagging cough or hoarseness can herald lung cancer, the leading cancer killer in men
and women.
Special Considerations
After eliciting a careful description of the patient's symptoms and important
background followed by an examination, the physician must make some judgement about
the patient's problem. Are his symptoms organic or psychogenic in origin? Are they
significant enough to require further investigation or should one temporise with treatment
of symptoms? A very large percentage of a primary physician's practice consists of patients
whose complaints are psychogenic in origin and do not warrant complete investigation, but
even the most astute physician often has trouble identifying these. There are
cancerophobic patients whose anxiety is focused on the fear of having cancer and who
are frequent visitors. Such patients also must be thoroughly examined. If the physician has
followed a patient for some time, and knows that the patient is emotionally stable and not a
complainer, even an ordinarily trivial symptom might deserve careful investigation.
Unfortunately, anyone can develop cancer, but a careful physician can often recognise
changes in symptomatology or findings on examination that suggest the need for further
investigation. Advanced cancers are usually easy to diagnose. Early ones are more difficult
and more important and the physician's judgement as to the need for further investigation
is crucial. Some of the special investigation tools available to the physician are described
below with brief comments as to their indications and limitations.
Physical examination
The physical examination is described in many texts and should be done methodically
and meticulously. Mistakes and misdiagnoses occur when the examiner performs
incomplete examinations. The patient may have a non-specific complaint for which the
diagnosis can only be found with a thorough examination. An oversight on the physician's
part may cost the patient's life. Local or even brief general anesthesia may sometimes be
helpful when examining an apprehensive patient or one who has a painful lesion.
In addition to the routine physical examination, special attention should be dedicated
to lymphatic, dermatologic, or neurologic symptoms of malignancy. A sound knowledge
of the routes of lymphatic spread is a prerequisite in the detection of both loco-regional and
systemic spread. Meticulous dermatologic exam may reveal not only the primary tumor
directly (melanoma, basal cell carcinoma) or indirectly by skin invasion (lymphoma, breast
carcinoma), but also exhibit clues to tumor origin through paraneoplastic syndromes.

44

Also is very important to appreciate the performance status of the patient. This is one
of the most powerful prognostic factor and decisional element in management of cancer
patients.
In oncology is very usefull to appreciate the performance status by two scores: the
ECOG/ WHO/ Zubrod score or Karnofsky scales/score (table 4.2):
ECOG/WHO (Zubrod)
Score Description
0
Fully active, able to
all predisease performance
without restriction
1

carry

Restricted in physically strenous

activity but ambulatory and able to
carry out work of a light or
sedentary nature (e.g. light house
work, office work)
Ambulatory and capable of all selfcare but unable to carry out any
work activi-ties. Up and about >50%
of walking hours.
Capable of only limited self-care,
confined to bed or chair >50% of
walking hours
Completely disabled. Cannot carry
on an self-care. Totally confined to
bed or chair

Karnofsky
Score Description
100 Normal, no complain, no evidence
of disease
90
Able to carry on normal activity;
minor signs or symptoms of disease
80
Normal activity with effort;
some signs or symptoms of disease
70
Cares for self, unable to carry on
normal activity or do active work
60
Requires occasional assistance, but
is able to care for most o his/ her needs
50
Requires considerable assistance
and frequent medical care
40
Disabled, requires special care and
assistance
30
Severely disabled, hospitalisation
indicated. Death not imminent
20 Very sick, hospitalisation indicated
Death not imminent
10
Moribund, fatal processes
Progressing rapidly

Table 4.2. Performance status scales/ score: performance status criteria

Effects of neoplasia on the host
Neoplasms are essentially parasites; with a few exceptions all masses require anatomic
evaluation (Robbins).
Local effects of tumor are:
direct effect of local growth;
direct effect of growth of metastasis.
The signs and symptoms arising from local growth vary with the site of the lesion
surrounding anatomic structures, rate of growth causing disease through compression,
obstruction, inflammation, hemorrhage and functional deficits.
Local effects of tumor:
- mass;
- nonhealing ulceration;
- hemorrhage;

45

- obstruction;
- perforation;
- inflammation;
- bone destruction;
- edema;
- space-occupying lesion;
- loss of sensory/motor function.
Metastasis deposits produce the same effects as the primary lesions with a multiplicity
of effects in the case of more than one metastasis.
Clinical problems associated with cancer can be divided into three groups:
1. Clinical syndromes associated direct with the primary lesion;
2. Clinical syndromes as distant, systemic effects associated with the tumoral products
such as ectopic hormons, growth factors;
3. Clinical syndromes associated with the treatment given to the patient:
effects of surgical procedures;
toxicity of radiotherapy and cytotoxic drugs.
Paraneoplastic syndromes
Tumor may produce signs and symptoms at distant from primary tumor or its
metastases and these are referred as paraneoplastic syndromes.
Paraneoplastic syndromes are defined as tumor-associated disorders of host organ
function that occur at sites remote from the primary tumor and its metastases. Hormones,
hormone precursors or cytokines released by tumor cells are the major mediators of such
syndromes. For diagnostic as well as therapeutic purposes, a working knowledge of
paraneoplastic symptoms is very useful. It is important to keep in mind that some
paraneoplastic symptoms can also be found with a variety of benign conditions.
The paraneoplastic syndromes may be due to:
1. tumor production of substances that directly or indirectly cause distant symptoms;
2. depletion of normal substances that leads to a paraneoplastic manifestation;
3. host response to the tumor that results in the syndrome.
The evidence for the existence of a paraneoplastic syndrome may range the mere
association of the syndrome with the presence of an actively growing tumor to the cloning
of the gene responsible for the syndrome. Among the best characterized of the
paraneoplastic syndromes are those producing polypeptides hormones, such as
adrenocorticotropin (ACTH) or paratyroid hormone, that affect organ function at remote
sites. In such situations, the paraneoplastic syndrome parallels the underlying tumor leads
to the disappearance of the hormone.
Additional tumor-derivated proteins responsible for paraneoplastic syndromes have
been identified, including various growth factors and cytokines such as Interleukine-1
(IL-1) and tumor necrosis factor (TNF). Antibodies produced by certain malignancies may
lead to neurologic syndromes such as Eaton -Lambert syndrome.
Many paraneoplastic syndromes, especially those of immune etiology do not respond
to treatment of the underlying malignancy.

46

Disorders
Amyloidosis
(amyloid light chain)
Acanthosis nigricans
Basexs syndrom

Dermatomyositis
Digital clubbing
Erythema gyratum repens
Florid cutaneous and
papillomatous warts
Flush syndrom
Hypertrichosis
Lanuginosa acquisita
Hypertrophic pulmonary
osteoarthropathy
Generalized melanosis

Features
Waxy nodules

Associated neoplasms
Multiple myeloma

Hyperkeratosis in
intertriginous areas
Papulosquamos lesions with
pruritus, predominantly palms and
soles
Gottrons papules, heliotrope rash
and proximal myopathy
Loss of the nail bed angle
Concentric rings forming a woodgrain pattern
Disseminated wartlike lesions
papillomavirus not found
Episodic head and neck flushes
Growth of lanuginous hair
primarily on ears and face
Periostitis of the long bones with
pain and swelling of joins
Diffuse grayish skin darkening

Gastric carcinoma,
intestinal adenocarcinoma
Squamous tumors of the
upper aerodigestiv tract
Gastrointestinal,various
carcinomas
SCLC
Lung and breast cancer
Gastric carcinoma
Carcinoid
Lung and colorectal cancer
Lung cancer and metastasis

Lymphoma, hepatoma
melanoma liver metastasis
Leser Trelat
Rapid onset of a large number of Gastrointestinal, lymphoma
seborrheic keratoses
Necrolytic migratory
Stomatitis circinate/gyrate rash Glucagonoma
erithema
with blistering and erosion
Paraneoplastic pemphigus Painful blisters with involvement
Lymphoma
of mucosa
Sweets syndrome
Fever, neutrophilia, painful red
Acute myelogenous
plaques/nodules, dermal
leukemia various
neutrophil infiltrates
carcinomas
Trousseaus syndrome
Migratory thrombophlebitis,
Pancreatic and lung cancer
vasculitis with septal panniculitis
Vasculitis
Without septal panniculitis,
Hairy cell leukemia,
erythematous plaques/nodules
various other carcinomas

Table 4.3. Paraneoplastic syndromes of the skin

The paraneoplastic syndrome may be the first sign of a malignancy and its recognition
may be a critical for early cancer detection. Certain paraneoplastic syndromes that secrete
proteins can be used as tumor markers in monitoring patients before and after therapy.
In some situations, the underlying disease cannot be treated but but the symptoms and
complications of the paraneoplastic syndrome must be treated. The comon paraneoplastic
syndromes are: endocrinological, hematologic, gastrointestinal, renal, cutaneous and
neurologic paraneoplastic syndrome (tables 4.3 and 4.4).

47

Disorder
Subacute cerebellar
degeneration

Features
Bilateral cerebellar
failure, ataxia,
dysarthria, dementia

Limbic encephalitis

Acute onset of mood

changes, impairment of
recent memory,
hallucinations
Uncoordinated eye
movements, myoclonia

Opistoclonus, myoclonus

Encephalomyelitis

Cancer associated
retinopathy
Necrotizing myelopathy
Dorsal root ganglionitis
Sensorimotor peripheal
neuropathy
Autonomic neuropathy

Stiff-man syndrom

Lambert Eaton syndrom

Variety of symptoms
can affect any part of
the CNS
Variety of visual
symptoms
Rapid ascending motor
and sensory paralysis
Subacute onset of
sensory loss
Distal sensory loss,
arreflexia and wasting
Intestinal
pseudoobstruction,
neurogenic bladder ,
orthostatic hypotension
Rigidity of skeletal
muscle with
superimposed cramps
Proximally accentuated
muscle fatigue

Tumors and antibodies

AntiHu:SCLC, sarcoma
neuroblastoma
Anti-Yo: ovary, breast, SCLC
Anti-Tr: Hodgkins lymphoma
Hodgkins lymphoma, SCLC

Neuroblastoma
Anti-Ri: breast, gynecologic,
SCLC, bladder
Anti-Hu: SCLC, sarcoma,
neuroblastoma
Anti retinal: SCLC, melanoma
Lung, kidney, Hodgkins
lymphoma
Lung
Lung, gastrointestinal, breast
SCLC

Anti-amiphiphisin: breast,
thymoma, Hodgkins
lymphoma
Anti-CGCC: SCLC,
thymoma,lymphoma

Table 4.4. Neurological paraneoplastic syndromes

Delay in diagnosis
Most adult tumors are slow growing and have already been present one to several
years at the time of diagnosis. For example, it is estimated that the average breast cancer
has been growing for 7 years 30 doublings at 80-100 days per doubling - by the time it is
diagnosed. Therefore, a few days or weeks delay in diagnosis and treatment is unlikely to
make any significant difference in the long-term outcome. Longer delays, however, may be
important and most specialists feel that the earlier cancer is diagnosed and treated the
greater the chances for cure.

48

Patient factors in delay include lack of knowledge about danger signals and risk
factors as well as fear that a given complaint may be caused by cancer and fear of the often
radical treatment that will be necessary if it is cancer. Public education is the most direct
means of addressing this issue.
Physician factors in delay include lack of suspicion that a given complaint may be due
to cancer, failure to know and to identify risk factors, and a pessimistic attitude about the
curability of cancer leading to an apathetic approach to early diagnosis and adequate
treatment.
LABORATORY EXAMINATIONS
History taking followed by physical examination will result in a working differential
diagnosis.
Laboratory results serve first to evaluate the general status of the patient's health and
also provide baseline values before therapy is commenced.
They may uncover disease-related involvement of organ systems or unrelated
pathologic conditions that have to he taken into consideration before treatment. Specific
tests are used to substantiate the diagnosis, collect prognostic data that are important for
the therapeutical decision-making, and provide baseline values of tumor markers for
follow-up reasons (table 4.5).
Exam
CBC
Blood culture
Liver panel

Renal
panel/electrolytes

Coagulations exam

Urine analysis

Questions
Hematology malignancies (diagnostic)
lnfection/anemia/leukopenia/thrombopenia
(diagnostic, pretherapeutic preoperative)
Cholestasis (pre-, intra-, posthepatic)
Hepatitis (infectious/chemical)
Alcoholism (preoperative)
Baseline values (pretherapeutic)
Nutritional status (albumin/total protein)
SIADH (paraneoplastic`/drug induced)
Hypercalcemia (paraneoplastic/metastases)
Hyper/hypocoagulation (preoperative, paraneoplastic platelet
dysfunction, vitamin K deficiency or liver dysfunction,
paraneoplastic hypercoagulability)
Proteinuria, hematuria, urinary tract infection

Table 4.5. General laboratory examinations

Tumor Markers
Tumor markers are cellular products that are released into body fluids or exhibited on
the cell surface. They may be produced by different types of normal and neoplastic cells
but their excess, due to the monoclonal proliferation of a specific cell type may lead to
tumor diagnosis or aid in the monitoring of tumor load during therapy. It has to be kept in
mind that tumor markers are often nonspecific and their levels may increase as a result of
nonmalignant conditions as well. Table 4.6 includes some common tumor markers and
their clinical uses.

49

Marker
- FP
- HCG
2 microglobulin
Calcitonin
CA 15-3
CA 19-9
CA 125
CEA
NSE**
PSA
Thyroglobulin

Upper limit
25g/l
< 1ng/ml
2g/ml
0,1ng/ml*
25 U/ml
37 U/ml
35 U/ml
5ng/ml
12g/l
2,5-4,0ng/ml
10ng/ml

Application in cancer
Testis, hepatoma
Testis, trophoblastic neoplasia
Myeloma, lymphoma
Thyroid (medullary carcinoma)
Breast
Pancreas
Ovary
Colorectal, breast, lung (small cell)
Neuroendocrine (oat cell)
Prostate
Thyroid

* Without calcium infusion, 0,10ng/ml, with calcium infusion, 0,55ng/ml;

** Possibly helpful.
Table 4.6. Helpful serum tumor markers
Biological markers
Despite extensive research, no single, simple test has yet been devised which indicates
whether a person has cancer. Nevertheless, there are certain laboratory procedures, which
are useful in confirming a cancer diagnosis and monitoring the outcome of therapy. The
discovery that measurable serological oncofetal proteins are in high concentration during
embryonic development followed by a virtual disappearance in the postnatal period and
reappearance with specific cancer types raised great hopes. Unfortunately, the sensitivity
and specificity of these biological markers is not sufficient for diagnostic purpose, since
several nonmalignant diseases are also associated with an increase of these antigens.
Currently the significance of such serological tumor markers can be summarized as
follows: They may (a) detect recurrent or latent cancer in previously marker-positive
patients; (b) allow monitoring of therapeutic effect; (c) be useful as prognostic tools;
(d) define extent of disease and (e) allow new therapeutic methods when conjugated with
toxins or cytotoxic agents.
The most useful tumor markers are carcinoembryonic antigens (CEA),
alphafetoprotein (AFP) and the beta subunit of human chorionic gonadotropin (HCG).
CEA is an oncofetal protein first described in 1965 since which time considerable work
has been done to increase its use in the management of colorectal cancer. Small increases
in serum CEA are found in several non-malignant conditions such as cirrhosis, certain
inflammatory processes, smoking, and with various other tumors. A normal CEA level is
common in early colorectal cancer and, therefore, its measurement is not useful as a
screening procedure. Current investigation is designed to determine whether elevated
levels of CEA following curative colorectal surgery can be used to identify recurrences
before clinical evidence is present - perhaps early enough so that reoperation may result in
a cure. Both AFP and HGC are biological markers currently being studied for use in
cancer detection, diagnosis, and follow-up. HCG is very useful in monitoring the
treatment of choriocarcinoma and testicular embryonal carcinoma. AFP is another
oncofetal antigen associated with primary liver cancer and certain testicular tumors. In
patients with an unknown primary cancer whose tumor fits a possible diagnosis of
testicular carcinoma, AFP and HCG assays, if positive, may indicate treatment that can be
curative.

50

Serum levels of alkaline phosphatase may be increased in a variety of liver diseases,

including metastatic cancer. Elevations also frequently occur with metastases to the bone.
The serum level of acid phosphatase may be increased in metastatic cancer of the
prostate. Prostatic acid phosphatase is a glycoprotein of two identical subunits with a
molecular weight of 100.000; differences in the carbohydrate portion create several
isoenzyme forms. Levels of the prostate-specific isoenzyme may be informative in
monitoring the malignant process. Unfortunately, only about half of patients with prostatic
cancer have elevated prostate-specific acid phosphatase enzyme levels.
More recently, some new tumor markers have been discovered. Among them, CA-125
is of interest in ovarian cancer since 80% of women with this malignancy appear to have
elevated levels. Again, to date measurement of this marker is not useful for screening. The
use of CA 19-9 as marker for identifying gastrointestinal cancers (pancreas, colon) is
currently under investigation.
Molecular Markers
Molecular markers are cellular products (DNA, RNA, proteins) that can be detected
immunohistochemically with in situ hybridization, PCR, or by blotting techniques.
Molecular markers can be cellular hormone receptors (estrogen receptors) indicating
possible responses to chemotherapy. Others are proteins that are produced in the synthesis
phase and G2 phase of the cell cycle (Ki-67, PCNA) and can thus be used to calculate the
proliferative index of a given tissue. Others again are proteins involved in cell cycle
checkpoint regulation (p21, p27, pRb, p53) or are oncogene products.
The world of molecular markers is evolving rapidly and becoming an increasingly
important part in cancer diagnosis. As soon as antibodies are available for cell surface
receptors, proteins involved in cell cycle checkpoint regulation, signaling pathaway and
DNA repair or apoptosis, they will be analyzed in human tumors and correlated with
patient survival. The drawback of molecular markers is the diversity of spontaneous
mutations in human tumors. Specific molecular markers might be valuable for a subset of
human tumors, for example, p21 and gastric cancer, while no showing prognostic significance in other subsets of human tumors, for example, p21 and gallbladder tumors. Data for
specific molecular tumor markers can thus not be generalized but have to be evaluated
individually. Germline mutations identified with carcinogenesis can be used diagnostically
(patient screening) and prognostically, and aid therapeutical decision making.
Genetic Testing
Germline mutations are passed on genetically, can be found in every cell of the
carrier, and predispose to tumor development in specific tissues. These features enable
diagnosis of the mutation in easily accessible cells (e.g., blood lymphocytes), surveillance
or prophylactic treatment of gene carriers (e.g., proctocolectomy in familial polyposis), and
screening of family members. As the oncogenic potential and trance of individual
mutations differ, implications and consequences of genetic testing have to be carefully
evaluated prior to its application. Specific attention has been focused lately on
commercially available tests for breast cancer susceptibility genes. General screening
seems unjustified as women a family history of breast cancer will have a negative test nine
out of ten times.

51

A negative test on the other hand does not exclude a hereditary risk from unknown
genes and should not lead to a lessened vigilance or surveillance. Once the relationship
between genotype and phenotype becomes clearer, it is likely that, in future years, genetic
profile will play a role in cancer diagnosis.
Tumor localization
Tumor localization, pathologic analysis, and staging are the next consecutive steps in
the patient's workup. The hypothetical diagnosis on the grounds of history, physical
examination, and laboratory exams will guide the search for the primary tumor. Direct
visualization with the chance to obtain tissue biopsies for pathologic analysis is the wellrecognized next stage in diagnosis. If the primary tumor or a metastasis is not easily
accessible, imaging studies might help in localization, differential diagnosis, and eventual
tissue diagnosis (Table 4.7).
Organ
Bone

Bone
marrow

Clinical setting
Primary tumor still surgically curable
and know to metastasise to bone
Primary tumor still surgically curable
but focal symptoms present
Therapeutic decision changes in case
of proven systemic metastasis

Brain
Liver

Focal symptoms
Staging before radio-chemotherapy
Preoperative, no symptoms, without
intent of hepatic reaction
Sonographic evidence of possibly
resectable liver metastases

Lung

Lymphatic
system

Intraoperative suspicious liver lesions

No symptoms, screening resectable
liver metastasis present, suspicious
X-ray
Localized primary tumor and
clinically suspicious lymph nodes
Localized primary tumor and Sentinel
node biopsy

Systemic disease

Total body

Possible resectable metastases of

neural crest tumors, neuro-endocrine;
screen scintigraphy-cally detectable
tumors

Table 4.7. The diagnosis of metastases

Diagnosis
Tc-scintigraphy

99m

X-ray, CT,
scintigraphy
bone marrow
biopsy (iliac crest,
Jamshidi trocar)
CT, MRI
US,CT (for
monitoring)
US
CT+ portal
angiography
(highest sensitivity)
Intraoperative US
X-ray, CT

US, CT
Lymphatic
immunoscinti
graphy
intraoperatively
Lymphography
(advantage over
CT: even regular
sized pathologic
lymph nodes can
be identified
123
I-MIBG
scintigraphy
111
In-octreotide
scintigraphy

Common primary tumors

Breast, lung, multiple
myeloma, prostate, thyroid,
Hodgkings lymphoma
Breast, SCLC, prostate,
thyroid, lymphoma
Lung, breast, melanoma
Colon, stomach, pancreas,
breast, lung

Lung, breast, colon,

stomach
Localized primaries: head
and neck (upper and middle
cervical), gastrointestinal
(supraclavicular left) breast
and lung (supraclavicular
right)
breast, melanoma, sarcoma
(axilla)
sarcoma, vulva, bladder,
prostate

52

For staging reasons and therapeutical considerations, the search for local and systemic
metastases of a known primary tumor is crucial. Exact anatomic knowledge and awareness
of preferred organ systems for metastases of specific tumors aid the search and help to
avoid unnecessary total body screens.
Table 4.7 gives an overview of the common methods currently used to detect
metastatic disease.
Diagnosis in oncology
1. Clinical diagnosis
- History: risk factors;
- Physical Examination.
2. Tissue diagnosis
- cytology of body fluids;
- cytology of tissue scrapings or brushing;
- fine needle aspiration (FNA);
- needle biopsy;
- incision biopsy;
- post-surgical pathological information.
3. Imaging Diagnostic for staging and Follow-up
- Radiological imaging and interventional procedures;
- Chest X-rays;
- Tomography;
- Gastrointestinal series Radiography;
- Barium enema Radiography;
- Angiography (DSA);
- Computed tomography (CT);
- Magnetic resonance imaging (MRI);
- Ultrasound examination;
- Radioisotope Scanning Techniques;
- Radio-Immune Scintigraphy - radio labeled Monoclonal Antibodies (MAbs).
4. Endoscopic procedures
5. Specialized investigations: bone marrow trephine, lumbar puncture
6. Biological markers
DIAGNOSTIC PROCEDURES
Diagnostic imaging in oncology
If metastatic cancer originating from an unknown (or as yet unknown) primary site is
suspected, a metastatic survey can be carried out.
This comprises X-ray examination of the skull, spine, pelvis, and chest areas
frequently involved by metastases from the most common cancers. Clear-cut unequivocal
metastases noted are easily diagnosed, but small changes may provoke argument as to their
significance.

53

Chest X-rays
Chest X-rays are indicated in patients with symptoms of lung cancer or with cancers
of other sites which metastasize to the lungs. A small primary tumor may be missed, even
with added views (e.g., lateral and tomograms). If the diagnosis is strongly suspected,
consideration should be given to repeated X-ray examinations at frequent intervals and
other investigations such as cytology. The use of chest X-rays as a screening procedure for
asymptomatic people has been discredited.
Tomography
Tomograms are often indicated to clarify abnormal findings noted in the ordinary
(PA) chest X-ray film. They may help to distinguish between malignant and non-malignant
lesions. Computed tomography has replaced tomography where it is available.
Barium Enema Radiography
This is indicated in patients suspected of having colorectal cancer. Small lesions in the
upper rectum may not be well visualised and thus sigmoidoscopy is often a necessary
investigation also. Lesions of the cecum may be difficult to visualise, and any minor
abnormality deserves further study. An air-contrast enema will identify small polyps
missed during more routine examination. Thorough cleansing of the colon prior to
examination is essential.
Gastrointestinal Series Radiography
Patients who present with symptoms of indigestion, pain after eating, blood in the
stools, unexplained anemia or weight loss, or change in bowel habits should have both
upper gastrointestinal and barium enema examinations. The fluoroscopic part of the upper
GI examination is probably the most important portion, for here the movement of the
bowel can be visualised, and the patient can be turned to visualise any angle of the bowel
desired. The bowel may also be compressed so that small lesion can be visualised. The
image magnifier and the use of videotape, on which the fluoroscopic examination can be
replayed, are of great help in increasing the accuracy of examination.
Angiography
Improvements in technology and the diagnostic acumen of the specialist in recent
years now mean that valuable diagnostic information about any organ can be obtained by
injecting contrast material into accurately placed intraarterial catheters. Vascular
abnormalities are frequently not diagnosable, however. Moreover, the insertion and
passage of catheters and injection of contrast material are uncomfortable and carry some
risk of complications. Phlebography and lymphography are less used for tumor diagnosis
than they were formerly. The latter was informative for detection of lymph node
metastases.
More recently digital angiography has been introduced. It has greater accuracy in
detecting small tumors.
Angiography is sometimes an essential component of specialised therapeutic
interventions such as chemoembolization or intra-arterial treatment in which it is critical to
have knowledge of the vascular supply of the tumor.

54

Computed Tomography
Computed tomography (CT), a diagnostic X-ray imaging technique, was originally
developed and used for evaluating intracranial masses that were difficult to examine using
conventional X-ray and ultrasound technology it has now been extended to studies of the
whole body. The image prodused is that of a body cross section. CT is especially useful
examing organs deep within the body for brain, mediastinal, central abdominal (such as
pancreas), retroperitoneal, and pelvic tumors. Its usefulness in delineating, in an accurate
manner, the extent of disease in the thorax and abdomen is often sufficient to justify its
considerable expense. Tumors as small as 1cm can be outlined quite accurately by CT
scans.
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) is the newest imaging method and has the
potential to revolutionize diagnostic techniques. It is non-invasive, there is no radiation
exposure, and, so far, no long-term deleterious effects on the human body have been
identified. It is very expensive currently, but costs should be reduced, as the technology
becomes more widely available. MRI is already replacing CT in examinations of the brain.
In contrast to CT scans, MRI can give a cross section in any plane instead of only in the
axial plane. MRI depends on the magnetism in cell nuclei, particularly hydrogen ion
concentrations. Because of this, it may be possible to distinguish certain alterations in
function with MRI. MRI opens the possibility for a whole new field of research in tumor
biology and in biochemically monitoring the effects of cancer therapy
While MRI has superior contrast resolution compared to CT, its spatial resolution, at
the current time, is generally less than that with CT. MRI technology is changing rapidly
and it seems very likely that because of its advantages, it will steadily replace CT as the
optimal examining technique for most body regions.
Ultrasound Examination
Ultrasound technology has developed greatly in the past few years and in certain
situations ultrasound is more useful than CT scan. It is particularly useful in differentiating
cystic from solid tumors of the thyroid, liver, pancreas, and ovary. It is often better than
CT as a guide for percutaneous needle biopsy because the transducer can be moved around
on the patient's body quickly and easily to identify the best access route for a biopsy with
the least likelihood of damage to other structures. More recently intracavitary ultrasound
devices, sometimes with a video camera, have become available. High-resolution
transducers are now available for thyroid, parathyroid (especially useful for reoperations),
breast, and scrotal imaging. Ultrasound is less expensive than CT, non-invasive, and has no
known deleterious effects on the body.
Radioisotope Scanning Techniques
Many radioactive isotopes are now used in the diagnosis of cancer and have proved
useful because some isotopes localise in specific areas and others do not. Radioisotope
scanning procedures are non-invasive techniques.
Bone scanning is valuable when patients have painful bone metastases and routine
X-rays reveal no abnormalities. Scanning is more sensitive in such cases and only rarely is
metastatic disease not revealed.

55

However, a bone scan is not a specific test; it also indicates abnormalities with benign
bone diseases, such as arthritis, and careful correlation of the results with clinical findings
is necessary.
Liver scans are more difficult to interpret and not as sensitive and specific as bone
scans. Small tumors may be missed. Some liver metastases can be localised by scan prior
to needle biopsy. Thyroid scans can delineate cold nodules in the thyroid.
Radioimmunoscintigraphy
Radioimmunoscintigraphy is the technique of using an antibody, which has been
labelled with radionuclide against some appropriate tissue antigen, so that after injection it
can be detected and imaged external to the patient to demonstrate the presence of a
malignancy. The ideal antigen has to be tumor specific, expressed in all cells in appropriate
density, accessible to a circulating antibody, and persist on the tumor cell in an
unmetabolized condition. At present the following types of antigens are used for such
purpose: dedifferentiation antigens (CEA, alpha-fetoprotein, beta subunit of human
chorionic gonadotrophin HCG-BHCG), idiotypic antigens in leukemias and lymphomas,
virus-related antigens in hepatomas, epithelial surface antigens (ovarian, colorectal, breast
cancer). The antibodies are raised by hybridoma techniques and are monoclonal. The
radionuclide label can be 99mTc, 123I, 131I or 111In.
Method
X-ray

X-ray
+contrast/
double contrast
Angiography

ERCP
Urography
CT

MRI

PET

Use in oncology
Thorax (pulmonary/mediastinal lesions)
Abdomen (suspected ileus or perforation)
Bones (first choice for suspected lesions)
Mamma (screening, diagnostic)
Thorax (esophageal npl; longitudinal extent; thyroid npl: esophageal involvement)
Abdomen (extent of gastric/intestinal neoplasms, possible second
Primary neoplasms and limited endoscopic accessibility, possible fistulas)
Diagnostic: e.g., angiomas, angiosarcomas neuroendocrine tumors
Preoperative: e.g., variability in vascular anatomy, neoplastic infiltration of major
vessels
Bile duct, gallbladder, hepatic and pancreatic npl (diagnostic, preoperative)
Diagnostic: CU npl
Preoperative: ureter/bladder involvement in Cl npl, ureter anatomy, possible fistulas
Diagnostic and preoperative: manifold indications with/without contrast (intravenous,
angiographic. intrathecal), used to guide fine needle biopsies, good evaluation of
enlarged lymph nodes limitations: discovery and staging of early tumors (e.g., G1 or
GU T l-T2 tumors), allergies to the contrast agent, cost, no sagittal or coronal planes
Diagnostic and preoperative: manifold indications especially CNS (no intrathecal
contrast necessary, no bone artifacts in posterior fossa), musculoskeletal system and
pelvis
Advantages: multiplanar imaging,
Limitations: poor lymph node visualuation, no advantage in over CT
thoracic/mediastinal diagnosis, long registration time with possible interfering patient
movements, artifacts by steel implants, cost
Diagnostic, monitoring:
Advantages: high sensitivity (picomolar), exact distinction between radiation necrosis,
edema and tumor recurrence (e.g., brain tumors), measurements of physiologic activity
(with possible estimation of malignant potential)
Limitations: high cost limits clinical use; specific markers and antibodies yet to be
developed

56

Scintigraphy

Ultrasonic
scanning

Diagnostic, staging, monitoring: bone tumors and metastases (99mTc diphosphonate),

131
99m
I
in
NaI
and
Tc-pertechnetat),
thyroid
cancer
(123I,
neuroblastoma/pheochromocytoma medullary thyroid carcinoma (123I-MIBG),
neuroendocrine tumors (111In-octreotide)
Advantage:
high sensitivity
Limitations:
costs, specificity, radioactivity
Diagnostic, preoperative, intraoperative: external and internal guiding of fine-needle
biopsies
Head: vessels, sinuses, lymph nodes
Neck: lymph nodes, thyroid, parathyroid
Mamma: distinguish palpable tumors (solid/cyst)
Thorax/extremities: soft tissue tumors, lymph nodes, vessel involvement (Doppler),
esophagus (endosono), heart (trans and thoracic transesophageal echocardiography)
Abdomen:
liver, gallbladder, kidneys, spleen, stomach (endosono ovaries,
pancreas (transgastric or hydrosono), rectum (endosono), vessels
Pelvis: bladder (endosono/hydrosono), prostate/seminal vesicles (transrectal), vaginal
cervix/uterus (transvaginally)
Extremities:
soft tissue sarcomas, musculoskeletal tumors, lymph nodes, vessel
involvement, cutaneous metastases
Advantages:
low cost, safe, good staging of infiltration depth and local lymph
nodes in endosonography
Disadvantages: limited use with gastrointestinal air

Table 4.8. Diagnostic imaging in Oncology

Study

Ultrasound

CT

MRI

Clinical utility
Detection of cystic nature
Guidance of biopsy and
centesis
Detection of hepatic lesions
Real-time
Low cost
Portable
No ionizing radiation
Cross-sectional method
Better contrast resolution,
detection of fat and calcium
Guidance of biopsy
High spatial resolution
Very rapid imaging with ultrafast units
Tumor characterization using
i.v. contrast enhancement
No ionizing radiation
Most sensitive for CNS, bone
marrow infiltration
Scans in any plane

Limitations
Low spatial resolution
Not useful in bone lesions, lung, intestine
Images are very operator-dependent

Uses ionizing radiation

Requires i.v. contrast to detect flowing blood
Scans limited to axial plane
Sensitive to miss-registration of scan due to
respiratory motion, unless spiral CT is used

Limited in patients with claustrophobia

Limited examination of the bowel
Not sensitive in detection of calcification
Long duration of examination
High cost

Table 4.9. Uses and limitations of imaging procedures in oncologic patients

57

Endoscopy
The role of endoscopy in cancer diagnosis is of great importance. With the aid of
optical devices, premalignant or malignant lesions can be visualized, photographed, and
removed for histological examination. In the 1960s, rigid endoscopes were used which
were introduced in the various orifices or cavities of the body. Today flexible fiberoptic
instruments are available which permit examinations of internal organs. The use of high
intensity cold light has made possible the production of high-resolution images, which can
be transmitted through video cameras.
Endoscopes are used for detecting malignant processes throughout the upper
respiratory tract, esophagus, stomach, and duodenum, and colonoscopes are used for
studying pathological lesions in the large bowel and rectum. Laryngoscopes are used for
upper respiratory tract and bronchoscopes for the lower respiratory tract cancer.
Mediastinoscopy is the procedure of choice for establishing the diagnosis with enlarged
mediastinal lymph nodes or tumors. Laparoscopy is used in examining for suspected liver,
ovarian, and peritoneal neoplasms. Arthroscopes allow synovial neoplasms to be
identified. Endoscopic procedures are sometimes combined with radiographic
examinations. Examples are retrograde pancreatography or bronchoscopy with
bronchography.
Cytology
During the past 30 years, the microscopic examination of exfoliated cells found in a
variety of body secretions or of cells scraped from mucous membranes has developed into
a highly specialized science. Cytological examination is particularly useful in the diagnosis
of in situ and early cancer of the uterine cervix; indeed, the proper use of cytological
screening of women at risk could eliminate cancer of the cervix as a cause of death.
When cancer is suspected in the endometrium, respiratory tract, oral cavity, urinary
bladder, or serous cavities, cytology is a useful diagnostic tool. With improved, carefully
controlled imaging techniques (i.e., fluoroscopy, ultrasound, CT), fine needle [No.20-2]
aspiration biopsy has become common for almost every anatomic site. Pathologists in
many centers are now experts in the cytological diagnosis of such material.
Biopsy
A diagnosis of cancer must be based on histological evidence. A tissue sample can be
obtained either by surgery or by needle biopsy. The importance of obtaining a tissue
sample for microscopic diagnosis of cancer prior to treatment cannot be over estimated.
There are many benign lesions that mimic cancer. At times, major surgical procedures may
be justified to obtain tissue for histological proof of malignancy. In addition to open biopsy
with a scalpel in lesions that are accessible, there are other possible biopsy procedures.
With the aid of endoscopes many lesions are amenable to needle biopsy. It should be noted
that only a sufficient tissue sample can assure the correct evaluation of the pathological
process. Therefore repeated biopsies may be required for the establishment of a diagnosis
of a carcinoma in some cases.
Bone marrow examination by aspiration or biopsy can be performed from the sternum
or iliac crest. This procedure is essential for diagnosing hematological malignancies.
It can also help to establish a diagnosis of cancer and its dissemination from a known
or unknown primary tumor. If there is microscopic cancer in the bone marrow, radical
surgical procedures are contraindicated. Bone marrow examination is also helpful aid in
staging of the patients with lymphoma.

58

PATHOLOGICAL ANALYSIS
A good pathological analysis is essential for decision making in cancer and a complete
clinical profile provides essential background information. Pathologic material can now be
used to detect underlying genetic alterations while evaluation of molecular (e.g.,
proliferation markers), cellular (dedifferentiation, polyploidy), prognostic factors, and
pathologic tumor staging serve to estimate the tumor's malignant potential (table 4.10).
The diagnosis of cancer must now also include pathologic tumor staging and histologic tumor grading as both are of high predictive value. Besides tumor stage and grade a
number of other biologic markers have been associated and correlated with survival
prognosis. For some tumors (e.g., lymphomas) prognostic indexes have been established in
which different factors enter with a defined value. Therapeutic decisions might then be
guided by the prognostic index.
Tumor grading classifies the malignant potential of a tumor according to its microscopic appearance. The histologic parameters used to categorize a tumor of low
(grade I), intermediate (grade II), and high (grade III) malignancy include dedifferentiation, proliferative potential, and vascularization. They also include cellularity, matrix
formation, margins, pleomorphism, mitotic activity, necrotic areas, hemorrhage and
inflammation. Because the consistency of a tumor is often very heterogeneous various
areas of the tumor have to evaluated. All of these factors are important in the diagnostic
workup of the patient.
Tool
Clinical information
Resected material
Light microscopy (tissue
staining)
Electron microscopy

Immunohistochemistry
In situ hybridization
Blotting procedures

PCR and in situ PCR

Use
Tumor localization, tumor size, macroscopic invasion, distant metastases
Macroscopic appearance, texture, structural relation to surrounding tissue
Cellular phenotype, accompanying inflammatory reaction tissue invasion
(T-classification), metastatic seedlings (N-classification [lymph nodes] and
M-classification (distant metastases), tumor grading
Differentiate between carcinoma, melanoma, and sarcoma identify
neuroendocrine differentiation and histiocytosis X aid the distinction of
small round cell tumors and spindle cellular soft tissue tumors
Specific antibodies recognize surface antigens or intracellular proteins that
lead to the identification of cellular origin
Identification and visualization of specific DNA/RNA sequences with probes
DNA (southern blot), RNA (northern blot) and protein are extracted from
tumor tissue (always including neoplastic and nonneoplastic cells) and
visualized with probes or antibodies
Identification of single copies of specific DNA/RNA sequences

Table 4.10. Uses and limitations of pathological procedures in oncologic patients

Summary
A proper history and physical examination are the fundamentals in establishing a
diagnosis of cancer. Advances in recent years have greatly facilitated the potential for
diagnosing not just cancer, but also other characteristics such as subtype and
aggressiveness, to mention but a few. The advent of molecular diagnostic laboratories and
genetic testing has introduced new and exciting methods in cancer diagnosis. The ability of
such new methods to facilitate early diagnosis of cancer is now one of the key areas in
cancer diagnosis.

59

SECTION 5
CANCER STAGING - THE TNM SYSTEM
Once a diagnosis of cancer is made, evaluation of the extent of spread of the cancer
using the various diagnostic procedures is essential before therapeutic decisions are made.
Radical treatment designed for cure (particularly surgical treatment) is usually not
indicated if there is spread of the cancer beyond the limits of the proposed treatment field.
Even when using chemotherapy, radiotherapy, or multimodal therapy, there must be reason
to believe there is a chance for cure (or major benefit) before radical treatment is proposed
for what may be extensive disease. For most cancers, treatment will vary, depending on the
extent of disease.
Therefore accurate assessment of spread is essential. This assessment is called
staging and an increasingly elaborate set of rules has been developed over the years to
make staging more accurate and meaningful.
For certain cancers where additional adjuvant treatment may be helpful, sophisticated
evaluation of possible or probable disseminated or residual disease is essential before
deciding whether to give adjuvant treatment at all, and, if so, what type is appropriate.
Current diagnostic studies are quite reliable in assuring that no residual or metastatic
cancer is present, which is greater than 1cm in diameter, but not very sensitive for smaller
tumors. These small, undetectable biological or metastatic tumors are called
micrometastases. However, a tumor of 1cm across may have 108 or 1 billion cells in it. In
an individual with a high likelihood of having several metastatic tumors of 107-8 cell-size
left behind, the chances of rapid appearance of large metastases are obviously very, very
great. A highly toxic treatment might be justified if the likelihood of residual cancer is high
and the benefits of the treatment are deemed worth the cost in toxicity. If the likelihood of
residual cancer is low, if the tumor is not very responsive to the available treatments, and if
the available treatments have significant toxicity, then treatment should usually be
withheld.
Clinical Staging
Staging of cancers is done for three main reasons: to help evaluate the results of
treatments, to allow comparison of one method of treatment with another, and, most
important for the individual patient, to determine the best current therapy. In addition,
staging gives some indication of prognosis, facilitates the exchange of information
between treatment centers, and contributes to the continuing investigation of human
cancer.
In order to determine the best treatment indicated for certain patients, it is necessary to
evaluate the results of past treatment. To do this and to compare one method of treatment
with another, there must be comparable groups. One cannot compare the results of
treatment of a group of patients with cancers, which have limited evidence of having
spread with another series, perhaps treated by another method, of predominantly advanced
cancers.
By trial and error, therefore, over the years, various factors involved have been
analysed and patients have been grouped in stages of progressive advancement from
0 to IV (Table 5.1).

60

Stage 0 cancers, if the lesion can be removed surgically, such as in cervical carcinoma
in situ, should be essentially 100% curable. Stage IV cancers, if the estimation of the
extent of thetumor is accurate, have a very low likelihood of cure. Stages I, II, and III
represents corresponding degrees of decreasing curability.
In order for staging to be of maximal value in evaluation of past treatment and therefore in
determining current treatment, the following important criteria must be met:
The staging method must be universally acceptable. If one system is used in one
country and a different one used in another country, it becomes impossible for results
to be compared.
The method should be simple.
The factors assigned to each of the progressive stages 0 to IV must reflect their genuine
influence on prognosis. A factor properly belonging in stage IV should not be placed in
stage II.
Communication must be precise. Physicians throughout the world must know how to
duplicate with precision the exact criteria for each stage.
The accepted method of staging must, in fact, be used as the basis of meaningful
determination of the results of various treatment methods.
Stage
0
I
II
III
IV

Description
In situ cancers (noninvasive, and thus no lymphatic or venous
metastases)
Early local invasion, but no metastases
Limited local extension of the tumor and/or minimal regional lymph
node metastases
Extensive local tumor and/or extensive regional lymph node
metastases
Locally advanced tumors or any situation with distant metastases
regardless of the extent of the local tumor

Table 5.1. Classical staging of cancers

Despite the obvious importance of the development and universal application of
staging for all cancers, to date the only generally accepted classification system has been
for carcinoma of the cervix. This classification system has been in use for many years and
has been of great value in estimating prognosis and evaluating therapy. Because of the lack
of consensus regarding adequate staging for most cancers, in recent years experts have
been trying to develop internationally acceptable staging criteria for a number of different
cancers. The TNM system has resulted.
The TNM System
The objectives of the TNM system are:
to aid the clinician in treatment planning;
provide some prognostic indicators;
assist in evaluation of treatment results; and
facilitate the exchange of information among oncologists.

61

To meet the stated objectives, a system of classification is needed whose basic

principles are applicable to all sites regardless of treatment and which can be supplemented
by information gained later by surgery and histopathology. Accordingly two classifications
are described for each site, namely: the clinical classification (pretreatment clinical
classification) designated as TNM (or cTNM) and the pathological classification
(postsurgical histopathological classification) designated as pTNM.
As a tumor grows and spreads and eventually becomes incurable, there are three
factors to be measured:
the extent of the local tumor;
the presence or absence of regional lymph node metastases and the degree of such
involvement and
the presence or absence of distant metastases.
In the TNM system the following general definitions are used:
T (Primary Tumor): Tx: primary tumor cannot be assessed; T0: no evidence of
primary tumor; Tis: carcinoma in situ; T1,-2,-3,-4: increasing size and/or local extent of the
primary tumor.
N (Regional Lymph Nodes): Nx: regional lymph node cannot be assessed; N0: no
regional lymph node metastasis; N1,-2,-3: increasing numerical involvement of regional
lymph nodes.
M (Distant Metastasis): Mx: presence of distant metastasis cannot be assessed; M0: no
distant metastasis; Ml: distant metastasis. Ml may be further specified according to site
(pulmonary = pul, osseos = oss, hepatic = hep, brain = bra, lymph node = lym, pleura =
pleu, peritoneum = per, skin = ski, others = oth).
If pathological TNM is used, the prefix p should be added to the TNM
nomenclature. Recurrent tumors are identified by the prefix r.
To date, cancers of all organs have been staged in this manner by special committees,
which also have the task of constantly revising and updating the system. Clinical TNM is
not as accurate as pathological TNM. Clinical TNM is used in comparing results of
radiotherapy and chemotherapy since no tissue is available for pathological review in these
cases. In contrast, trial results or surgery with adjuvant treatments might be compared in
patients possessing p TNM as well. P TNM is obviously more useful in estimating
prognosis than is clinical TNM.
Anatomical staging of the gross extent of disease was developed by surgeons and
pathologists to separate cases into specific categories for better evaluation of treatment
modalities. For example, in patients with malignant lymphomas, the results of staging
laparotomy can significantly influence treatment strategy.
Decision making
The practice of clinical oncology demands the knowledge of the natural history and
clinical stage of the tumor. The actual decision to treat a patient will be based on the
probability of benefit for an individual patient. The following levels of decision making are
to be considered:
- To treat or not to treat.
- Radical or palliative treatment.
- Local, regional and/or systemic treatment.
- Adjuvant treatment.

62

- Quality of life.
- Clinical evidence - clinical trials.
- Cost - effectiveness.
Treatment options can be individualized at three levels of decision (Figure 5.1).
Radical treatment is given with the intent of cure or long control when the progress is
good.
Palliative treatment is given to improve the quality of life (QL) for a patient with
small or no impact upon survival.
As a general principle, a primary malignant tumor require local, regional treatment:
surgical excision and/or radiotherapy: metastatic disease require systemic treatment:
chemotherapy or hormonotherapy.
Adjuvant treatment is that which is given following primary treatment to prevent
recurrence and metastases.
Adjuvant treatment can be postoperative radiotherapy, following excision of tumor,
reducing for example the risk of local relapse in the breast after lumpectomy.
Adjuvant systemic therapy reduces the risk of distant metastasis on the high-risk
prognostic groups.
Clinical Diagnosis

Staging and history

Decision 1

No treatment

Active treatment

Decision 2

Radical

Palliative
Surgery
Radiotherapy
Chemotherapy

Decision 3

Primary

Adjuvant

Surgery
Radiotherapy Radiotherapy
Chemotherapy Chemotherapy

Figure 5.1 - Flowchart for treatment decision (Neal-Hoskin)

63

Decision making implies the knowledge regarding pathogenesis of cancer,

understanding the causes of cancer, disease outcome, related morbidity to an individual
patient, treatment and probability of benefit.
Reliable information about the relative role of surgery radiotherapy and
chemotherapy, demonstrate that locale treatment that includes surgery and/or radiotherapy
could be expected to be successful in 40% of cases, apart from skin cancers and in situ
cervical carcinomas, 30% of cancer are cured by surgery, radiotherapy or both.
Many patients (40%) are candidates for systemic drug treatment with potentially
curable (5%) and with some possible prolongation of life 10% (Souhami - Tobias cit.
Steel).
Combined modality therapy with drugs and radiation can give a greater tumor
response and may lead to an improvement in therapeutic results.
Guidelines for the management (Casciato - Lowitz) include:
Comprehensive (holistic) medical care;
Make decisions without subjecting the patient to every available test, weigh
between risk and benefits;
Optimize the patient's functional status;
Prolong life at a functional level tolerable to the patient and individualize the
goals therapy: curative, palliative;
Never desert a patient, even if the patient refuses the recommended therapy.
Quality of life relate the treatment effect with the length of time over which benefit
may occur, resulting some concepts like Quality Adjusted Life Year (QUALY) to measure
treatment out come.
Measuring of quality of life can be scored with standardized questionnaires such as
European Organization for Cancer Research (EORTC QLQ-C 30).
The demonstration of cost effectiveness is nowadays an important component of any
clinical trial evaluating new cancer treatment mainly in the cases of expensive procedures
with small benefit.
Summary
Cancer staging codifies the description of cancer states to enhance communication of
cancer data between institutions, practitioners, and monitoring or treatment organisations.
The most commonly accepted staging methods reflect a cancer biology dogma that is well
entrenched, namely, an untreated primary cancer increases in size progressively, eventually
manifests dissemination to lymph nodes, and ultimately manifests metastatic spread to
distant anatomic sites. Both the American Joint Committee on Cancer (AJCC) and the
Union International Contre le Cancer (UICC) have proposed the TNM staging system for
universal application. Tumor growth (T), spread to primary or regional lymph nodes (N),
and metastatic dissemination (M) are the events in the natural history of a cancer that this
system seeks to define. Once classified, a malignancy may be grouped with classes of the
disease with similar behaviour or prognosis (stage classification). This process of staging
may utilise only clinically derived parameters (physical examination, radiologic
procedures, blood and serum data) or surgically/pathologically derived parameters
(histopathologic examination of surgically resected tissues). Occasionally, the grade of a

64

tumor (its differentiation or degree of malignancy) is utilised in the further stage

grouping of a cancer.
Cancer staging plays a central role in the practice of oncology.
The TNM system is a complex tool for classifying cancer that provide a vital link
between reserch and medical practice and is appropiate for use in most cancer.
Doctors who provide care for cancer patients should record the stage of disease in
everys records using the TNM staging system.
Institutions that provide care for cancer patients should create processes to ensure that
stage is routinely use and accurately recorded and should regulary compil and report the
management and outcome of cancer by stage.
Agencies that certify doctors who treat cancer and those that accredit institutions that
provide care for cancer patients should recognise the use of he TNM system as standard of
care.

65

SECTION 6
SCREENING AND EARLY DETECTION IN CANCER
Screening refers to the clinical application of simple tests to a selected population
to segregate individuals who probably have the malignancy in question from those who
most likely do not.
Screening is used synonymously with early detection or secondary prevention and
involves testing people who are asymptomatic to find hidden or preclinical disease.
The implicit assumption providing the basis for screening is that diagnosis and treatment,
if made and undertaken before persons develop signs or symptoms of the disease, will
result in a more favourable course and outcome than when diagnosis occurs at the time
signs and symptoms become clinically evident. Unfortunately, to prove that early
detection does in fact achieve such benefits is very difficult and has been accomplished
definitively for only a few conditions. The ideal motive for mass screening is the lowering
of morbidity and mortality in a population through early detection and treatment of
asymptomatic persons. Screening can be done centrally where large populations are tested;
this is called 'jia45 screening and it is from studies such as these that conclusions about
efficacy of early detection can be made. As some tests for screening have been shown to
have some benefit, there has been increasing discussion of the costs and ways to make the
most cost-effective use of tests. Since at any given point in time in a population the number
of people who have hidden cancer is small, the cost of testing can be very great.
General Principles of Cancer Screening
There are three areas to be considered in cancer screening: the characteristics of
cancers, the tests that are available, and the evaluation of screening programs.
Features of Cancer Important in Screening
The cancer to be screened should be one, which has serious consequences for health in
the population for whom screening is being considered. Mortality is the most common
such serious consequence, but if mortality from a particular type of cancer occurs only in
the elderly, the mortality rate itself is a less than complete measure of the seriousness of
the disease.
It is very important to know how a cancer develops before it is normally detected in
determining whether the cancer is favourable for screening. There must be a detectable
preclinical phase (DPCP) of some duration so that a screening test could detect the disease
significantly in advance of the time when symptoms develop and a clinical diagnosis is
made (Fig.6.1). A very short DPCP would make it impossible to detect the cancer in a
population significantly in advance of the normal time of detection; the optimal time is to
detect a cancer before it has metastasised. Lung cancer can be detected early, before
symptoms occur, but most cancers have already metastasised by this time.
In the absence of good data about the natural history of preclinical cancers it is
difficult to be dogmatic about the potential impact of cancer screening.

66

There must be more effective treatment for a screening-detected cancer if it is to be

considered favourable for screening. Early detection does not necessarily lead to more
effective treatment. Finally, since certain cancer therapies involve morbidity and some
mortality, there must be a consensus as to treatment.
It seems most favourable to screen for cancers of the breast, cervix and colon, as well
as malignant melanoma, less so for cancers of the lung, prostate, thyroid, bladder, stomach,
uterus, ovary, oropharynx, testes and lymph nodes.

common cancer
a high prevalence in preclinical state
associated with substantial morbidity and mortality
long disease detectable nonmetastatic preclinical phase
preclinical detection of cancer improved treatment outcomes
effective screening test (s) available

Table 6.1. The important characteristics of a cancer that make suitable for screening
Screening Tests
Clinicians must be concerned with the application of a test as well as with the
measures of practical test performances. Clearly, a screening test must be comfortable and
acceptable to patients, since any discomfort from the test is a strong disincentive to repeat
examinations. Convenience, long-term side effects, and low cost are also important.
Standard measures of test performance are outlined in Table 6.2.

high sensitivity
high specificity
inexpensive
risk-free
simple
easy to administer
lends itself to mass implementation
leads to early treatment and reduced cancer-specific mortality
low psychological and financial costs attached to workup of false positives

Table 6.2. The characteristics of a ideal screening test

In screening practice, a change in test sensitivity is often achieved at the expense of
specificity and vice versa. Specificity acts on the preclinical disease-free population approximately 99% of individuals. Reduced specificity results in needless diagnostic
workups of healthy individuals, associated with some morbidity and high cost. A good test
must have very high specificity, on the order of 99%. One of the difficulties with currently
available biological markers for different cancers is that they are not specific for cancer
alone.
It is critically important to recognise that the measures of test performance sensitivity and specificity - are specific to a population examined. In particular, the
sensitivity of a test on a population with symptomatic disease is obviously going to be
greater than that for a population of asymptomatic individuals.

67

As the prevalence of disease in a population goes up, the predictive value of a positive
test also increases. The astute clinician will question whether the results given in a
particular report might actually apply to his use of the test on the population he is studying.
Evaluation of Screening Programs
If a neoplasm is indeed favourable for screening and if the performance measures of
the appropriate tests are reasonable, then the important question is whether there are firm
data validating the ideal motive for screening: does the screening, early diagnosis, and
treatment actually benefit the individuals of the screened population. The ideal kind of
evaluation is a controlled trial in which patients are assigned randomly to a screening
program or to regular health care, followed by comparison of the survival and morbidity
from the cancers that develop in each group. At present, such data are available only for
cancers of the breast. Evaluations that are not from controlled trials involve selection of
possibly different and unrepresentative patients whose courses of disease may be different.
A second problem is lead-time bias. Basically when cancers are diagnosed in advance
of the usual time individuals survive longer. (The usual time is the time when a cancer
would normally be diagnosed because of symptoms.) The question is whether absolute
survival is longer than it would have been had the cancer not been detected early. If death
occurs at the same time it would have anyway, then screening only increases the time the
patient knows he or she has cancer. Figure 6.1 illustrates this concept.
Detection by
screening

Symptomatic
diagnosis

Birth

Death

Survival
normally

Lead-time

Survival with
screening

Fig.6.1. The concept of lead time

Cancers may be detected early and survival may be longer, but the important question
is whether death is averted or delayed. Lead time bias occurs because survival will always
be longer if cancers are detected early. Because of lead time bias, mortality needs to be
studied in evaluating the impact of a screening program
A third problem is length bias sampling. Individual cancers have differing natural
histories. Cancers that have long natural histories and long DPCPs are most likely to be
detected in screening programs. These same cancers are more likely to have a long natural
clinical history and thus are not representative of all cancers occurring in the population.
The cancers found in screening will have improved survival because they have long
natural histories. Cancers that are diagnosed between screening examinations are likely to
be fast-growing malignancies.

68

Much has been learned in recent years about how to maximise the benefit from any
screening program. Optimal test performance is essential. For example, the sensitivity of
the Pap test for cervical cancer depends on the care with which the test is done. A second
way to maximise the benefit of a screening program is to focus on high-risk patients. A
third approach to maximising benefits of screening is to consider the optimal interval
between tests. The subsequent discussion of screening for specific cancers will make some
of these points more clinically relevant.
Cancer of the Breast
Among women in many societies, breast cancer is the most frequent major
malignancy and the leading cause of cancer death. Thus, the interest in benefits from mass
screening and early detection is particularly great for this disease. The most useful risk
factor is a personal history of breast cancer in the individual woman or a family history of
breast cancer in one or more first-degree relatives. When a woman has once had breast
cancer, she runs a risk of approximately 1% per year of developing breast cancer a second
time. When one or more first-degree relatives have breast cancer, the risk is increased
three- to tenfold greater than that of the normal population. The level of risk of this
situation is governed by the ages of the relatives when the breast cancer developed,
whether the relatives had unilateral or bilateral breast cancer and the proportion of women
in that particular family in whom the disease developed.
Self-Examination of the Breast
There are three established procedures for the early detection of breast cancer. The
first is breast self-examination (BSE). Several studies suggest that women who carefully
examine their breasts find smaller breast cancers and have a better prognosis. While the
evidence currently available falls short of being definitive because of selection bias, lead
time, and length biases, the general interpretation is that more widespread practice of BSE
could downstage breast cancers in the population and improve overall survival rates for the
disease.
Several factors impact on patients' ability or willingness to perform BSE. Patients are
often fearful of the examination. Further, they distrust their own judgements regarding
findings in their own breasts. Third, the examination is of an intimate nature. To examine
the deeper tissues of the breast requires inflicting some discomfort on ones's self,
something most individuals are not inclined to do. Finally, BSE must be conducted in the
face of powerful disincentives. Women are aware that breast amputation or some form of
potentially disfiguring surgery will be necessary if something is found. This negative
reward provides a powerful disincentive.
Clinicians must address these problems by careful teaching of BSE in the context of
doing breast examinations on patients themselves. Normal anatomic landmarks should be
identified - rib ends glandular areas of the breast, the inframammary ridge, and the axillary
tail. The clinician must emphasise the importance of adequate pressure to delineate any
abnormalities in the underlying tissues and the need for spending adequate time.

69

Examination by a Health Care Professional

Breast examination by a health professional is also useful in detecting small breast
cancers. There is some evidence that the application of this procedure has a definite impact
on breast cancer mortality. The Health Insurance Plan of New York began a study in 1963
of periodic breast examinations and mammography. While it is difficult to be certain of the
individual contributions of mammography and breast examinations in the associated
reduction in breast cancer mortality seen in this study (Table 6.3), many experts believe
that a significant component of the reduction was a consequence of the professional breast
examinations. As has been emphasised in earlier comments, examinations are clearly only
beneficial if they are very carefully conducted. In general, annual examinations are
indicated in mature women. More frequent examinations may be indicated in women at
greater risk because of a personal or family history of disease.
Mammography
Evaluating the use of mammography (X-ray examination of the breast) as a method
for early detection of breast cancer is complicated.
Risks in Asymptomatic Women
The first possible risk of mammography in healthy women is that radiation may cause
cancer. This risk is very small. Mammography is not 100% sensitive. Mammograms may
diagnose cancer 30%-80% of the time it is present. The specificity of mammography in
healthy women is 91%-95%.

Patient age at 5 years after 5 years after 14 years after 5 years after
entry (years) start of screning start of screning start of screning start of screning

40-44
45-49
50-54
55-59
>60
Totals

Study
9
10
8
7
5
39

Control
11
9
23
10
10
63

Study
18
28
29
24
19
118

Control
26
35
36
32
24
153

Table 6.3. HIP study: breast cancer deaths

Table 6.3 shows the result from the large Health Insurance Plan (HIP) randomized
clinical trial of breast cancer screening for 4 years with mammography and physical
examination. The table shows that both 5 and 14 years after screening began, the numbers
of deaths in the screened (study) group were smaller than the numbers in the control group.
Because of the design of the study, definitive conclusions about whether younger and older
women benefited cannot be drawn (Shapiro, 1982).
This means that 5%-9% of all women who have a mammogram taken will have a
positive test, while only I in 10-I in 100 of these will actually have breast cancer. Both
the sensitivity and specificity of mammography improve as women become older because
the breast becomes less fluid filled and more replaced by fat. A major disadvantage of
mammography in asymptomatic women is that it is expensive.

70

Benefits in Asymptomatic Women

The benefits of screening mammography are three fold: increased probability of cure
if the disease is present: peace of mind for doctors and patients; and possible cost benefit.
To discuss the second and third issues briefly, when the test is negative, it is very likely
that the patient does not have the disease. This can reassure both patients and physicians.
Regarding cost benefit, there are very few and only crude analyses available at present to
indicate that a strategy of periodic mammography in any population of women in fact
decreases total health care costs in comparison with a strategy of no mammography. Eddy
has calculated that mammography is extremely expensive in younger women.
The most important benefit of mammography is the increased probability of cure for
women over age 50. Data that address this issue come from several sources. The Health
Insurance Plan (HIP) trial previously mentioned (data shown in Table 6.3) involved
physical examination and mammography annually for 4 years offered to a study group of
31000 women with a randomised control group of comparable size. Table 6.3 indicates
that improved mortality persists for study patients at 14 years from entry. Since the
numbers were small for women in whom breast cancer developed before age 50 (in
contrast to those under 50 at entry into the trial), benefits to women under 50 are uncertain.
These data are generally interpreted to support the belief that mammography in women
over 50 does decrease mortality from breast cancer. Again, however, it is uncertain how
much of this benefit is due to mammography.
More recently, investigators in Holland, Italy and Sweden have reported one case
control studyes and one nonrandomized population trial. In each of these studies, decreased
mortality has been demonstrated consequent to screening for breast cancer. In one study
both clinical examination and mammography were used, in the other two mammography
alone was employed. Women over age 50 were found to have benefited in all three trials;
there are no clear data indicating benefits to women under age 50.
These data are encouraging for substantiating the hypothesis that breast cancer can be
detected before it is usually diagnosed so as to absolutely benefit survival. However, at
present the optimal approach to screening for breast cancer has not been defined. Given the
major costs involved in any screening program for breast cancer, definition of the most
cost-effective approach is the current challenge.
Cancer of the Cervix
Invasive carcinoma of the cervix has continued to decline in incidence over the last
two decades in many Western countries, probably partly because widespread Pap test
programs have led to diagnosis of more preneoplastic lesions - dysplasias and carcinoma in
situ (CIS). These are vigorously treated and thus never develop to the invasive lesion stage.
The women at highest risk for invasive cervical cancer are those with dysplastic lesions or
CIS. Women, often from lower souci-economic groups, who have never had Pap tests are a
second high-risk population.
Improving the efficacy of a society's effort in cervical cancer prevention and screening
will come about, first and foremost, through better systems of reporting, such that all
abnormal tests are acted upon, and by recruiting more women into Pap testing programs.
Another way to increase the efficacy of this screening effort is by considering the aspects

71

of test performance. Directing attention to the factors listed in Table 6.4 would markedly
improve test performance and obviate the need for more frequent testing. In countries
where use of the cervical Pap test has contributed to decreased mortality, careful attention
to these factors has clearly played a major role.
Sites sampled:
Endocervical canal transformation zone
Ectocervix
Vaginal pool
Sampling technique
Slide preparation technique
Interpretation of smear
Laboratory quality/accuracy
Integrated reporting system
Table 6.4. Factors affecting the sensitivity and specificity of the cervical Pap test
The actual performance measures of the cervical Pap test vary according to
circumstances, which are known. This list notes those major factors, attention to which
will maximise these performance measures in clinical practice.
Cervical cancer begins at the transformation zone between ecto- and endocervical
epithelia. The sample must be taken from this zone, which with increasing age may
become invisible in the endocervical canal. Endocervical (saline moistened cotton) swab
and endocervical or aspiration are recommended techniques. Prompt slide preparation and
laboratory quality control are very important.
A third way to improve Pap test efficiency is to optimise test frequency. The generally
accepted recommendation is that Pap tests be performed less frequently than annually for
women with two consecutive annual normal tests. This recommendation is based on
current understanding of the natural history of early and preneoplastic carcinoma of the
cervix which is of several years duration in most women in whom the disease develops.
Screening frequency should be determined by rates of progression and natural history of
the disease in question. There is no evidence to indicate that on average the natural history
of cervical cancer is becoming more rapid for modern women. Some cancers will develop
very rapidly and may thus be missed by less frequent testing. The existence of such cases,
however, should not be the practical basis for testing the remaining population frequently.
Cancer of the Colon and Rectum
In many Western societies, colorectal cancer is the second greatest cause of cancer
death. Unfortunately the symptoms that characterise the development of this neoplasm are
common in the population even in the absence of the disease. Thus, there are no cardinal
symptoms and very often patients present with advanced disease.
These are four groups of persons at increased risk for colorectal cancer. First there are
those who have had a personal history and/or a family history of colorectal cancer. Second,
there are individuals with polyposis syndromes, well-recognised genetic syndromes
characterized by the development of multiple polyps through the bowel. These individuals

72

are at very high risk for developing colorectal cancer early in life if the affected part of
colon is not surgically removed. The third group at increased risk for colorectal cancer are
persons with ulcerative colitis. The intermittent nature of symptoms in patients with
ulcerative colitis tends to lull patients and practitioners into less than rigorous monitoring
of these patients. Duration of symptomatic disease longer than 7 years, early age at onset
of disease in the second or third decades of life, and disease throughout the bowel arc all
associated with increased risk for the development of colonic neoplasms later. Careful
follow-up of patients with long-standing ulcerative colitis, which when available should
include colonoscopy at annual to biennial intervals, is indicated.
The fourth group of individuals at increased risk for colorectal cancer are those who
have had identified colorectal adenomatous, and villous polyps. Villous polyps show
evidence of cancer in more than one-third of cases. Thus, these lesions should be removed
on diagnosis and the stalk examined for evidence of invasive cancer.
At present, the data supporting widespread colorectal cancer screening are incomplete
and controversial. In general, 5 year survivals by stage of colorectal cancer are as follows:
Dukes' A (cancer confined to the mucosa) 80%-90%; Dukes' B (cancer confined to the
bowel wall) 45%-58%; Dukes' C (cancer associated with spread to regional lymph nodes
only) 12%-35%; and Dukes' D (colorectal cancers spread to distant tissues such as liver
and lung) 0%-5%.
In studies done in the UK and the US using slide tests for trace amounts of blood in
stool, approximately 2% of tests were positive. These tests were done with the
Hemoccult test in which patients on a special diet collected six slides. The distribution of
cancers by stage in these studies was favourable, with Dukes' A and Dukes' B cancers
being detected more frequently than usual when patients present with symptoms. However,
for definitive data on the effect of the Hemoccult test on mortality from colorectal
cancer, further maturity of the studies in Britain and the US will be needed.
While some colorectal cancers produce carcinoembryonic antigen (CEA), the
available tests cannot detect the small quantities of CEA made by early cancers and so
this test is not useful as a screening test for this disease. At present, there are no other
biological markers for colorectal cancer.
Malignant Melanoma
In some Western societies the incidence of malignant melanoma has the greatest rate
of increase. In recent years much has been learned about the features of early melanoma
and its precursor lesions that is directly applicable to clinical medicine in the context of
screening. While there have been no randomised trials of screening for malignant
melanoma on which to firmly base clinical efforts in its early detection, experience in
Australia suggests that early detection of melanoma may have a favorable impact on
mortality from the disease. The biology of the disease with its long preclinical phase, the
characteristic changes that are easily recognisable to the trained observer (Table 6.5), and
the improved prognosis with excision of this lesion all strongly suggest it is a favorable
cancer for screening. The performance measures of the test - visual inspection with trained
observers - should be good. In the context of a physical examination for any other reason, a
brief careful examination of the skin is likely to be worthwhile.

73

Melanoma
Size
Color
Surface (palpable)
Shape
Surrounding skin

Patient-reported sensations
Location

Precursors

Occupation of patient
Skin markings

Over 1cm, increasing in

size
Varied, of an autumn
maple leaf, Flag sign
Hard, elevated area;
scaling, oozing, bleeding
Irregular notched border
Fingers of pigment
penetrate; erythematous

Non-malignant skin
lesion
Less than 1cm stable size
Browns; often become pale
with increasing age
Macule progresses to soft
papule with age
Round, oval
Unremarkable or white,
halo

Itchiness, tenderness
Back most common site

None
Over entire body but more
common over scalp sunexposed surfaces
Family history; dysplastic
Excess sun exposure in
congenital nevi; giant hairy youth; family history of
nevus;excess sun exposure; similiar lesion at same or
Type I/TI (easily burned
mirror image site
skin)
Indoor workers
All workers
Absent
Often present

Table 6.5. Characteristics of malignant and non-malignant pigmented lesions of the skin
The most important visual features of a malignant lesion are color, irregular shape and
raised, irregular surface, particularly if there arc changes in these.
Screening for Other Cancers
Cancer of the Lung. In a cigarette smoker over 45 years of age, who is a potential
candidate for surgical resection should a lung cancer develop, chest x-ray at annual
intervals may be a reasonable policy. However, there are no firm data indicating clear
benefit from such a procedure in terms of reduced mortality, and annual chest x-rays are
not recommended.
Cancer of the Prostate. In men over the age of 60 whose general health otherwise
would make them candidates for radical prostatic excision or radical radiotherapy to the
prostate, and in the context of a physical examination for other reasons, careful digital
palpation of the prostate at annual intervals may be of some benefit in detecting minimal
prostate cancer that can be cured. The use of prostate ultrasound and serological tests for
prostate specific antigen (PSA) are under evaluation as screening tests.

74

Cancer of the Thyroid. In patients with a history of head and neck radiation in
childhood, a periodic careful physical examination of the thyroid gland is indicated. A
thyroid scan is not indicated.
Primary Cancer of the Liver. The use of serological screening for alpha-fetoprotein
(AFP) in individuals at increased risk for this cancer (usually because of known hepatitis B
carrier state) is being evaluated.
Cancer of the Stomach. Patients at increased risk for gastric cancer should have
specific programs designed for them based on their age, the presence a precursor condition,
and family history. These programs should include very carefully conducted radiologic and
endoscopic studies. In Japan the use of a rapid examination of the stomach with a gastric
camera has proved beneficial in diagnosing early and curable stomach malignancies.
Cancer of the Oropharynx. At physical examination, careful oropharyngeal
examination is indicated in patients who are cigarette smokers and who may consume
more alcohol than is in their best interest. Special examinations of the oropharynx (apart
from a general physical examination) are not indicated.
Test or Procedure
Sigmoidoscopy, preferably
flexible
Fecal occult blood test
Digital rectal examination
Prostate examination
Papanicolaou test

Sex
M&F

Age
50 and over

Frequency

M&F
M&F
M
F

50 and over
40 and over
50 and over
18-40

Every year
Every year
Every year
All women who are or who have been
sexually active, or have reached age 18,
should have an annual Papanicolaou test and
pelvic examination. After a woman has had
three or more consecutive satisfactory normal
annual examinations, the Papanicolaou test
may be performed less frequently at the
discretion of her physician.
Every 1-3 years with Papanicolaou test

Pelvic examination

Over 40

Every year

Endometrial tissue sample

Breast self-examination
Breast clinical examination
Mammography

F
F
F
F

At menopause,
if at high risk
20 and over
20-40
Over 40
40-49
50 and over

At menopause and thereafter at the discretion

of the physician
Every month
Every 3 years
Every year
Every 1-2 years
Every year

Health counseling and

cancer checkup

M&F
M&F

Over 20
Over 40

Every 3 years
Every year

Every 3-5 years

Table 6.6. American Cancer Society Recommendations For The Early Detection
Of Cancer In Asymptomatic People

75

Cancer of the testes. At physical examination of middle-aged men, the scrotum should
be examined for masses. Since men can make this examination themselves, some
explanation of the purpose of the examination may be useful.
Cancer of the Ovary. In routine gynecologic examination early small cancers of the
ovary cannot be detected. In women with a family history of this disease, the use of
periodic ultrasound examinations and of a serological test for an ovarian cancer-specific
antigen (CA-125) is under evaluation as screening tests.
Rare Childhood Cancer. While small neuroblastomas can be detected by screening for
VMA (vandillylmandelic acid) the costs of the test and the rarity of the disease make such
screening extremely expensive.
Certain procedures have been found adequate to detect potentially curable cancers in
asymptomatic individuals (Table 6.6).
Summary
Cancer screening refers to the process by wich a large number of people within a
population undergo one or more tests designed to find ocult cancer. The main reason for
detecting preclinical disease is to initiate treatment at an earlier stage in the natural history
of cancer. Only if earler treatment results in treatament in improved outcomes will the
screening have been worthwile. The most importnt outcome of the screening action is
often the most difficult to achieve: namely, reduced cancer-specific mortality. Deciding
wheter to screen for a particular cancer involves consideration of the biology and natural
history of the cancer, the prevalence of the cancer and the degreee of morbidity and
mortality the cancer causes in a population. The decision to initiate screening is also
dependent on the quality of the screening or tests avaible. Financial, ethical and societal
issues must be resolved.

76

SECTION 7
PRINCIPLES OF SURGICAL ONCOLOGY
Principles of cancer management
Multidisciplinary Team Approach is the most valuable therapeutic principle of
treatment achieved in last twenty years.
Planing Treatment comprise four steps:
1. To establish a complete database including extent of disease and prognostic factors.
2. To establish the goals of treatment.
3. To plan a specific treatment program.
4. To implement the program and analyse treatment results.
Before the 20th century, surgery was the only form of therapy available to the cancer
patient. Accordingly, many important milestones in our understanding of the
pathophysiology of cancer were made by observant surgeons. There is ample evidence that
such basic principles of surgical oncology as wide local excision of malignant tumours
were well known even to the surgeons of ancient Greece. In the 17th century, Hunter
described the importance of the lymphatic system in the progression of cancer and discouraged operation in the presence of fixed regional lymph nodes. During the latter portion
of the 19th century, advancement of operative technique made possible resectional therapy
of malignant disease by surgeons such as Billroth (stomach, esophagus, larynx), Kocher
(thyroid), and Halsted (breast). During the first half of the 20th century, surgical skills
were refined to the point where it was technically possible to remove malignant tissue from
virtually any organ. In addition, radiotherapy, chemotherapy, hormonal therapy, and
immunotherapy were introduced. The need to integrate technically complex surgical procedures with these newer modalities led to the evolution of the surgical oncologist. The
surgical oncologist is a surgeon who commits to the care of patients with cancer as an
active participant in a multidisciplinary approach.
The surgeons current role in the field of oncology is multifaceted and can be identified as specific goals. These goals include: cancer prevention, screening, diagnosis,
staging, all aspects of treatment, monitoring for recurrence and the development of new
diseases, and the pursuit and application of new knowledge from both basic scientific and
clinical perspectives.
Surgery for Cancer Prevention and Screening
The mission of the surgical oncologist is to minimise the morbidity and mortality
related to cancer; prevention and early detection of malignancies are obvious top priorities.
Certain tumours are more likely curable when detected and treated at an earlier, less
advanced stage. Surgeons have historically initiated and supported educational programs
for health professionals and public awareness programs to identify such patients. Surgeons
must be knowledgeable of the natural history, etiology, and epidemiology of malignancies
if we are to reliably impact prevention and early detection.
Screening refers to the clinical application of simple tests to a selected population
to segregate individuals who probably have the malignancy in question from those who
most likely do not. It is important to recognise that screening programs are applied to an

77

asymptomatic, apparently healthy population and must be evaluated to verify the

magnitude of reduction of the morbidity and mortality of the targeted disease. Adherence
to this principle often precipitates debate. Consider, for example, the proper age for
screening women with mammography for breast cancer, a controversial screening issue in
recent years. Although screening is clearly effective and precisely defined for many
diseases such as cervical cancer, not all cancer are suitable for screening; the prevalence
and duration of the asymptomatic but clinically detectable curable disease state in the
screened population may be insufficient to justify testing costs, especially in an
increasingly hostile economic health care environment.
Unfortunately, albeit less frequently recognised by the legal profession and lay public,
certain malignancies are governed by a biologic nature characterized by incurability from
the earliest possible date of clinical detection. Apparent increasing in survival rates
afforded by screening programs using fixed endpoint survival measure are an illusion
created by lead-time bias, with no real, long-term, overall survival impact. In the absence
of effective therapy, it is hoped that this subset of cancer may eventually be prevented.
Examples of diseases associated with a high incidence of cancer that can be prevented
by prophylactic surgery are: multiple polyposis of the colon, ulcerative colitis, multiple
endocrine neoplasia, familial breast cancer, familial breast cancer.
Condition
Polyposis coli
Cryptorchidy
Familial breast cancer

Associated cancer
Colon
Testicular
Breast

Prevention
Colectomy
Orchidopexy
Mastectomy

Table 7.1. The surgery for prevention

If colectomy is not performed in these patients, about half will develop colon cancer
by age of 40. By the age of 70, virtually all patients with multiple polyposis will develop
colon cancer. It is therefore advisable for all patients containing the mutant gene for
multiple polyposis to undergo prophylactic colectomy before the age of 20 to prevent these
cancers.
Other disorders that require early treatment to prevent subsequent cancers include
cryptorchidism and multiple endocrine neoplasia. Cryptorchidism is associated with high
incidence of testicular cancer that can be prevented by early prophylactic surgery.
Consider also the example of multiple endocrine neoplasia type IIA (MEN-IIA). In
the recent past patients were screened with the cumbersome pentagastrin stimulation test
for calcitonin release as the indication for prophylactic thyroidectomy to prevent
medullary carcinoma of the thyroid.
Through the work of the surgeon Samuel Wells perhaps more than any one individual,
polymerase chain reaction (PCR)-based DNA testing for mutations in the RET protooncogene has been developed, proven effective as a straightforward definitive test, and
used as the indication for preventive surgery in multiple endocrine neoplasia.
A more complex example of the role of surgery in cancer prevention involves women
at high risk for breast cancers. Because the risk of cancer in some women is increased
substantially over normal risk (but does not approach 100%), counselling is required.
Women in this situation must carefully balance the benefits and risks of prophylactic
mastectomy.

78

A careful understanding of the factors involved in increased breast cancer incidence is

essential for the surgical oncologist to provide sound advice in this area. Statistical
techniques can provide approximation in the risk for patients depending on the frequency
of disease in the family history, the age at the first pregnancy and the presence of
fibrocystic disease.
For example, a women with a family history of breast cancer in a sister or mother who
has fibrocystic disease and is nullparous or had a first pregnancy a late age has an 18%
probability of developing breast cancer over a 5-year period. These estimates can be of
value in advising women about prophylactic mastectomy.
Cancer Diagnosis
The diagnosis of cancer requires histopathologic confirmation prior to initiating
therapy for most clinical situations. Some malignancies are readily accessible for biopsy
and may be diagnosed preoperatively. Others, such as small bowel and pancreatic lesions,
are usually biopsied at the time of surgery with definitive resection following frozen
section analysis. Multiple techniques of acquiring cells or tissue for diagnosis are
available, and new methods of obtaining samples for analysis with less invasive
approaches such as endoscopy and laparoscopy have increased the role of biopsy procedures over recent years. Each approach has distinct advantages and disadvantages, but all
originate in certain fundamental principles.
The following principles guide the performance of all surgical biopsies:
a. biopsied tissue should be representative of the lesion in question. Areas of
hemorrhage, necrosis, and infection should be avoided when selecting biopsy sites.
Multiple specimens are most often helpful. Clamping, tearing, crushing, and charring of
tissue creates distortion and should be avoided.
b. the choice of biopsy technique should satisfy the tissue sample needs of the
pathologist. For some tumors, electron microscopy, flow cytometry, or other specialised
techniques may be necessary; sufficient tissue must be obtained and properly submitted. If
biopsy specimens are immediately placed in formalin, the opportunity to perform these
specialised diagnostic tests may be lost.
c. care should be taken not to contaminate new tissue planes during the biopsy. Large
hematomas after biopsy can lead to tumor spread and must be scrupulously avoided by
securing excellent hemostasis during the biopsy. Care should be taken not to use
instruments that may have come in contact with the tumor when obtaining tissue from a
potentially uncontamineted area
d. needle punctures and incisions should be carefully placed for excision as part of the
subsequent definitive surgical procedure. Incisions on the extremity should be placed in the
direction of the underlying muscle, almost always longitudinally. Hematomas may
increase the magnitude of subsequent surgery and enlarge required fields of radiation
therapy-meticulous hemostasis is mandatory for optimum therapy. Drainage exit sites
should also be carefully planned, for similar reasons.
e. close cooperation should exist between the surgeon and the pathologist. The
pathologist should always be provided with relevant clinical information. The surgeon
should orient, label, and when indicated, ink the specimen for the pathologist.

79

Certain specifics of each biopsy technique must be considered in choosing the

optimum approach. Fine-needle aspiration biopsy cytology involves the aspiration of cells
through a small-caliber needle. The needle may be guided into the suspicious lesion by
palpation or image-directed assistance. Cytologic analysis provides a tentative diagnosis of
malignancy and allows the surgeon to proceed with the staging evaluation. However,
major surgical resections should not be undertaken solely on the basis of the conclusions of
fine-needle aspiration biopsy cytology. A small but significant risk of a false-positive
diagnosis exists in the hands of even the most experienced cytopathologist. Fine-needle
aspiration biopsy cytology diagnosis must be confirmed by definitive histologic studies of
tissue.
Core needle biopsy refers to obtaining a tiny piece of tissue in the hollow of the
specially designed needle.
Excisional surgical biopsy provides the pathologist with the entire lesion. As such
excisional biopsies are most useful if they can be performed without compromising the
outcome of the definitive operation. It is important to note that a diagnostic excisional
biopsy makes no effort to achieve a gross or histologic margin of normal tissue. This is an
important point of concern reexcisions of biopsy sites initially done with diagnostic
intent identify residual carcinoma in up to 50% of cases even when the pathologist
reported the original diagnostic excision as having negative margins. Definitive
excisions must proceed with therapeutic intent on the part of the surgeon.
Diagnostic Biopsy
Establishing the pathologic diagnosis is the first step to successful management of the
patient with malignant disease. A variety of techniques are available for obtaining tissue.
A. Needle Aspiration Biopsy: The least invasive is the needle aspiration biopsy. This
technique is performed by passing a 22-gauge needle percutaneously into the suspected
tumor. The needle may be guided by direct palpation of the mass. For deeper lesions, the
needle may be guided by ultrasound, CT scan, or other imaging techniques. The needle is
then passed through the mass 4-6 times while aspirating continuously. Any material
obtained is immediately expressed onto a microscope slide and fixed for cytologic
examination. Depending on the type of tumor involved, the diagnostic accuracy of this
technique can be greater than 90%, and a false-positive diagnosis of malignancy is rare.
This same technique may yield enough material for Chromosomal analysis by flow
cytometry and for immunoperoxidase staining for special markers. Needle aspiration
biopsy is most useful for solid, epithelial neoplasms. Its utility is limited for many
sarcomas. Its role in patients with lymphoid malignancies is restricted to differentiating the
process from an epithelial neoplasm.
B. Needle Biopsy: Needle aspiration yields only enough tissue for diagnosis by
cytologic techniques. If a histologic diagnosis is required, additional tissue may be
obtained by the technique of needle biopsy. A specially designed needle (eg, VimSilverman, Trucut) is passed into the mass as described above. The needle is designed to
remove a core of solid tissue from the lesion. This core of tissue is then frozen or fixed and
submitted for standard histologic analysis. In contrast to needle aspiration cytology, needle
biopsy may result in adverse complications such as bleeding or clinically significant
perforation of the viscera or thorax. Seeding of malignant tissue across tissue planes is also
possible.

80

C. Excisional Biopsy: A commonly employed technique for establishing a tissue

diagnosis is the excisional biopsy. It involves complete excision of the lesion in question.
This technique is ideally suited to cutaneous lesions less than 1 cm in diameter and small
breast masses. In most cases, excisional biopsy is intended only to establish a definitive
diagnosis; thus, although it constitutes adequate therapy for most benign lesions, malignant
lesions likely will require additional therapy. An advantage of the excisional biopsy is
avoidance of the need for more extensive procedures when the diagnosis is uncertain. In
addition, it may form the initial component of effective local therapy when combined with
radiotherapy. Excisional biopsy is the method of choice for obtaining diagnostic nodal
tissue from patients with lymphoma or leukemia. In these settings, examination of the
architecture of the entire node is critical to definitive diagnosis.
D. Incisional Biopsy: To establish a tissue diagnosis before definitive resection,
particularly when preoperative chemotherapy or radiotherapy is being considered, an
incisional biopsy is useful. Careful planning should place the incision in a location that
permits its excision as a part of a more extensive operation. In addition, careful hemostasis
avoids dissemination of cancer cells along tissue planes by postbiopsy bleeding. This
technique is useful for approaching large neoplasms and is the standard diagnostic
technique for sarcomas.
Surgery for Staging
Pathologic staging of malignant disease is an important role. Most often, staging is
incorporated into surgical management of the primary lesion. Thus, axillary node
dissection is integral to surgical management of carcinoma of the breast. Similarly,
resection of primary lesions of the head and neck as well as the gastrointestinal tract
incorporates regional lymph node dissection. The presence or absence of lymphatic
metastasis then serves as a guide to further regional or systemic therapy.
In some cases, such as Hodgkin's disease, the staging procedure is not related to any
therapeutic operation. Stage I or stage II Hodgkin's disease may be treated with
radiotherapy alone. Stage III patients may be treated with either radiotherapy or chemotherapy, or a combination of both, in the presence of bulky pelvic disease. Stage IV disease
requires systemic chemotherapy. Accurate pathologic staging is a prerequisite to effective
treatment. Fully one-third of patients with Hodgkin's disease are misstaged based on
clinical findings alone. Addition of lymphangiography, radionuclide scans, and CT scans
estimate but do not definitively diagnose intra-abdominal or systemic disease.
Accordingly, the staging laparotomy has become integral to the management of patients
with Hodgkin's disease. Patients with satisfactory cardiopulmonary function and no other
contraindication to operation should be considered for staging laparotomy. This operation
consists of a thorough exploration of the abdominal contents through a long midline
incision, liver biopsy, splenectomy and sampling of periaortic lymphoid tissue. Evaluation
of this tissue guides the need for further radiotherapy and chemotherapy. The mortality rate
for staging laparotomy should be less than 1%.

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Preoperative Considerations and Staging

Cancer patients are often elderly and sometimes in poor nutritional status. The general
condition of the patient must be thoroughly evaluated before treatment. Cardiac
pulmonary, renal, nutritional, and other assessments are necessary to prepare the patient for
major surgery. Ensuring adequate preoperative hydration is increasing important in this era
of outpatient mechanical cleansing of the bowel and the obligators preoperative fasting for
general anesthesia.
A preoperative mechanical cleansing bowel prep should be used for colon surgery as
well as for all patients undergoing extensive abdominal procedures; an unexpected en bloc
partial colectomy may occasionally be necessary. The recovery from ileus is I also thought
more tolerable by some if mechanical cleansing is accomplished preoperatively. Patients
undergoing major liver resections also require preoperative bowel preparation to reduce the
risk of postoperative encephalopathy.
Timing the surgical intervention in patients receiving chemotherapy or radiation is
important to ensure that bone marrow suppression will not complicate the immediate
postoperative period. Bleeding problems should be suspected by a history of suggestive
symptoms, or of drug use including aspirin and preoperative chemotherapy. A screening
complete blood cell count with differential is usually necessary. Baseline liver function
tests and tumor markers should be obtained prior to surgery, as trends in these levels may
be monitored during follow-up. A chest X-ray film is usually indicated as a baseline and to
identify potential other new primary cancers, metastases or other pulmonary pathology.
Sepsis is a special consideration as a potential complication in immunocompromised
patients with metastatic diseases and in patients receiving chemotherapy. The source of
infection can vary, but must be identified and is usually best eliminated four surgical Ds:
drainage, debridement, diversion, and drugs (antibiotics).
Patients recently treated with steroids are another special consideration. They should
receive steroid supplements to prevent an Addisonian crisis.
A detailed history and thorough physical examination is the key to minimising the
unnecessary costs associated with extensive radiographic testing in the staging evaluation.
In recent years clinicians especially those from primary care and medical oncology
specialities, have increasingly relied on various scans and other expensive imaging to
evaluate potential sides of metastases. In many cases these studies have not altered the
treatment approach and often unnecessarily duplicate the operative findings for indicated
operations. Surgeons must endeavor to educate other physicians as to the accuracy of
operative staging and uniformly document these findings as a regular part of the operative
record. All oncologists must have a thorough knowledge of the natural history of the
disease and appropriately investigate potential sites of metastases if they are to practice
cost-efficient medicine.
The surgeon must also be familiar with the natural history of the disease under
consideration and likely patterns of metastasis to guide his or her operative exploration. As
an example, the propensity for ovarian cancer to metastasise to peritoneal surfaces
mandates the need for routine surface biopsies and washings. Staging the disease is the
most important factor in establishing the prognosis; it must be diligently and accurately
pursued.

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Cancer Therapy
For most solid tumors there is no more effective treatment modality than the proper
operation for the particular stage of malignancy. The surgical treatment of cancer has the
goals of cure, prolongation of duration of life among uncured patients, the palliation of
clearly defined symptoms, and the local control of disease as a prophylactic measure to
prevent subsequent complications. The surgeon should clearly recognise that prophylactic
surgery causes associated surgical morbidity in an often asymptomatic patient. If we are to
reliably help more patients than we harm, we must proceed with prophylactic interventions
only after thoughtful consideration of the natural history of the disease and the individual
patient's operative risk.
The extent of the appropriate local excision varies with the individual cancer type and
the site of involvement. For many malignancies definitive surgical therapy requires only a
wide local excision defined by a sufficient margin of normal tissue. The magnitude of the
required surgical resection may be modified when surgery is integrated with adjuvant
treatment modalities. In some instances, effective adjuvant modalities have led to a
decrease in the magnitude of surgery and preservation of function not possible without
multimodal therapy. Consider our success in preservation of limb function with sarcoma
surgery as we integrated surgery and radiation therapy. Rationally integrating surgery with
other treatments requires a careful consideration of all effective treatment options. It is a
knowledge of this rapidly changing field that often distinguishes the differentiated surgical
oncologist from more generally oriented surgeons.
In some diseases, such as ovarian cancer, extensive local metastases preclude the
surgical excision of all gross disease. The debulking or cytoreduction of selected cancers
may lead to enhanced local disease control. However, for most solid tumors any significant
patient benefit has been offset by associated surgical morbidities reductive surgery is
usually of significant benefit only for diseases that respond to other treatments to control
small residual deposits of unresectable disease.
Although cure is most noble goal of surgery, about 70% of patients with solid
tumors have regional or distant metastases when they present with their first symptoms.
Surgical resections designed to include regional lymphatic metastases can cure some
patients. But lymph node metastases, depending on the specific organ site and disease, may
be an indication of systemic disease.
Patients with a limited number of pulmonary, hepatic or cerebral metastases can also
enjoy an extended life with surgical resection. For example, the resection of pulmonary
metastases in sarcoma patients may benefit as many as 30% of carefully selected patients.
Similarly, hepatic resection of colorectal metastases enhances long-term survival; patients
with solitary hepatic metastases from colorectal cancer have a long-term survival of about
30%, a magnitude of benefit dramatically exceeding the uniformly fatal result in untreated,
age-matched cohorts.
Palliative surgery is defined as the surgical relief of intractable symptoms; it does not
apply to the asymptomatic patient. Judicious use of surgery for the relief of pain can
improve the quality of life for many. Palliative surgery also includes the remove of masses
causing disfigurement and operations for emergencies from complications related to
hemorrhage, obstruction or perforation. Perforations of abdominal, pelvic, or thoracic
viscers may result from direct tumor invasion or from tumor lysis with systemic

83

chemotherapy as tumors respond and disintegrate. Decompression of the central nervous

system is another emergency situation that must be promptly addressed to preserve
neurologic function.
Urinary obstruction is another relatively frequent complication. Urinary diversion
must be carefully considered; it may sometimes only prolong patient suffering its: an
intractable, incurable malignancy. However, it may sometimes palliate symptoms due to
urinary fistulas or injuries resulting from bladder irradiation. Fecal stream diversion should
be similarly considered but palliation is often much more beneficial in terms of quality of
life issues. Locally advanced tumors of the aerodigestive tract may be managed by
fulguration or laser surgery to establish patency without the disadvantage of a diverting
cutaneous intestinal stoma. Feeding gastrostomies are sometimes required for feeding
advanced head and neck cancer patients, or for palliative decompression with peritoneal
carcinomatosis in the terminally ill.
Surgery for primary cancer
There are three major challenges confronting the surgical oncologist in the definitive
treatment of solid tumors:
- accurate identification of patients who can bee cured by local treatment alone;
- development and selection of local treatments that provide the best balance between
local cure and the impact of treatment morbidity on the quality of life;
- development and application of adjuvant treatments that can improve the control of
local and distant invasive and metastatic disease.
Curative resection
For many patients with solid neoplasms, surgical resection alone is curative. The
success of this mechanical procedure is dependent on the size and location of the primary
tumor, the presence of metastatic lesions, and the biologic behaviour of both. The diagnosis of malignancy, however, does not give a license to perform the most extensive
resection that is technically possible. The boundaries of the curative resection are
determined with two objectives in mind. First, enough tissue is removed so that the patient
is likely to be cured in the absence of clinically significant systemic disease. In the thyroid,
this may represent the entire gland and no lymphatic tissue. By contrast, curative resection
of a gastric antral cancer should include only enough stomach to assure margin-free
removal of the cancer but all regional lymphatic tissue.
The second boundary of the potentially curative resection is established by the need to
ascertain the likelihood of systemic disease. Thus, axillary dissection is an essential
component of a curative resection for breast cancer, since the presence of metastatic cancer
in axillary lymph nodes establishes a rationale for further systemic therapy. It does not,
however, increase the number of patients cured by local resection alone.
Surgery for palliation
Palliative therapy should be considered for a patient with evidence of widespread
malignancy and no hope of cure by resectional therapy. For example, more than 25% of

84

patients with gastric cancer present with advanced disease manifested by a palpable abdominal mass. Before a palliative resection is under-taken, several points should be
considered. First, the patient must be truly symptomatic. Resection of the primary lesion in
the asymptomatic patient with widespread metastatic disease is not palliative. Second, the
surgeon must be thoroughly familiar with the symptoms to be palliated. For example, pain
caused by invasion of retroperitoneal structures will not be alleviated by resection of the
gastric primary. Third, the patient with advanced cancer is a poor operative candidate, and
less invasive surgical procedures such as endoscopic laser therapy, stent placement, or
radiotherapy should be considered.
Surgery for debulking (surgery for residual disease)
In some cases, a patient presents with an extensive lesion such as a retroperitoneal
sarcoma that is not amenable to curative resection. Although this patient is relatively
asymptomatic it may be advisable to recommend a debulking procedure. The procedure is
designed to remove the greatest amount of tissue consistent with a safe operation and rapid
postoperative recovery. This strategy facilitates further therapy with radiation or
chemotherapy. There are several reasons for this phenomenon. First, the cells in the central
portion of the tumor are the least metabolically active and the most resistant to both
radiotherapy and chemotherapy. Second, debulking reduces the number of malignant cells
in the body by one or two orders of magnitude before initiation of cytotoxic chemotherapy.
Second-Look Procedures
The second-look procedure was proposed by Wangensteen in 1951. Patients
undergoing potentially curative resections or gastrointestinal malignancy were reexplored
6 months after their primary operation to test the theory that this strategy would result in
early diagnosis and resection of intra-abdominal metastases. A few patients were rendered
disease-free by second-look operations. However, the majority either underwent a negative
exploration or were found to have unresectable disease at the time of the second look.
More recently, several authors have advocated second-look procedures after
potentially curative resections for colon cancer based on an elevation of carcinoembryonic
antigen (CEA). Again, some patients have probably been rendered disease-free by these
operations, but most have disclosed either irresectable disease or no cancer at all. The
advisability of recommending second-look procedures for all such patients remains
controversial. Similar debate surrounds second-look operations for ovarian cancer.
Surgery for metastatic disease
In the past, presence of metastatic disease was considered evidence of incurability.
More recently, resection of lesions metastatic to the central nervous system, lungs, and
liver has become common. Al though the most favorable results are associated with
resection of a solitary metastatic lesion, resection of small numbers of multiple metastases
is becoming more common. These operations are recommended most often when the
patient is symptomatic, when further regional or systemic chemotherapy is planned, or
when resection may render the patient disease-free. Resection of pulmonary and hepatic

85

metastases from colorectal cancer should be performe, in appropriate patients, when there
is a chance of achieving a margin-free resection and there is no other evidence of
disease. Resection of pulmonary metastases from sarcoma prolongs survival in patients
with a tumor-doubling time of more than 40 days. Axillary or femoral nodal metastases
from melanoma should be removed to avoid breakdown of the overlying skin or to reduce
tumor burden for chemotherapy or immunotherapy. Similarly, resection of isolated
metastases for renal cell carcinoma may be an important adjunct to immunotherapy or
curative in its own right.
Surgery for reconstruction and rehabilitation
Surgycal techniques are being refined that aid in the reconstruction and rehabilitation
of cancer patients after definitive therapy. The ability to reconstruct anatomic defects can
substantially improve function and cosmetic appearance. The development of free flaps
using microvascular anatomic techniques is having a profound impact on the ability to
bring fresh tissue to resected or heavily irradiated areas. Loss of function (especially of
extremities) often can be rehabilitated by surgical approaches. This includes lysis of
contracture or muscle transposition to restore muscular function that has been damaged by
previous surgery or radiation therapy.
Surgical management of complications of therapies
Ideally, the surgical oncologist is included in the planning of aggressive medical
management of malignant disease. Such a relationship facilitates the early and expeditious
diagnosis and treatment of the complications inevitably associated with aggressive cancer
therapy. These complications may be relatively minor, such as cutaneous bums after
radiotherapy or extravasation of cytotoxic agents. Patients undergoing intensive therapy
also suffer more serious complications such as gastrointestinal bleeding or perforation
during treatment of tumors involving the gastrointestinal tract.
Management of these complications in the immunocompromised patient or the patient
with widespread metastatic disease may differ markedly from that recommended for other
groups of patients. For example, placement of gastrostomy of jejunostomy tubes should be
avoided in immunocompromised patients. Similarly, operations involving division and
reanastomosis of the bowel are avoided whenever possible. These patients require
particular attention to preoperative and postoperative care. Correction of coagulation and
platelet deficits preoperatively is essential. Postoperatively, meticulous attention to electrolyte balance, hydration, and nutritional support is essential.
Specialised surgical procedures
Among the surgical procedures unique to the field of surgical oncology is isolated
limb perfusion, most commonly employed as an adjunct to the treatment of extremity
melanoma. For example, a melanoma of the lower extremity is treated by cannulating the
femoral artery and femoral vein. Cannulas leading from these vessels are then connected to
a roller pump, an oxygenator, and a heating unit. Next, the limb is isolated by placing a
tourniquet around the vessels separating the cannulas from the systemic circulation.

86

Oxygenation and circulation is provided to the limb by the roller pump and oxygenator.
The limb is then perfused with super-normal doses of cytotoxic agents, usually at elevated
temperature. This form of therapy may be more effective than conventional systemic
therapy for the treatment of metastatic melanoma confined to one region. Randomised
trials are in progress.
Other forms of regional therapy include arterial perfusion of selected primary or
metastatic cancers via an implantable pumping device. Such forms of treatment may be
conducted by the surgical oncology service or in conjunction with the medical oncologist.
Vascular Access
Effective vascular access is an absolute prerequisite to effective systemic
chemotherapy. Most cytotoxic agents are highly irritating to peripheral veins, and
extravasation can cause necrosis and ulceration of surrounding tissues. Accordingly, access
to the central venous system is required for most patients. The choice of technique depends
on the individual requirements of the patient and the treatment regimen.
A. Percutaneous Catheters: Basic central venous access can be provided by a singlelumen 16- or 20-gauge polyurethane catheter passed percutaneously into the subclavian
vein. These catheters may be safely placed under local anesthesia while the patient lies on
a stretcher or hospital bed. The most common complications are pneumothorax and inadvertent puncture of the subclavian artery. These catheters are ideal for continuous infusions
or very frequent intermittent use (i.e., daily). They are easily removed upon completion of
therapy or to diagnose or treat catheter infection. Their main disadvantage is that they
provide only one lumen for vascular access. Percutaneous polyurethane triple-lumen
catheters, like the single-lumen catheter, can be placed under local anesthesia outside of
the operating room. They have the same advantages as the single-lumen catheter and are
used in the same setting. They are selected when one lumen is inadequate to provide for
the patient's intravenous needs. Their disadvantage is a higher incidence of infection
related to more frequent access.
Routine maintenance for both single- and triple-lumen percutaneous catheters includes
three-times-weekly aseptic cleansing of the skin entry site and application of a fresh sterile
dressing. Each limb of the catheter is flushed with 1ml of sterile heparin solution. The
patient must be carefully taught to avoid inadvertent contamination of the catheter or a
possible air embolus during the heparin flush. On completion of therapy, these catheters
are easily removed.
B. Indwelling Cuffed Catheters: When continuous therapy for longer than 3 months
is anticipated, an indwelling cuffed silicone catheter may be indicated. Single-, double-,
and triple-lumen varieties are available. These catheters are usually placed in the operating
room under local or general anesthesia. They require creation of a subcutaneous tunnel 1520cm in length and introduction of the catheter into the subclavian vein either directly
using a sheath type introducer or via the cephalic vein. These catheters incorporate a
porous Teflon or Dacron cuff placed 1-2cm below the level of the skin. Ingrowth of tissue
to this cuff provides secure anchoring. The role of the cuff in mitigating ascending
infection from skin microorganisms is questionable. Maintenance includes a sterile
dressing at the entry site and daily or weekly flushing of the catheter lumen with
heparinized saline. Because these catheters are constructed of soft silicone material, they

87

may develop leaks following abuse or long use. In many instances, leaks may be repaired
by a variety of techniques. After tissue in-growth of the cuff has occurred, removal of these
catheters requires freeing the cuff from the subcutaneous tissue. However, it is often
possible to remove these catheters under local anesthesia on an outpatient basis.
C. Implantable Infusion Ports: Yet another alternative for vascular access is
provided by the totally implantable vascular access port. These devices contain a single- or
multiple-lumen silicone catheter. Rather than extend through the skin, this device is
connected to a subcutaneous port incorporating a compressed silicone septum. After
introduction of the silicone catheter into the subclavian vein, the port body is placed in a
subcutaneous pocket created below the clavicle. After the wound has healed, access to the
port is achieved by carefully preparing the skin over the port with a bactericidal solution
and passing a noncoring needle through the skin, through the compressed silicone septum,
and into the lumen of the port body. Fluid may be introduced into the central venous
system or blood may be aspirated from the central venous system without difficulty.
Access is completed by flushing the port with heparinized saline. The noncoring needle is
then with-drawn from the patient. The great advantage is that these ports are entirely
subcutaneous and no pans protrude from the skin. Thus, patients with these ports are free
to swim or engage in other activities without the obvious intrusion of a vascular access.
Their main disadvantage is that they must be inserted and removed in the operating room.
They are best suited for patients for whom access is required intermittently and for brief
periods. All advantages are I lost if an indwelling percutaneous needle is left in place for
extended periods. They become occluded more frequently when used for blood sampling
and for administration of drugs.
Within the world of medicine, the collective personal commitment of surgeons to their
patients, and even individual personalities, are considered by some to be characteristic.
This commitment and the associated character traits do not reflect personality so much as
an attitude toward illness. That attitude is perhaps best characterized by actions that result
from a prompt evaluation of treatment alternatives, in the context of the biology of an
individual patient's disease and overall general health, and culminate in an acute
therapeutic intervention with obvious, inherent treatment risks, most often outweighed by a
profound therapeutic impact. Such has been the history of surgery, the first effective
treatment modality for cancer, and currently the most effective treatment modality for
patients with solid tumors. To understand the state-of-the-art and the future of surgical
oncology as a discipline, we begin with a historical perspective.
Follow-up monitoring
One goal of follow-up monitoring is early detection of local, regional, or distant
metastases to extend life after surgery or other therapy. Unfortunately, the impact is such
screening program has historically been poorly studied. Most screening programs are
organised by intention, but without definitive scientific basis. Some current patterns of
follow-up practised by some disciplines frankly defy logic. Consider the routine follow-up
of pancreatic cancer patients with computerized tomograms of the abdomen and chest.
What is the evidence to suggest that any treatment based on based finding offers
significant therapeutic impact? Such patients are also frustrated by the anxiety of equivocal
results and may suffer the unnecessary morbidity of invasive biopsies in an attempt to

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clarify diagnosis. Proper follow-up monitoring can only be prescribed in the context of a
clear understanding of the natural history of the disease, and a realistic probability of
therapeutic impact in the screened population. During the last 25 years, long-term venous
access for the administration of chemotherapy, nutritional supports, and for blood drawing
has been progressively refined with numerous technological advances. Broviac introduced
the first silicone rubber catheter just over 25 years ago after proving less thrombogenic
than conventional materials of the time. The Hickman catheter, with a larger internal
diameter, was subsequently developed as a modification of the Broviac type. Numerous
studies have confirmed reliability and acceptable complication rates for these devices. In
recent years there has been a virtually continuous series of modifications of the existing
vascular access devices, often with little if any significant improvement, but often in
association with exaggerated claims and marketing fanfare on the part of the technology
industry. Fundamentally long-term vascular access devices take he form of external
catheter devices such as the Broviac, Hickman. Lenonard, or Oroshong, and a variety of
totally implantable venous access reservoirs or ports. An intensive educational program for
patients, families, and caregivers of meticulous catheter maintenance is essential to achieve
extended catheter function in the absence of complications.
The development of surgical oncology as a speciality area of surgery involve a clear
definition of its role. There are six major area in which the modern surgical oncologist can
play a valuable role in the care of cancer patients:
- coordinating surgical oncology efforts with medical and radiation oncologists;
- providing expert consultation for unusual or difficult oncologic problems;
- providing unique expertise in surgical cases unfamiliar to general surgeons (e.g. soft
tissue resection, exenterations, head and neck resections, isolation limb perfusion);
- coordinating experimental research programs in oncology where possible;
- organising surgical oncology teaching programs for staff, residents and students;
- organising clinical research protocols for surgical oncology patients.
Summary
Surgery was the only method of treatment of cancer for centuries and remains today
the primary treatment for the vast majority of patients who are curable.
The surgeon's cuurent role in the field of oncology is multifaceted and can be
identified as specific goals. These goals include cancer prevention, screening, diagnosis
staging, all aspects of treatment, monitoring for recurence and development of new
diseases and pursuit and application of new knowledge from both basic scientific and
clinical perspectives.

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SECTION 8
Principles of radiation oncology
Radiotherapy is, together with surgery, one of the two main methods for the locoregional treatment of cancer. Currently, 50-60% of the patients with cancer receive
radiotherapy during the course of disease and, if properly used, 40-50% of these can be
cured. For the other half, incurable with any therapeutic method, palliative intent for the
relief of specific symptoms will improve the quality of life.
Reliable information about the roles of surgery, radiotherapy and chemotherapy are
difficult to obtain. Souhami and Tobias (cit. Steel) estimate that apart from skin cancers
and in situ carcinoma of the cervix, probably 30% of the cancers are cured by surgery,
radiotherapy or both. Relapsed cases (18%) and advanced cancers (22%) are candidates
for chemotherapy but their contribution to the overall cure rate may be only around 2%,
with some prolongation of life in another 10%.
The use of ionizing radiation implies the understanding of three basic problems:
The first is radiation physics; the second is the radiobiology and the third is the
relation with the tumor biology. Finally, we should refer to the clinical considerations
linked to planning of radiotherapy.
In biological terms, the purpose of radiotherapy is to deliver a dose (quantity) of
radiation (rays) to a patient, that is capable of eradicating or controlling the tumor cells
within the target tumor volume. That goal must be achieved with an acceptable level of
normal tissue side effects.
Radiotherapy is an effective method that can eradicate the malignant process in the
loco-regional volume in patients treated with curative intent (table 8.1).
Another important clinical goal is to yield palliative relief in patients with incurable
cancer.
The interest in radiotherapy is explained by three considerations (Tubiana):
1. Combinations of surgery and radiotherapy have made a more active treatment
possible.
2. Improved local control of the primary tumor does not suffice to cure the patients,
but in some cases, can improve long term survival. Loco-regional recurrences can
initiate distant metastasis
3. Systemic treatment has a limited effectiveness on most solid tumors.
8.1. Basic concepts of radiation physics
Ionizing radiation is a form of electromagnetic or particulate energy that during
absorption causes ionization. The electromagnetic radiation is considered to have a dual
aspect, being both a wave and a particle (a photon).
Ionization is distributed through tissue.
The quantification of radiation, in delivery and absorption within the target volume, is
the central problem in radiotherapy planning.

90

Tumor type
Skin
Melanoma
BCC, SCC
Kaposi sarcoma
Head & neck
Adult CNS
Lung
NSCL
SCLC
Thyroid
Well differentiated
Poorly differentiated
Thymus
Breast
Female genital tract
Vulva
Cervix
Uterus

Radio
Sensitivity
-/+
++ / +++
++ / +++
+ / ++
-/+

Poor
Good /excellent
Responsible, if HIV-negative
Good tumor well localized
Variable but not usually possible

- / ++
++ / +++

Occasional
Rare

++ / +++
-/+
-/+
+ / ++

+ / ++
+ / ++
+ / ++
-/+
-/+
-/ +++

Ovary
Soft-tissue sarcoma
Bone sarcoma
Genitourinary tract
Renal (adult)
Bladder
Penis
Testis
Gastrointestinal tract
Esophagus
Stomach
Colon
Rectum
Anus
Hodgkins disease
Non-Hodgkin lymphoma

+ / ++
-/+
-/+
+ / ++
+ / ++
+ / +++
+ / +++

Multiple myeloma
Leukemia

++ / +++
+ / +++

Paedriatic malignancy

Radiocurability

+ / ++
+ / ++
+ / +++

- / +++

Excellent; radioiodine uptake often food

even in metastatic cases
Rare
Unusual
Poor because many cases metastasise
widely
Possible with small tumors, but surgery
often preferred
Good, especially for localized tumors
Moderate, though surgery preferable in
operable cases
Poor
Possible but unusual
Good, especiallys in Ewings sarcoma
Poor
Good, especially with localized tumor
Good
Good, especially with seminoma
Occasional
Poor
Rare
Occasional
Good
Excellent, if localized
Poorer than in HD since more patients have
extranodal disease
Poor, unless total body irradiation given
Good, if systemic RT given with marrow
transplantation
Good for brain tumors (now the main
indication for RT in children)

Table 8.1. (Withers, 1993) - Efficacy of radiotherapy

BCC - Basal Cell Carcinoma
SCC - Squamous Cell Carcinoma
SCLC - Small Cell Lung Carcinoma
NSCLC - Non-SCLC
HD - Hodgkin's Disease
Radiosensitivity score: - doubtful or minimum, + responsive but at high doses; ++ generally responsive;
+++ highly responsive.

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Figure 8.1. The roentgentherapy tube

Figure 8.2. - Telecobaltotherapy machine

Figure 8.3. Linear accelerator

8.1.1.Radiation Beams of Clinical Value
The Units and Methods of delivery
Ionizing radiation can be delivered in three technical modalities:
1. External percutaneous beam irradiation (teletherapy) from sources at distance
from the body: telecobaltotherapy and linear accelerators are used for fractionated
radiation therapy.

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External beam radiation therapy equipment comprises:

Superficial X-ray machine, 50-150 KVp, 5-10 mA HVL=1-8 mm Al, TSD (TargetSkin-Distance)=15-20cm, e.g. Phillips-Muller 100kV tube (Figure 8.1)
Orthovoltage X-ray machine 150-500 KVp, 10-20 mA, HVL=1-4 mm Cu, SSD
(Source-Skin Distance) = 40-50 cm
60 Cobalt machine (Figure 8.2), 1.17 MeV and 1.33 MeV photon energy; with 50%
penetration at 10 cm, SAD (Source-Axis Distance) = 80 cm (Figure 8.2)
linear accelerators, 6-8-10-12 MeV, producing high energy photons or electrons
(Figure 8.3).
2. Brachytherapy, in which the radiation sources (137Cs, 192Ir) are in a close contact
with the target volume (interstitial or intracavitary in remote afterloading units) producing
continuous irradiation or as permanent implants of short-lived radionuclides such as 125I.
3. Systemic irradiation from radioactive isotopes (131I, 32P, 89Sr) administrated
intravenously, intracavitary, or via the digestive tube.
8.1.2. Electromagnetic radiation
Electromagnetic radiation consists of roentgen and gamma radiation; the first is
produced by special machines, the second is produced by the decay of radioactive isotopes.
The initial beams were limited by their low energy - 10-400 kV (kilovolts). Superficial
(10 - 100 kV), or orthovoltage (100 - 400 kV) beams were used mainly for the treatment of
tumors on the body surface. This soft radiation being readily absorbed by the skin caused
severe adverse reactions.
In the last decades megavoltage beams were introduced, produced by telecobalt units
and accelerators with energy varying from 1-25 MeV, achieving important clinical
advantages like: skin sparing and better maximal doses below the skin, depth doses to
tumors with increased tumor control. The sharply defined edges of these beams allow the
treatment of lesions located near critical tissue.
Tumor localization is nowadays possible with new imaging methods: CT, improving
the target volume delineation.
Computerized dosimetry enable accurate mapping of the dose distribution in the plane
trough the center of the volume and three-dimensionally. Shaping the beam with lead
shields, filter wedges and compensators allow the use of complex fields tailored to the
individual patient.
The intensity of electromagnetic rays dissipates with the reversed square of the
distance from the source; that means that for a beam, the intensity decrease with increasing
depth.
The penetration of the radiation into the body is directly proportional to the generating
energy (Figure 8.4).
Penetration is characterized by the thickness of a material (Al, Cu, Pb) which reduces
intensity of the radiation beam with 50%, or HVL (half value layer).
The three dominant absorption mechanisms depend on the energy of radiation
(Figure 8.5).

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Figure 8.4. Relationship between energy and penetration

Figure 8.5. Absorption mechanisms of radiation

1. Photoelectric absorption predominates at lower energies and depends of the atomic
number.
2. Compton absorption, in which the photon does not give up all energy to a single
electron but reappears as a secondary photon.
3. Pair production process, for energy greater than 1 MeV.
8.1.3. Corpuscular radiation
Electron therapy
Electron beam therapies are available using accelerators.
They are ideal for treating superficial tumors by avoiding irradiation of the underlying
normal tissue; the maximal dose is reached with fall in depth, compared with high-energy
photons (Figure 8.6).

94

High Linear Energy Transfer (high LET) beams like mesons, protons, heavy ions, fast
neutrons, produce more ionization per unit path, releasing energy as a Bragg peak at the
point of depth interest.
Neutrons have a greater (x 3 - 5) biological effect for the same physical dose.

Figure 8.6. Depth dose decrease for electrons compared with photons
8.1.4. Dosimetry
The fundamental quantity, which describes the interaction of radiation with living
matter, is the amount of energy absorbed per unit of mass, called absorbed dose. Types of
doses commonly used in radiation therapy are (Figure 8.7):

Figure 8.7. Types of doses used in radiotherapy

The effectiveness of a physical dose depends by the dose rate per fraction dose, total
dose, and overall time of application.

95

It is important that the tumor dose is relatively homogeneous within the target
volume, because the hot spots of dose cause complications and the minimum dose in the
target volume produces the possibility of tumoral recurrence.
The choice of the dose according to the balance of the probability of cure (tumoral
control) versus the risk of major complication to normal tissue.
The distance separating this two possibilities (probability) represent the therapeutic
gain (Figure 8.8).

Figure 8.8. The therapeutic gain

8.1.5. Brachytherapy
Can deliver high dose to a small tumoral volume, with relative lower doses to the
subjacent normal tissue.
This method require a direct access, interstitial or intracavitary to the target volume and
are used manly in conjunction with teletherapy.
The specific goal is to boost the dose to a central tumoral volume following external
beam irradiation to a larger treatment volume.
The dose decreases rapidly as a distance from the applicator increases.
Historically, natural radium was used as removable sources manually applied.
Nowadays, afterloading techniques are used; as the implantation of the cancer with
radioactive material: 137Cs for LDR machines (Low Dose Rate) and 192Ir for HDR (High
Dose Rate) machines.
Hollow tubes or intracavitary applicators are inserted (Figure 8.9). They receive the
radioactive sources, only when they have currently placed and computer dosimetry is
performed. The main advantage is the absence of the irradiation during the procedure.

96

Figure 8.9. Manchester type applicators for cervical cancer

8.2. Clinical practice of radiotherapy
8.2.1. Radiotherapy alone
Radiotherapy can be used with curative intent for anatomically limited tumors of the
skin, oral cavity, pharynx, larynx, uterine cervix, vagina, prostate, Hodgkin's disease stages
I, II A.
The advantage of the treatment with radiotherapy alone is the preservation of the organ
and/or the function.
The target volume encompasses the tumor with a safety margin around its and the
regional lymph node draining area which is likely to be involved.
The tumoricidal dose should take into account the biological growth characteristics of the
tumor, the size of the target volume and radiosensitivity of the critical normal tissue.
Some tumors such as lymphomas or seminomas are controlled by doses of 40-46Gy;
other need doses of 60-75Gy (e.g. for cancers of the uterine cervix).
8.2.2. Combination of radiotherapy and surgery
Radiotherapy is associated with surgery under the form of:
preoperative irradiation;
postoperative irradiation;
intraoperative radiotherapy (IORT).
RT can control locally the recurrence after surgical excision of the tumor (e.g. breast
and blander cancer).
This effect is due to the different mechanism of failure for the two techniques.
Irradiation failure occurs in bulky masses: surgical resection being limited by the
critical normal tissue, with microscopic disease extending beyond the macroscopic border
of the tumor; this excision of the bulky mass and the radiotherapy can eradicate
microscopic disease; the result is taken in more conservative treatment.

97

Preoperative irradiation with small doses 20 - 40Gy has some theoretical advantage:
reduce the size of the tumor and unresectable tumors may become operable;
the incidence of distant metastases may decrease because fewer viable clonogenic
tumoral cells may be dislodged by surgical maneuvers.
After 50Gy is necessary to wait 3 - 4 weeks to allow the tissue to recover from the
irradiation reactions.
8.2.3. Radiochemotherapy
Combined modality treatment with radiation and drugs is used in the management of
many types of cancer.
Mechanisms were by radiochemotherapy might lead to therapeutic benefit are:
spatial cooperation: chemotherapy can eradicate subclinical metastasis if the
primary tumor is treated effectively by surgery and/or irradiation;
interaction or cooperation between radiation and cytostatic drugs sometimes
called additive or synergistic, or independent cell kill.
The most important remains the therapeutic index as a measure of the damage to a
tumor as compared with that to the critical normal tissue.
The addition of a drug to irradiation will improve the therapeutic index only if cell
killing in the tumoral tissue is increased more than toxicity to normal tissue.
Anticancer drugs may have different effects to increase acute and late radiation
toxicity.
Combined modality treatment is used for different tumor sites: head and neck, nonsmall-cell lung cancer, small-cell lung cancer, esophageal cancer, colorectal and anal canal
cancer, bladder cancer, breast cancer.
To obtain a therapeutic gain we can use two methods:
administration of the drugs which do no provoke toxic effects in the normal critical
tissue, included in the irradiation volume;
introduction of a delay between the two modalities and reduces the cumulative
effect on normal tissue.
Concomitant regimes rise the risk on the normal tissue with the decrease of the
tolerated radiation dose.
Alternating regimes with chemotherapy, one cycle every month and radiotherapy
course is interdigitated between.
START (State-of-the-art) oncology treatment protocols in Europe are available on the
web at www.oncoweb.com.
8.3. Radiation interaction with biological materials
8.3.1. Direct and indirect actions of radiation
The two important mechanism of interaction with biological molecules implies direct
and indirect actions of radiation (Figure 8.10):

98

Figure 8.10. (Hall, 1988) Direct and indirect actions of radiation

The direct effect with release of ionizing energy in the structure of the target
molecule (nucleic acids);
The indirect effect in which the initial energy absorbed by one molecule is
transferred by intermediary radiation products to other molecules.

There is a good correlation between chromosome and chromatid aberrations and DNA
content.
The sequences of processes that take plan in the cells following exposure to ionizing
radiation are 3 main phases:
Induction:
- ionization and excitation;
- initial DNA damage;
Processing:
- fixation / missed repair;
- residual DNA lesion;
Manifestation:
- chromosomal aberration;
- fragment loss, micronuclei;
- cell death.

99

This direct effect is most common for high linear energy transfer (LET) radiation,
indirect action is dominant for sparsely ionizing radiation (e.g. X-ray).
Typical LET value for Co 60 = 0,3 KeV/(, comparing with 14 MeV neutrons =
12 KeV/m.
Relative biological effect (RBE) is the ratio of the doses of 250 KV X-rays and the
testing radiation required for equal biological effect.
Thus, high LET radiation very densely ionizing has a corresponding high RBE; but the
absolute value or RBE depends on the level of biological damage and therefore on the dose
level.
Because cells contain at least 70% water, indirect action involves reactive species
generated from water molecules. These short-lived free radicals with unpaired electrons
interact secondary with biologically important materials: proteins, enzymes, lipids.
Oxygen environment is necessary for the radiobiological effects, prolonging the life
reactive species.
This sensitization is called the Oxygen Enhancement Ratio (OER), being the ratio of
the doses required to reduce survival.
OER increase rapidly as oxygen concentration in tissues increase (OER for mammalian
cells = 3); as LET increase the OER decrease (e.g. for neutrons). Thus, the interest in the
use of tumors with radiation-resistant hypoxic cells has increased.
Stages of radiation action are (Figure 8.11, 8.12):
Primary
radiation

Basic
interaction

Charged
particles

Colisional
processes

Free
radicals
Ions

Chemical
reaction

Altered organic
molecules

Biological
effects

Secondary
radiation

Figure 8.11. The stages of radiation action

Physical stage: activated/excited or ionizing molecules;

Physico-chemical stage - free radicals, free atoms are produced by the interactions
of secondary electrons with water;
Chemical stage - free radical (hydroxyl radicals and peroxides) each other and with
the milieu;
Direct damage accounts for 20 - 30% of radiation damage and indirect effect -70- 80%.
Biological stage represents the sequential response of the organism to the
irradiation.
Approximate duration of the biological stage varies from 10-6 seconds up to many
years - These direct or indirect effects are at random, an important biological principle in
the nature of cell killing. The cell is damaged and loses its reproductive capacity,
becoming sterile (reproductive death).

100

Figure 8.12. Effects of ionizing radiation (Perez, 1984)

8.3.2. The radiobiology of tumors
Some tumors are highly curable with radiotherapy, other not.
The principal methods used for the comparison of the effect of radiation on
experimental tumors are:
Tumor growth delay
Results obtained with different radiation doses are platted as a dose-response curve,
comparing with control tumors.
Tumor control

101

The radiation dose that controls 50% of the tumors (TCD - 50).
Cell survival
Cell kinetic compartments of a tumor can be divided into four compartments
(Figure 8.13):
proliferating cells (P): growth fraction;
resting cells (Go compartment): quiescent cells (Q);
sterile or differentiated compartment;
dead or dying cells.
Some Go may be clonogenic, capable of repopulating a tumor; movement from the Q
to P compartment is called recruitment; only 1% of cells might be clonogenic.
Factors affecting tumor growth rate:

T
potential doubling time - is coming up from Tpot = s

LI

Ts = duration of the S-phase;

= 0,7 - 1;
L1 = labeling index with tritiated thymidine

cell loss factor = 1

Tpot
Td

Tumor doubling time (Td) is determined by:

the cell cycle time (Tc) around 2 days in human tumors;
the growth fraction (GF) around 40%;
the rate of cell loss-high in carcinomas (90%);
potential doubling time ( Tpot 5d);
volume doubling time ( 70d).

Figure 8.13. The tumor cell compartments

102

If the cell time is short, growth fraction is high and tumor grow faster.
Clonogenic assays have formed the basic of cell response studies in tissues.
A surviving fraction can be calculated as the ratio of plating efficiency.
Surviving fraction =

PE treated
PE control

0,02
0,2

= 0,1 or as a percentage 18%.

As outcome of irradiated cells there are many possible paths:

may die - interphase death, but require large doses, excepting the lymphocytes
(< 100 cGy);
may produce aberrant attempts at division;
may stay unable to divide but functional;
may divide once or more before all the progenitors becomes sterile;
may suffer no alterations.
Apoptosis (programmed cell death) is also important.
Normal tissues and tumoral cells in the some tumoral tissue are heterogeneous
exhibiting different degrees of radiosensitivity to damage.
The cell life cycle is essential to understand radiobiological responsiveness.
The cell growth cycle can be divided into four stages beginning with M (mitosis) G1
(gap 1), S (DNA synthesis) and G2 (gap 2); it can identify a G0 period in which, the cells
may not divide.
The method of analyzing the life cycle is the measuring the uptake of H3 thymidine in
the cells synthesizing DNA. Another method is the flow cytometry that quantifies the
percentage of cells in the various stages of the cell cycle, using laser activated fluorescent
dyes bound to cellular DNA.
Generation times ranges from 8 - 30 hours with G1 = 1,5 - 14h; S = 6 - 9h, G2 = 1 - 5h,
M = 0,5 - 1h.
Effects of Radiation on Cell Cycle Progression
The most sensitive phase are said to be the G2 and M phase and the most resistant, the
late S phase. Mitotic index and growth are delayed; the decline of the mitotic index is
followed by a cessation of the increase in cell number. The delay time increases linearly as
the radiation dose increase (up to 8 - 10 Gy) then it flattens out; the cause of the mitotic
delay is G2 block. The cycle is characterized by prolongation of the generation time.
Cell Death - Survival curves
Models of radiation cell killing.
The dose-effect relationship for reproductive death is determined by in vitro colony
plating efficiency assay techniques.
Survival curves plot the fraction of cells surviving radiation against the dose given and
survival is determined by the ability to form colonies (Figure 8.14).

103

Figure 8.14. (Puck and Marcus, 1956) Colony plating efficiency after irradiation
In the case of bacteria, the survival is a constant exponential function of dose; single
target - single hit inactivation.
Survival curves for mammalian cells are commonly sigmoidal in shape approximating
the curves predicted by the single hit, multiple target mode of inactivation (Figure 8.15).

Figure 8.15. The cell survival curve

Survival curves of a cultured tumor cells have a shoulder that indicate as repair of
sublethal or non-lethal and potentially lethal cellular damage.
This is characterized by the extrapolation number, n and the quasi-threshold dose Dq
were Dq = D0 le n (n).
The three parameters D0, Dq and n are related by the expression:
Log e n =

Dq
D0

The dose required to reduce the survival fraction to 37% on the terminal exponential
portion of the curve is known as the D0. This term is related to the slope of the exponential
survival curve: the D0 for mammalian and tumor cells range of 110-240 cGy.
Characteristics of sublethal damage - include repair within 2 - 4 h after irradiation.

104

It has revealed:
general presence of a shoulder;
modifications of slope (and shoulders by radiation with different LET);
Dq is a measure of sublethal damage repair.
Bone marrow stem cells have a smaller Dq (0,6 Gy) comparing with skin (" 4 Gy).
Elkind recovery effect shows that if the dose of radiation is divided into two
fractions and a few hours elapse between fraction, the shoulder will return.
Radiation fractionation schemes must account if or not the fractions size is
sufficient to minimize the shoulders;
If the dose rate is lowered, D0 increase, the slope of the curve becomes less steep.
The survival curve is best described by a linear quadratic model, with the two
components of the survival fraction curve.
S = e- (D + D2)
Total cell kill is the sum of single lethal hit events () and accumulation of sublethal
multi hit events (). The / ratio can be determined this value (20 - 25 Gy) is high for
acutely responding tissue and low for late-responding tissue (2 - 4 Gy).
The cell survival curve in acutely responding tissue has longer initial linear regimes,
while the curves for slowly responding tissue are curvier there is less fractionation effect
in tumors and acute responding tissues, than in the late responding tissues. At least 6 hours
are necessary for repair of accumulated sublethal damage in late effect tissue and sparing
of late injuries may be possible trough the use of doses less than 2 Gy per fraction
(Fletcher in Levitt).
Increasing dose per fraction will result in greater increase of late rather than acute
injury.
8.3.3. The relationship between cell survival and tumor response
Incomplete radiotherapy or/and chemotherapy leads to a temporary tumor regression
followed by recurrence. Re-growth is due to repopulation by surviving clonogenic cells.
The biological factors that influence the response of the normal and neoplastic tissue to
fractionated radiotherapy are summarized in the 4 Rs of Radiotherapy (Withers).
These factors are responsible for the slope of an iso-effect curve.
Repair - refers to the process of restoring of the DNA, has been evidenced by
cellular recovery during the few hours after exposure.
Re-assortment (Redistribution) cells that survive after first dose will tend to be in a
resistant phase (S) of the cell cycle and in a few hours may progress into a more
sensitive phase (G2).
Repopulation - during the course of radiotherapy, some clonogenic cells that
survive may proliferate and repopulate r apidly, thus increase the number of cells
that must be killed. Can be measured after irradiation in vitro with 2 Gy by SF2
(Survival Fraction after 2 Gy).
Re-oxygenation - the cells that survive a first dose will tend to be hypoxic, but after
the oxygen supply may improve, lead to an increased radiosensitivity. Hypoxic
fraction of cells are radioresistant.

105

Some conclusions derived from the study of experimental tumors are:

The tumor-size effect: large tumors are more clonogenic cells and require high
radiation doses for control.
Accelerated repopulation post irradiation.
The tumor-bed effect: growth rate of recurrent tumors is slower than the rate of
untreated tumors of the some size.
Radiosensitivity - is the fifth R.
Is a measure of the susceptibility of cells to radiation injuries.
Radioresistance - is the reciprocal to radiosusceptibility and it is a relative notion,
this term is misused clinically.
Radiocurability - is related to site and extend of tumor, its biological behavior and
host related factors.
Genetic control of radiosensitivity is associated with radioresistance with the raf
oncogene; radiosensitivity in xeroderma pigmentosum in which the radioinduced damage
cannot be repaired are lead to the XRCC 1 gene.
Radiosensitivity are modulated trough epigenetic mechanisms only that after gene
expression.
There is a increasing evidence for gene activation for exposure to low doses of
radiation. Genes that synthesize the fibroblast growth factor (FGF), or tumor necrosis
factor (TNF) are involved in the biological response to radiation (Figure 8.16).
RT

cytokines
TNF, Il-1
TGF
PDGF
FGF

clonogenic cell

radioinduced
ageing

clinical effect
Figure 8.16. The cellular radiation response
Tissue Effects
Proliferative organization of tissues categorizes them in two categories of tissues:
Hierarchical (H-type) tissue (skin, mucosae, bone marrow) with stem-cell
compartment, precursor compartment with proliferating rapidly cells and mature
functional cells.
Flexible (F-type) tissues without a precise separation between the compartments in
which some functional cells have the capacity of renewal. The tissues are slowrenewing (kidney, lung, liver).

106

8.3.4. Adverse reactions of radiotherapy

A. Early complications
Are observed in tissue with a rapid cell turnover or early responding tissues: bone,
skin, mucosa. After a time from irradiation they are reversible depending of the received
dose, shorter treatment tissues are associated with more injury; sometimes consequential
late reactions may occur.
Gastrointestinal tract:
- nausea and vomiting;
- stomatitis, ulcerations, bleeding;
- and/or diarrhea.
Hematopoetic tissue:
- anemia, leukopenia, thrombocytopenia secondary to myelosuppresion.
Reproductive organs:
- temporary or permanent amenorrhea;
- permanent sterility.
B. Late complications
Manifests - month or even years after irradiation; they are not reversible, occurring
after a latent period.
The late responding tissues are: lung, liver, brain, subcutaneous tissue; showing limited
recovery that depends on the size of the initial dose.
The most used scale for reporting normal tissue injury is: RTOG/EORTC and WHO,
clinically oriented and derived from a system for use in medical oncology (Table 8.2).
Grading
HEMATOLOGICAL
Hemoglobin (g/100ml)
Leukocytes (1000/mm3)
Granulocytes (103/mm3)
Platelets (1000/mm3)
Hemorrhage

11.0
4.0
2.0
>100
None

9.5-10.9
3.0-3.9
1.5-1.9
75-99
Petechiae

8.0-9.4
2.0-2.9
1.0-1.4
50-74
Mild
loss

1.25
1.25

1.26-2.5
1.26-2.5

2.6-5
2.6-5

5.1-10
5.1-10

>10
>10

1.25
No change

1.26-2.5
Soreness/
erythema

2.6-5
Erythema, can
eat solids

>10
Alimentation
not possible

Nausea/Vomiting

None

Nausea

Transient
vomiting

Diarrhea

None

Transient
< 2 days

Tolerable
> 2 days

5.1-10
Ulcers;
requires liquid
diet only
Vomiting
requiring
therapy
Intolerable,
requiring
therapy

GASTROINTESTINAL
Bilirubin (ULN)
Transaminases (ULN)
Alkaline
Phosphatase (ULN)
Oral

blood

but

6.5-7.9
1.0-1.9
0.5-0.9
25-49
Gross
loss

blood

<6.5
1.0
<0.5
<25
Debilitating
blood loss

Intractable
vomiting
Hemorrhagic
dehydration

107

RENAL
Blood urea nitrogen or
Blood urea creatinine
(ULN)
Proteinuria (g%)

1.25
No change

1.26-2.5
<0.3

2.6-5
0.3-1.0

5.1-10
>1.0

Hematuria

No change

Microscopic

Gross

Gross + clots

PULMONARY

No change

FEVER WITH DRUG

None
No change
No change

Exertional
dyspnea
Fever
38o-40oC
Bronchospasm
Dry
desquamation,
vesiculation,
pruritus

Dyspnea
at rest
Fever > 40oC

ALLERGIC
CUTANEOUS

Mild
symptoms
Fever
< 38oC
Edema
Erythema

HAIR

No change

Minimal
loss

INFECTION
(specify site)

Non

Minor
infection

CARDIAC
Rhythm

No change

Function

No change

Sinus
tachycardia
> 110 at rest
Asymptomatic
but abnormal
cardiac sign

Pericarditis

No change

Asymptomatic
effusion

NEUROTOXICITY
State of consciousness

Alert

Transient
lethargy

Peripheral

None

Constipation*

None

Paresthesias
and/or
decreased
tendon
reflexes
Mild

PAIN**

None

Mild

hair

Bronchospasm
Moist
desquamation,
ulceration

>10
Nephrotic
syndrome
Obstructive
uropathy
Complete bad
rest required
Fever
with
hypotension
Ana phylaxis
Exfoliative
dermatitis;
necrosis
requiring
surgical
intervention
Non-reversible
alopecia

Moderate,
patchy
alopecia
Moderate
infection

Complete
alopecia, but
reversible
Major
infection

Unifocal PVC,
atrial
arrhythmia
Transient
symptomatic
dysfunction;
no therapy
required
Symptomatic;
no tap required

Multifocal
PVC

Ventricular
tachycardia

Symptomatic
dysfunction
responsive to
therapy

Symptomatic
dysfunction
non-responsive
to therapy

Tamponade;
tap required

Tamponade;
surgery
required

Somnolence
< 50% of
waking hours
Severe
paresthesias
and/or mild
weakness

Somnolence
> 50% of
waking hours
Intolerable
paresthesias
and/or marked
motor loss

Coma

Moderate

Abdominal
distention
Severe

Distention and
vomiting
Intractable

Moderate

Major infection
with
hypotension

Paralysis

ULN = upper limit of normal value for population under study.

* This does not include constipation resultant from narcotics.
** Only treatment-related pain is considered, not disease-related pain. The use of narcotics may be helpful in
grading pain, depending upon the tolerance level of the patient.

Table 8.2. WHO recommended toxicity gradings

108

Definition of early and late of radiation damage are: interactions with surgical
modalities arm edema after mastectomy; radiotherapy, combination chemotherapy,
tolerance dose is less for large volumes. The effect of treatment depends on the volume of
the tumor, age of the patient, fractionation sensitivity, dosimetric aspects, interaction with
surgical treatment and chemotherapy.
Clinical tolerance of an organ depends largely on its organization in separate functional
units, as well as the possibility of surviving clonogenic cells migrating and repopulating
the tissue (skin, intestinal mucosa).
Tolerance is determined by the characteristics of the stem cells and also by the
proliferative structure of the tissues.
Late reactions include tissue necrosis, fistula, the formation of dense fibrotic tissue
(bone necrosis, radiation pneumonitis) and sometimes the second malignancy.
In organs with serial units like spinal cord, inactivation of anyone unit causes loss of
function of the whole organ.
8.3.5. Genetic effects of radiation
The primary considerations concern the impact of an increased mutation rate due to
irradiation over and above that which occurs spontaneously, upon individual descendant
and populations.
Genetic damage is produced by radiation of test explosions, atomic bombings, atomic
industry, X-ray diagnosis and nuclear medicine.
The genetic effect of radiation is different from the somatic effects, in that that there is
no threshold dose for mutational effects, even a small dose may cause chromosomal
damage and aberrations.
It is estimated that 3 rem (0.03 SV) is the average dose that doubles the probability of
genetic effects.
Effects of irradiation on the embryo and fetus.
Classic somatic effects:
1. Lethal, induced by small doses before or immediately after implantation or with
high doses during intrauterine development.
2. Malformations due to exposure during the period of organogenesis.
3. Growth disturbances without malformations induced at all stages of development
but particularly in the latter part of pregnancy.
Large doses of radiation, greater than 250 Gy before 2-3 weeks of gestation
produce abortion or resorption.
Between 4-11 weeks of gestation severe malformations occur.
Between 11-16 weeks skeletal, ocular, genital abnormalities are observed, but
reduced growth, microcephaly and mental retardation are more likely to be
observed; the same situation occurs between 16-20 weeks.
After 30 weeks of gestation only functional disabilities may appear.
The maximum permissible dose to the fetus, from occupational exposure of the mother
should not exceed 0.5 rem (5 mSV).
If the embryo receives a dose above 10 cGy during the first 6 weeks after conception,
an abortion should be performed.

109

The radiation hazards to the embryo and fetus demonstrate the radiosensitivity and
susceptibility to the induction of malformation by radiation.
A particular abnormality may be produced with high incidence at a particular stage, but
not at all form irradiation at other stages. Small head size has been observed following to
an exposure of more than 1 Gy.
Critical periods correspond to the second to sixth week of gestation; irradiation at more
advanced stages produce less obvious and more delayed effects.
Low doses are effective in teratogenesis if applied at the critical time. The incidence of
cancer 40 years following intrauterine exposure to < 0,3 Gy is 3 to 9 times greater.
The amount of acute parental irradiation required to double the spontaneous mutation
rate (doubling dose) is about 2 - 4 SV.
In conclusion irradiation involving women of child bearing age should be restricted to
the ten day following the last menstrual period (Ten day rule); to preclude the possibility of
fertilization having taken place.
8.3.6. Radiation carcinogenesis
Environmental radiation is a known carcinogenic stressor, has been associated with
leukemia and solid tumors of the thyroid, lung, breast, skin (table 8.3). Carcinogenic
potential is related to the energy, dose, and host factors.
An increased incidence of leukemia appeared in the Japanese atom bomb survivors
within 2 - 5 years after exposure, peak rate occurred at 7 - 8 years and steady decline. A
significant relationship between exposure and deaths from multiple myeloma, cancer of the
breast, lung, ovary, urinary bladder, colon has been observed in survivors after latent
periods ranging from 15 to 35 years (UNSCEAR 1988).
Increased incidence of thyroid cancer may occur following either external or internal
exposure of the thyroid gland, the risk being greater for external irradiation during
childhood.
The risk of excessive Radon 222 exposure is lung cancer.
Thorotrast with Thorium 232 has as late effects liver angiosarcoma; oral Radium 226,
228 - osteosarcoma, topical Strontium 90 - lenticular cataracts from eye applicators and
skin burns.
Source of exposure
Exposed population
Types of cancers
Professional X-rays
Radiologists
Skin, leukemia
Contamination neutrons
Nuclear industry
Myeloma, leukemia, lung
Radon
Uranium miners
Lung, sinuses
Diagnostic X-rays
Antepartum pelvimetry
Leukemia
Repeated fluoroscopy
Breast
Therapeutic X-rays
Treatment of benign
Thyroid, skin, breast,
conditions
leukemia
Cobalt 60
Treatment of cervix cancer Leukemia, rectum, bladder
Nuclear weapons
Atomic bomb survivors
Leukemia, breast, lung,
Atmosferic testing
thyroid, myeloma
Table 8.3. Radiation induced cancers

110

8.3.7. Radiation protection

Adequate protection may require a limitation not only of the average dose received by
the population as a whole, but also the accumulated individual dose .
The total dose to gonads and other sensible tissues: bone-marrow, thyroid can be
controlled and reduced to a maximum permissible dose. To provide radiation protection is
necessary a good basic and applied information, education and professional standards,
methods of good medical practice.
The objective should be to keep man's exposure as low as reasonable (ALARA
principle), out yet at the same time not discontinue the use of radiation altogether.
The value of permissible dose from external sources of ionizing radiation, ICRU
Publication 60, 1991: 500 mSV/year.
8.4. Clinical radiobiology
8.4.1. Basic Clinical Parameters
The interplay between radiocurability and tolerance in radiotherapy include:
Tumor control vs. dose
Time factor
Normal tissue tolerance
The ultimate experimental system is the cancer patient.
Tumor dose
- Gross cancer - doses giving a high control rate are correlated with increasing
volume of cancer (e.g. 70 - 80 Gy control 65% of 2 - 3 cm tumors);
- Subclinical disease - consists of aggregates of cancer cells that cannot be seen
or felt; 50 Gy eradicate 90% of the occult deposits.
- Postoperative setting - postoperatively, for the prevention of recurrences is
necessary to irradiate as soon as possible.
The basic dosimetric data used in treatment are:
the dose calibration data reference point in the field;
dose distribution data.
Measurement techniques are made with ionization chambers, electrometers or
thermoluminiscent dosimeters (LIF) in water phantom.
Dose optimization can be made with:
small entrance and exit dose;
small side scattering dose;
small differential tissue absorption;
optimal homogenous target dose;
small integral dose: optimal dose to the target with a minimum dose around it.
In seeking maximum application of treatment planning, we should keep in mind
several factors that will affect its impact on the out come radiation therapy.

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8.4.2. Clinical use of radiotherapy

Prescribed radiation doses should be carefully planned primarily for patients treated
with high doses of irradiation delivered with a curative aim and in selected patients
receiving special palliative therapy who requires complex treatment techniques or high
irradiation doses.
Techniques of Irradiation
For the patients treated with isocentric technique or multiple fields or using special
beam - modifying devices (e. g. wedges), the contribution of treatment planning with
computed tomography (CT) used to optimize the dose distribution may be significant.
Isodose curves may be superimposed on grayscale image of CT scans for better
appreciation of the dose to normal tissue. If patients are to be treated with single or
anteroposterior-posteroanterior or lateral opposing portals, the gain from CT - based
treatment planning will be minimal.
In patients treated with brachytherapy, treatment planning will document accurately the
placement of the radioactive sources and the dose distributions in the treatment volume in
several planes.
Field size
Even if large portals are used, the need to determine the target volume is critical. As
the field size is reduced, the demands for accurate treatment planning and
repositioning/immobilization techniques increase even more. With the shrinking field
technique an adequate tumor dose has presumably been given to the larger portals to
eradicate the microextensions of the disease in that volume.
Beam Quality
Depending on whether photons or electrons or high linear energy transfer (LET)
particles, such as p mesons or protons will be used, it is critical to determine the target
volume and the dose distributions related to the physical characteristics of the beams.
Electrons have a definite range in tissue and the depth at which a certain dose is required
must be determined accurately in selecting the electron beam energy. Also, high LET
particles such as p mesons and protons have a specified depth at which the maximum dose
can be delivered, again requiring an extremely accurate definition of tumor volume.
The absorption of radiation in tissue is represented by isodose curves, that is, surfaces
which connects points receiving equal doses of radiation (Figure 8.17) (Radiotherapy Isodose Charts). The shape of the isodose curves is dependent on five factors:
a.the photon energy of the treatment beam;
b. the radiation source size and the collimator parameters (width and length);
c. the distance between the X-ray source and the patient's skin (focus - skin distance
FSD);
d. the presence of a filter (e.g. wedge-filter) and
e. the relative exposure time.

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Figure 8.17. Different isodose charts for different energies

The depth below the surface of maximum dose is mainly dependent on photon energy.
For each treatment machine exists a large family of isodoses curves representing all
possible combinations of the parameters.
Methods of beam modification
Within the tumor volume the given dose should be as high as is possible compatible
with clinical requirements and technical possibilities.
There are 2 types of possibilities:
beam direction techniques
Isocentric mounting machine in which the rotation axis of the gantry, the floor and the
collimator system all meet at the isocenter. The treatment beam will always be centered on
the tumor center. This facilitates the alignment of the fields as well allowing rotation or
area therapy (Figure 8.18).

Figure 8.18. Conventional uniform beam radiotherapy

beam modifiers
- Flattening filters for photon and for electrons (bolus)
- External beam modifiers a wedge filters to achieve a uniform dose to a tumor
on one side of the body without treating from the other side
- Tissue compensators for tissue obliquity
- Beam shaping blocks, for protecting normal organs

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Fractionation
Conventional: 1,8 - 2 Gy per fraction, 5 days per week;
Unconventional
- hyper-fractionation - fraction smaller than 2 Gy are given 2 - 3 times daily to
achieve a high control rate, acute effects are stronger, but not late effects;
- accelerated fractionation and accelerated hyper-fractionation - give to the
therapeutic ratio decrease the dose per fraction and shortening of overall
treatment time.
Clinical treatment planning
Comes before physical planning; first step is to decide the sequence of radiotherapy or
surgery.
The procedures involved in effective administration of radiation therapy comprise a
complex, closely integrated operation that should include the following:
1. Knowledge of the natural history and pathologic characteristics of the tumor.
2. Adequate evaluation of the patient and staging procedures to determine the full
extent of the tumors.
3. Definition of treatment strategy, to select the best method or combinations to be
applied, which may depend on the stage, type of tumor, and the routes of spread.
4. Treatment planning, with accurate definition of the target volume and radiation
ports.
5. Treatment isodose (volumetric) computations to determine the distribution of
irradiation within the volume of interest.
6. Accurate and reproducible repositioning and immobilization techniques for daily
treatment delivery.
7. Applicable dosimetry, portal localization, and verification procedures, to ensure
quality control throughout the therapeutic process.
8. Periodic evaluation of the patient during and after therapy, to assess the effects of
treatment on the tumor and the patient tolerance.
Factors limiting radiotherapy
1. Clinical Factors
Inadequate appraisal of the full extent of the tumor
Clinically unrecognized distant metastases at the time of initial treatment
2. Physical and Technical Factors
Inaccurate definition of target volume
Inadequate treatment planning
Unreliable patient repositioning and immobilization techniques
Lack of adequate verification - dosimetry techniques
3. Biologic Factors
Initial cell burden because small tumors are more easily eradicated than large
tumors
Hypoxic cell subpopulations, which must require greater doses of irradiation
Repair of sublethal or potentially lethal damage between fractions
Variation in radiosensitivity throughout cell proliferative cycle
Lack of knowledge of human cell kinetics and biologic equivalents for various
dose rate - fractionation regiments
Limited tolerance of normal tissue

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4. Less well - defined factors include the general condition, nutritional status, other
disease, and immune response (Perez-Purdy).
Anatomic information including the size and position of tumor volume and normal
surrounding structure can be determined by cross-sectional imaging methods and then
transferred to the Dose Computer Planning.
These methods are:
simulator radiography with skin markers and contrast media;
computed axial tomography;
magnetic resonance imaging;
The simulator duplicates all the mechanical features of the treatment apparatus,
determining and defining the treatment volume, field localization, beam orientation,
custom field, blocking and verification simulator of the plan.
Radiation planning systems have CT capability incorporated in their software
programs, provide correction of homogenities in the medium and photon dose calculations.
New approaches are 3D RTP systems.
Quality assurance - Treatment planning
High quality planning and delivery including verification, supportive care during
treatment will contribute to enhance the efficacy of irradiation in the treatment of patients
with cancer.
Overwhelming tumor cell resistance
Combined radiotherapy and chemotherapy by:
- spatial cooperation;
- independent cell kill.
Hyperthermia enhance the effects of radiotherapy by direct cell killing and
radiosensitivization.
Targeted radiotherapy is a irradiation by means of radionuclides that are selectively
delivered by tumor seeking molecules; targeting agents may be: monoclonal
antibodies, growth factors, tumor associated proteins, coupled with emitters: (131I,
90
Y).
Photodynamic therapy involves the interactions between a photosensitizer
(haematoporphirin) and light of a suitable (400 nm) wavelength, producing free
radicals and singlet oxygen leading to destruction of the vasculature.
Particle beams in radiotherapy: high-LET radiations are more effective per Gray.
Overcoming hypoxic cell resistance:
- hyperbaric oxygen;
- hypoxic cell radiosensitizer by electron-affinic compounds (misonidasole,
etamizole);
- pharmacological modifications of tumor blood flow.
8.4.3. General management and survey of the patient treated with radiotherapy
For almost all patients who require radiotherapy there will be some side effects. It is
the radiation oncologist's responsibility to minimize the morbidity of irradiation, avoiding
normal critical organs or minimizing the dose for these areas (Table 8.4).

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Organ
Brain (whole)
Spinal cord (10cm)
Lens
Lung (whole)
Heart (whole)
Liver (whole)
Kidney (whole)
Bladder
Mouth, salivary glands
Alimentary canal

Tolerance (Gy)
55
45
0,5 1
20 30
40
25
20
40 60
30 40
30 45

Pituitary gland
Thyroid
Testis
Ovary
Bone marrow (segmental)
Bone and cartilage
Skin

45
45
15
12
30
55 60
50 60

Adverse effects (subacute or late)

Infection, necrosis
Transverse myelitis
Cataract
Pneumonitis, fibrosis
Paricarditis, myocardopathy
Hepatitis
Nephritis, nephrosclerosis
Cystitis, ulceration, fibrosis
Mucositis, loss of taste, xerostomia
Mucositis, strictures, ulceration,
fistulae (55Gy)
Hypopituitarism
Hypothyroidy
Sterility
Sterility
Aplasia
Necrosis, fracture
Epithelitis, atrophy, fibrosis,
ulceration

Table 8.4. The radiation tolerance and potential toxicity (Feldmeier, 1993)
With the exception of total body irradiation (TBI), radiotherapy is a local therapy and
side effects are confined to the organs included in the field of treatment.
Concomitant chemotherapy enhances such reactions.
The recall phenomenon refers to a process in which a radio-induced reaction in a
previously irradiation area, is enhanced or repeated when doxorubicin or actinomycin is
given weeks or months after radiotherapy.
Systemic effects:
Symptoms of malaise, fatigue, depression, are frequently linked to the psychological
effects of coping with cancer.
Skin:
Skin reactions are less common in high-energy photon beam treatment with skinsparing effect.
Acute reactions appear after 35 - 40 Gy, consisting in erythema, dry desquamation,
pruritus and moist desquamation. They respond to keeping this area clean and dry; severe
pruritus or moist desquamation benefit from topical corticosteroids. Use of any cosmetic
lotions, deodorants is forbidden; also, patients should protect irradiated areas from the sun
and heat.
Hair loss occurs at 15 Gy but is transient with doses ( 40 Gy and permanent after
high doses.
Hyperpigmentation, telangiectasies and fibrosis appear after doses exceeding 45 Gy.

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Oral cavity and pharynx

Acute phase is associated with mucosites, pain, xerostomia and dental caries in the
chronic phase.
Before the treatment a dentist should examine the patients; extractions should be
performed at 2 weeks before irradiation.
Prophylaxis consists in avoiding the use of alcohol, tobacco, spicy foods and a careful
oral hygiene with gargle with a solution of salt and baking soda, and daily fluoride
applications.
Xerostomia can be overcome by artificial saliva preparations and sialogogues
(pilocarpine 5 mg 3/d).
Oral candidiasis is treated with oral nystatin or ketoconazole.
Gastrointestinal tract
Esophagus
After 30 - 40 Gy esophagitis develops, with pain on swallowing. Treatment consists in
a soft diet, antacids and xylocaine 2% before meals.
Nausea and vomiting are controlled by antiemetic drugs.
Small Intestine
In the case of including a significant portion of the small bowel in the field of radiation,
enteritis appears, manifested by diarrhea, pain, anorexia is common.
The treatment consists in bland diet, Imodium, Codein, antiflatulent agents
(dimethicon), aspirin.
Late effects include malabsorption, obstructions through adhesions, bleeding, fistulas
at doses > 50 Gy. Nutrition management is crucial (Table 8.5).
Colon and Rectum
The most common injury after pelvic irradiation is the procto-sigmoiditis with bleeding
and tenesmus.
Symptomatic treatment may give relief.
Anal area
This area is very sensible to radiation; cleaning and drying with corticosteroid anesthetic cream may help.
Liver
If the liver is irradiated with 25 - 30 Gy, associated with chemotherapy, appear signs of
acute hepatitis with nausea, fever.
Veno-occlusive disease is observed in the cases with total body irradiation for the
conditioning in bone marrow transplantation.

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Irradiated Area
HEAD, NECK

UPPER
ABDOMEN

PELVIS,
LOWER
ABDOMEN

Problems
Dry mouth
Change in or
loss of taste
Mucositis
Nausea
(occasional)
Indigestion
(occasional)

Foods Encouraged
Supplementary feedings
Small frequent meals
Bland foods
Increased fluid intake
Foods served at room
temperature
Chewing sugar-free gum
or sucking hard candy to
aid dry mouth
Use a straw if mucositis
is present
Nausea,
Carbonated drinks
Vomiting
Small frequent meals
A light meal 11/22 hours
before treatment
Cold, nonodorous foods
Cold, clear liquids
Relaxation, chewing
foods well, eating slowly
Dry crackers or toast
after rest or sleep
Diarrhea,
Low residue diet
Malabsorption Small frequent meals
High protein diet
High fluid intake
Low residue or elemental
supplement to increase
protein calories

Foods Discouraged
Alcohol
Carbonated beverages
Extremely hot or cold
foods
Spicy or highly
seasoned foods
Acidic foods
Foods with sharp,
rough edges
Sweets
Gas-forming foods
Alcohol
Fried, greasy foods
Foods with high fat
content
Cooked foods with
strong odor
Not eating for long
periods of time

Alcohol
Foods with
roughage
Spicy or highly
seasoned foods
Gas-forming foods
Foods with a high fat
content
Milk, milk products,
milk-based formulas
unless well tolerated

Table 8.5. Nutritional Management with Radiotherapy

Endocrine system
Pituitary gland
Irradiation of the pituitary gland may result in children, decreased growth hormone
levels, and for the adult increased prolactin and thyroid-stimulating hormone and cortisol.
Thyroid
Irradiation of the neck with doses higher than 25 Gy, may develop hypothyroidism.

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Lung
After irradiation of the lung: > 20 Gy to both or > 40 Gy to 1/3 of one lung appear
radiation pneumonitis with cough, fever, dispnea; ground-glass image in the irradiation
area. Chronic changes include fibrosis mimicking the radiation fields. Antibiotics and
steroids may be helpful.
Cardiovascular system
Heart
With > 40 Gy pericarditis may result, after 3 - 6 months, effusions can occur.
Constrictive pericarditis and cardiac tamponade require pericardectomy. Steroids and nonsteroidal anti-inflammatory drugs can be used.
Only the careful planning in the treatment of lung cancer or mantle fields in lymphoma
can avoid pericarditis or fibrosis of the myocardium.
Vascular system
Radiation damage to the arteries is manifested as accelerated atherosclerosis; are
observed at high-dose junctions of the fields.
Genitourinary system
Bladder
During pelvic irradiation for neoplasm of the uterus, rectum, prostate, bladder, after
more than 30 Gy, appear acute radiation cystitis with dysuria, hematuria, polakyuria.
Any infections should be treated before irradiation; in the case of negative culture:
fluids, diet, anti-inflammatory and antispastic drugs.
After > 60 Gy chronic cystitis with fibrosis, hematuria, and fistula occur; if symptoms
cannot be controlled, treatment is urinary diversion.
Kidney
If the kidney is irradiated with doses > 20 Gy, might appear radiation nephritis with
headache, nausea, anemia, hypertension, elevated creatinine and blood urea nitrogen.
Treatment is prophylactic - with renal shielding in the case of abdominal bath
radiotherapy.
Ovaries and testes
Are the most sensible organs and even low doses 150 - 300 cGy produce amenorrhea,
with higher doses, 8 - 10 Gy, infertility occurs.
Vagina
After external radiotherapy combined with intracavitary brachyterapy with doses
exceeding 50 Gy, fibrosis and dyspareunia appear.

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Central Nervous System

Brain
During cranial irradiation symptoms of increased pressure: headache, vomiting and
papilledema can be prevented with dexamethasone (4 mg 4/d).
For patients (children), treated with higher doses than 20 Gy, combined with
intrathecal chemotherapy for leukemia or non-Hodgkin lymphomas, appears a somnolence
syndrome.
The most serious chronic effect is brain necrosis with doses greater than 50 Gy; the
differential diagnosis between tumor recurrence and radiation necrosis is possible only
with PET (positron emission tomography).
Spinal cord
A few months after irradiation of the cervical cord in the case of a nasopharyngeal
carcinoma, with spinal cord doses of more than 40 Gy can appear electric shock-like
sensations into extremities on neck flexion, called Lhermitte sign.
Radiation myelopathy occurs months or years after doses higher than 50 Gy, with
paresthesias, progressive motor and sensorial paralysis.
Eye
1000 cGy produce lenticular cataracts, especially if given in a single dose; acute
kerato-conjunctivitis should be treated with steroids and antibiotics.
Blood
Bone marrow suppression can be observed in the cases of irradiation with large fields,
associated with chemotherapy.
Leukopenia, thrombocytopenia and deep anemia may need the interruption of the
treatment.
The use of G-CSF (granulocyte-colony stimulating factor) may decrease the severity of
suppression.
Bone
In the case of the children who have received > 20 Gy to bone or bone-growth
cartilage, shortening of the bone might be observed. The most serious complication of
bone irradiation is osteonecrosis with doses higher than 60 Gy or less in combination with
chemotherapy.
The most common localization is the mandible, which is included in fields for head and
neck cancers and is prone to dental extractions and infections.
Extractions after irradiation of the mandible should be avoided, or it is possible only
with antibiotic coverage.
The patients may be given instructions concerning the treatment and the possible
complications; informed consent before radiotherapy is necessary.

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The principles of rehabilitation in oncology

Rehabilitation of the cancer patient should:
1. Help the patient to develop and retain his fullest physical, psychological, social,
vocational and educational potential within the limits imposed by the disease and
consistent with treatment plan.
2. Begin at diagnosis and continue through all the phases of the disease.
3. Adopt a holistic approach.
4. Be achieved through the combined efforts of a multidisciplinary team.
5. Include the patient and nearest relative in this team.
6. Adopt a goal-oriented approach, which should be assessed and addressed on a
continuing basis.
7. Include education, which is a major component of the rehabilitative process. This
concerns not only health professional but also the general public.
Summary
Radiation oncology represents the branch of medicine concerned with application of
radiation for treatment of neoplastic disease. Radiotherapy, like surgery, is a loco-regional
therapeutical mean. This application requieres not only a sound knowledge of medicine
and oncology but also expertise in the principles of radiation physics and radiation biology.
In most countries certification for practice of oncology requires 3 to 5 years of
prostgraduate training following medical scool and intership. This training generally
occurs in university-affiliated departments with emphasis not only on clinical aspects of
radiation oncology but also on reserch and teaching.

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SECTION 9
SYSTEMIC THERAPIES IN CANCER

Cancer spreads throughout the body shortly after the tumor cells develop the ability to
invade blood and lymph vessels. Such spread may be overt, in the form of visible
metastases, or undetectable, in the form of micrometastases. A variety of approaches are
used to treat cancer that has spread beyond the regional application of surgery and
radiation therapy, including chemotherapy, hormone therapy, and immunotherapy using
biologic response modifiers.
Systemic Therapies
Some malignancies, such as leukemia, lymphomas and other aggressive solid tumors,
which metastasize before they have been diagnosed, not allow surgical excision or
radiotherapy.
Systemic therapy comprises drug therapy with cytotoxic or hormonal agents and
immunotherapy with biologic response modifies.
I.

CHEMOTHERAPY

Chemotherapy is the treatment of cancer by chemical agents that kill rapidly growing
cells. When cancer cells are rapidly dividing, they are particularly sensitive to
chemotherapy; those cancers that are the most rapidly growing (Burkitt's lymphoma, acute
leukemia, germ cell cancer, and several others) may be cured by chemotherapy in many
cases. Most chemotherapy acts by inhibiting the synthesis of deoxyribonucleic acid
(DNA), the cellular genetic material.
Tumor kinetics
The rate of growth of a tumor is a reflection of the proportion of actively dividing
cells (the growth fraction), the length of the cell cycle (doubling time) and the rate of the
cell loss. Variations of these three factors are responsible for the variabale rates of cell loss.
Variations in these three factors are responsible for the variable rates of tumor growth
observed among metastatic and primary tumors of the same histology.
Tumor characteristically exhibit a sigmoid- shaped Gompertzian growth curve, in
wich tumor doubling time varies with tumor size.
Tumor grow most rapidly at small tumor volumes. As tumors become larger, growth
slows based on a complex process dependent on cell loss and tumor blood and oxigen
supply.
In order to have the best chance for cure, chemotherapy must be given that can be
achieve a fractional cell kill in a logaritmic fashion (ie, 1-log- kills is 90% of cells) From
these concepts, chemotherapy models have been developed utilizing alternating non-crossresistant therapies, induction-intensification approaches and adjuvant chemotherapy.
Chemotherapeutic agents are divided into groups, based on the mode of action and on
the phase of the cell cycle in which the drug is active. Regardless of the mechanism or cell

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cycle phase of a drug's action, however, it is always the rapidly dividing cells that are most
sensitive. Some chemotherapeutic agents are reported to be most active during a particular
phase of the cycle, while others appear to act relatively independently of a specific cycle
phase. Accordingly, drugs are classified as being cell cycle (phase)-specific or cell cycle
(phase)-nonspecific in action.
This classification, however, should not be considered absolute, since the precise
mechanism of some agents is not known and others act by more than one mechanism.
Chemotherapeutic agents, sometimes called cytotoxic agents because they kill cells, also
produce toxic side effects on rapidly dividing host tissues, such as bone marrow and
intestinal mucosa.
Classification of cancer chemotherapics
Just as bacteria may develop resistance to antibiotics, cancer cells may become
resistant to chemotherapeutic agents. Using several drugs at the same time (combination
chemotherapy) is one way to minimise such resistance. Even when cancer is not curable, it
is often possible to provide palliation for months or even years.

1.
2.
3.
4.
4.
5.
7.

Pharmacologic Classification
Alkylating agents
Antibiotics
Antimetabolites
Plant alkaloids
Miscellaneous
Hormones
Biologic response modifiers

Classification of cytostatic drugs:

1. Alkylating agents
1.1. Nitrogen mustards - Mecloretamina
- Clorambucil
- Melfalan, Estramustin
1.2. oxazofosforine: - Ciclofosfamida, Ifosfamida
1.3 etilen-amine:
- Trietilenthiofosfamid (Thiotepa)
1.4. alkilsulfonats: - Busulfan
2. Pseudoalkilating agents :
2.1. purine analogues: Dacarbazine ( DTIC), Temozolomid
2.2. nitrozureas: BCNU, CCNU, Metil-CCNU, ACNU, Fotemustina, Streptozotocin
2.3. Platinum agents: Cisplatin (C-DDP), Carboplatin, Oxaliplatin
3. Vegetal cytostatics
Spindle cell drugs:
3.1. Vinca alkaloid: Vincristin, Vinblastin Vindesin, Vinorelbin, Vinzolidin
3.2. Epipodophylltoxins: Etoposid, Tenoposid ( VM-26)
3.3. Taxanes: Paclitaxel ( Taxol), Docetaxel ( Taxotere)
Camptothecin analogues (topoizomerase I inhibitors): Irinotecan (CPT-11),
Topotecan

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4. Antimetabolites:
4.1. folic acid antagonists: Metotrexat, Ralitrexed, Trimitrexat, Edatrexat
Piritrexim, Lometroxol
4.2. purines analogues: 6- Tioguanin, 6- Mercaptopurin, Azatioprin,
Pentostatin, Fludarabin fosfat, Allopurinol,
Cladribin
4.3. pirimidins analogues: Citozinarabinozin, 5-Azacitidin,
Fluoropirimidine: - 5-Fluorouracil.
Uracil-ftorafur
Floxuridin
Gemcitabin.
5. Antitumor antibiotics:
5.1. transcriptions antibiotics: Dactinomicin ( Actinomycin D)
5.2. anthracyclyclines and anthracylyclines analogue: Doxorubicin, Daunorubicin,
Epirubicin, Idarubicin, Aclarubicin, Pirarubicin, Zororubicin, Mitoxantron,
Menogaril.
5.3. antibiotics partial alkylating: Mitomicin C
5.4. antibiotics radiomimetics: Bleomicin
6. Miscellaneous chemotherapeutic agents: Hexametilmelamine, Hidroxiureea,
L- Asparaginase, Mitotan (Op-DDP), Procarbazin
Chemotherapeutic agents classified by mechanism of action
Alkylating Agents
These agents form highly reactive electrophiles (positively charged compounds),
which interact with nucleophilic (electron-rich) groups such as amino, carboxyl,
phosphate, or sulfhydryl groups, thus forming a covalent bond. One of the most Important
interactions is the alkylation of the 7-nitrogen of the purine base guanine of DNA, which is
highly nucleophilic (Figure 9.1). If this same reaction occurs to adjacent guanine, a crosslinking of DNA will result. This appears to be the major effect of these agents.

Figure 9.1. The cell cycle activity for anticancer drugs

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These alkylating agents are divided into three main subclassifications: classic
alkylators, nitrosoureas, and miscellaneous DNA binding agents.
The alkylating agents impair cell function by forming covalent bonds to the amino,
carboxyl, sulfhydryl, and phosphate groups in biologically important molecules. The most
important site of alkylation is on DNA, (NA, and proteins. The electron-rich nitrogen at
the 7 position of guanine in DNA is particularly susceptible to alkylation.
Alkylating agents depend on cell proliferation for activity but are not cell cycle phasespecific. A fixed percentage of cells are killed at a given dose. Tumor resistance probably
occurs through efficient glutathione conjugation or by enhanced DNA repair mechanisms.
The various alkylating agents are classified according to their chemical structures and
mechanisms of covalent binding.
Classic alkylating agents
Nitrogen mustards
The nitrogen mustards are powerful local vesicants. The metabolites of these
compounds are highly reactive in aqueous solution, in which they are rapidly taken up by
body tissues. The hematopoietic system is especially susceptible to these compounds.
Mechlorethamine (nitrogen mustard [Mustargen] is primarily used today in
combination therapy for Hodgkin's disease, but it is also efficacious in non-Hodgkin's
lymphomas (NHL), chronic leukemias, and some solid tumors. Mechiorethamine is given
by IV infusion (0.4 mg/kg ideal body weight). It is rapidly metabolized to a reactive
carbonium ion and chloro-ethyl alkylating groups. Inactive metabolites are excreted in the
urine. Severe nausea and vomiting can be dose limiting; therefore, the patient should
always be premedicated with antiemetics. Since the compound is a powerful vesicant,
utmost care should be taken to prevent extravasation.
Chlorambucil (Leukeran), an aromatic derivative of mechlorethamine is primarily
used for the treatment of chronic lymphocytic leukemia (CLL). It is also useful in
Hodgkin's disease, indolent lymphomas, and Waldenstroms macroglobulinemia. It has a
reliable absorption in the GI tract and is given orally at a dose of 0.1-0.2 mg/kg for 3-6
weeks as required. The dosage must carefully be adjusted to the patient's response and
should be reduced as soon as there is a decline in the leukocyte count. Intermittent
biweekly or monthly pulse therapy has also been used.
Cyclophosphamide (Cytoxan, Neosar) is a stable, inactive compound formed as a
cyclic phosphamide ester of mechlorethamine. It is used as a single agent and in
combination therapy for a wide variety of neoplasms. It can be given both orally and
intravenously. Dosing regimens are numerous and variable, depending on the malignancy,
patient response, and other therapy. Cyclophosphamide is generally given as a large IV
dose divided over several days, but it may also be scheduled with relatively small doses
given more frequently on a continuous basis. High-dose cyclophosphamide (up to
120mg/kg) is also used as part of combination chemotherapy with bone marrow
transplantation (BMT).

125

Cyclophosphamide must be activated by the hepatic cytochrome P450 microsomal

oxidase system. In the liver, cyclophosphamide is converted into two intermediate
products, 4-hydroxycyclophosphamide and aldophosphamide, which together are in steady
state. 4-Hydroxycyclophosphamide cat' be further converted by the liver to nontoxic
metabolites that are excreted by the kidneys. In the tissues, aldophosphamide is
nonenzymatically converted to the alkylating phosphoramide mustard and acrolein.
Ifosfamide (Ifex), a structural analog of cyclophosphamide, is currently approved for
third-line combination chemotherapy of germ-cell testicular cancer. A favorable response
rate (20%-40%) has also been observed in soft-tissue sarcoma. Ifosfamide produces a
better response than cyclophosphamide in sarcoma, and dose intensification can be
achieved more readily with ifosfamide. It is also highly effective in combination salvage
regimens in NHL. Ifosfamide may have potential uses in the leukemias, as well as in
NSCLC and ovarian and breast cancers.
Ifosfamide is given at a dose of 1.2 g/m2/d via slow IV infusion for 5 consecutive
days. Treatment is repeated every 3 weeks after hematologic recovery. To prevent bladder
toxicity, aggressive hydration with at least 2 L/d of fluid should be given during therapy. In
addition, mesna (Mesnex), a sulfhlydryl-containing compound that actively binds to
acrolein, should be given for uroprotection. Lethargy, somnolence, and confusion are seen
with higher doses of ifosfamide. CNS toxicity appears to be increased by hepatic and renal
dysfunction.
Melphalan (Alkeran) is a nitrogen mustard developed from the amino acid
L-phenylalanine. It is a bifunctional alkylator and causes interstrand, intrastrand, and
DNA-protein cross-links. Melphalan has activity in multiple myeloma, and is usually used
in combination with prednisone or other alkylating agents. It is also used in ovarian cancer
and as adjuvant therapy in breast cancer. In addition, melphalan is utilized in regional limb
perfusion of nonresectable malignant melanoma, with favorable responses. IV preparations
of melphalan have been used in sarcomas, and high doses have been given as part of
combination therapy with BMT for refractory malignancies.
Melphalan is given orally; however, investigational IV preparations are available. The
usual oral dose is 6 mg/d (3 tablets). Melphalan is poorly absorbed when taken with food
and therefore should be given on an empty stomach. Absorption is variable, with a
bioavailability of 30-50%. The majority of the drug is cleared in the feces, with only 1530% excreted by the kidneys. If the patient has moderate to severe renal dysfunction dose
reduction up to 50% should be considered.
Renal toxicity is the dose-limiting side effect, whereas the other nitrosoureas are
limited by a dose-dependent myelosuppression.
Carmustine (BCNU [BiCNU]) is used in a variety of tumors. It is given in a single
IV dose of l50-200mg/m2 over 1-2 hours every 6 weeks. This dose may also be divided
into daily injections of 75-100 mg/m2 successive days. Repeat courses are given after
hematologic recovery', which can be delayed. Local irritation can be seen with infusion
and can be relieved with ice applied at the IV site. BCNU also induces nausea and
vomiting and should be given with antiemetics.

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Gliadel is a new drug delivery system of carmustine used as an adjuvant to surgery to

prolong survival in recurrent glioblastoma multiforme. It is a dime-size wafer consisting of
polifeprosan 20, a biodegradable polyanhydride co-polymer, and carmustine in an 80:20
molar ratio, respectively. Up to eight wafers are placed in the brain cavity created by tumor
removal, and this is followed in 3 weeks by radiation therapy to the brain. Side effects are
minimal and include fever, pain, and abnormal healing.
Lomustine (CCNU [CeeNU]) has antitumor activity similar to that of BCNU. CCNU
is more lipophilic than BCNU and crosses the blood-brain barrier to a greater degree. It is
given as a single oral dose of 130 mg/m2 every 6 weeks. The course is repeated after
hematologic recovery. Toxicities are similar to those of BCNU. Delayed nephrotoxicity
has been reported.
Streptozocin (Zanosar) is a naturally occurring glycosylated methylnitrosurea
produced by Streptomyces achrornagenes, and has both antibacterial and antitumor
activity. The glucose moiety in streptozocin is not present in the other nitrosoureas, and
this may contribute to the reduced myelotoxicity and tumor specificity seen with this
agent. Streptozocin is taken up into B-cells of the islet of Langerhans, which results in
significant activity in pancreatic is let-cell tumors.
The dose-limiting toxicity is renal damage, which can be severe and even fatal. Renal
function should be monitored before, during, and after each course of streptozocin.
Proteinuria should be monitored with a routine urinalysis in patients with preexisting renal
disease. Variations in blood glucose levels also occur and these levels should be followed
frequently.
Platinum agents - Cisplatin (Platinol) is an inorganic heavy metal complex that has
activity typical of a cell cycle-phase-nonspecific alkylating agent. The compound produces
intrastrand and interstrand DNA cross-links and forms DNA adducts, thereby inhibiting
the synthesis of DNA, RNA, and proteins.
Cisplatin is given at a dose of 50 mg/m2 IV or more every 3 weeks or 20mg/m2 IV
daily for 4-5 days every 3-4 weeks. For testicular cancer, cisplatin is given at 20 mg/m2 IV
daily for 5 days with combination therapy every 3 weeks. For ovarian cancer, it is given as
50 mg/m2 IV with combination therapy every 3 weeks, and for bladder cancer, as
50-70mg/m2 IV every 3-4 weeks. Cisplatin is 90% protein bound, and it is widely
distributed, except in the CNS. The drug is excreted in the urine.
Cisplatin has also been administered via intraarterial infusion in a variety of
malignancies. Higher doses and longer infusion times have been achieved; however, a
therapeutic advantage has not been convincingly established. Cisplatin has also been
shown to be an effective radiosensitizer, improving the response to radiotherapy.
The dose-limiting toxicity is cumulative renal damage. This can be severe, with a
maximal effect on renal function 10-20 days after therapy. Nephrotoxicity can be reduced
by providing liberal hydration and mannitol diuresis with therapy. Platinum also causes
potassium, magnesium, calcium, and phosphate wasting. Doses should be reduced
according to creatinine clearance, and the drug is contraindicated in a patient with a
creatinine clearance < 60mg/ml. Cisplatin is highly emetogenic, producing acute and
delayed nausea and vomiting, which can last up to 5 days. An effective antiemetic regimen
should be given with cisplatin chemotherapy.

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Both cyclophosphamide and chlorambucil are orally bioavailable and are used both
intravenously and by mouth; melphalan and HN2 because of either variable bioavailability
or chemical reactivity are best utilized by the intravenous route. Except for the requirement
for hepatic metabolism of cyclophosphamide which prolongs its primary elimination as
well as the disappearance of its metabolites ( ~ 8h), the elimination of the alkylating agents
is rapid (< 2 hours) in the blood owing to chemical decomposition.
The toxicity of alkylating agents is primarily hematopoietic. Some alkylating agents
have more prominent effects on granulocytes (NN2); with other agents, platelet toxicity
may be more pronounced (melphalan) although granulocytopenia occurs often;
hematologic toxicity is most frequently observed 8 to 14 days after drug administration. In
addition to hematologic toxicity, the cyclophosphamide metabolite acrolein can irritate the
bladder mucosa, requiring strict attention to hydration and urine flow for its safe use; and
ifosfamide metabolites, in addition to irritating the bladder, may produce renal tubular
injury. All of the alkylating agents can produce alopecia, nausea, and vomiting, as well as
gastrointestinal mucosal damage, gonadal dysfunction, and infertility. These agents are
also those most closely associated with treatment-related second malignancies. Clear-cut
evidence connects alkylating agents with the development of secondary leukemias, the
frequency of which is related to the amount of alkylating agent received. The presumed
mechanism of this effect is damage to normal bone marrow stem cells resulting in
mutagenic changes.
Alkylating agents are among the most widely used antineoplastics and form an
important part of curative therapy regimens for Hodgkin's disease and non-Hodgkin's
lymphoma as well as important surgical adjuvant regimens for breast cancer. Alkylating
agents are also the class of drugs whose doses can be most readily escalated, as well as the
class with the steepest dose-response curves in vitro. Thus, these drugs are frequently
employed as part of high-dose chemotherapy regimens administered with autologous or
allogeneic bone marrow support.
There are several other families of alkylating drugs in which the classic nitrogen
mustard backbone has been altered. The nitrosoureas are bifunctional alkylating agents
linked to a nitrosourea moiety. Nitrosoureas are lipid soluble and appear to be among the
most effective agents for use in central nervous system (CNS) tumors. It is believed that
their lipid solubility enhances penetration through the blood-brain barrier and hence
delivery into the CNS. These agents have a unique pattern of toxicity for normal tissues,
although their mechanism of tumor cell killing seems to be DNA crosslinking like the
more classic alkylating agents. Nitrosoureas tend to exert their most pronounced toxic
effects on the hematopoietic system at a later time than do classic alkylating agents.
Following nitrosourea therapy with carmustine (bischloroethylnitrosourea, BCNU) for
example, the nadir of myelosuppression occurs at day 30 to 36 although drug
disappearance from the circulation is rapid; further, nitrosoureas appear to have the ability
to damage bone marrow stem cells more effectively than other classic alkylating agents.

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Non classic alkylating agents

Dacarbazine (DTIC and others). The recommended doses of Dacarbazine for
melanoma and Hodgkin's disease are given in Table 4. Dacarbazine is administered by
short IV infusion. Local pain may be experienced and extravasation should be avoided
because of severe pain and tissue necrosis. Upon administration, approximately 50% of the
drug is activated by the hepatic P450 system. Spontaneous photodegradation is an
alternative form of activation.
The dose-limiting toxicity of dacarbazine is myelosuppression. Severe nausea and
vomiting begins 1-3 hours after the drug is given, and prophylactic antiemetics should be
used. At higher doses, a flu-like syndrome of fever, hypotension, myalgia, and malaise
may be experienced.
Procarbazine (Matulane) is given in the MOPP (mechlorethamine, Oncovin,
procarbazine, and prednisone) combination for Hodgkin's disease at a dose of 100 mg/m2/d
orally for 14 days. As a single agent, daily doses of 50-200 mg orally can be given for
10-20 days. If renal, hepatic, or bone marrow dysfunction is present, doses should be
significantly reduced. Since initial doses are emetogenic, procarbazine should be started at
lower doses.
Hexamethylmelamine (altretamine [Hexaleni) is used primarily as a second-line
agent for relapsed ovarian cancer but is also used in a wide variety of neoplasms. It is
given orally as 4-12 mg/kg/d for 14-21 days. The drug is generally absorbed erratically.
Liposomal IV administration is currently being evaluated. Nausea and vomiting are dose
limiting.
Myelosuppression is mild, allowing the drug to be combined with other more marrowtoxic drugs. Mood alterations, hallucinations, and peripheral neuropathy can occur but
resolve when the drug is stopped.
Carboplatin (Paraplatin) is used primarily for the treatment of advanced ovarian
cancer. It can be given intravenously or intraperitoneally. Carboplatin also has shown
activity in NSCLC, head and neck cancer, metastatic seminoma, endometrial cancer, and
relapsed or refractory acute leukemia.
Single-agent carboplatin is given as 360 mg/m2 IV every 4 weeks. This is usually
administered as a short IV bolus, but the drug has also been given by continuous infusion
for up to 21 days. Carboplatin is often given at a dose of 300 mg/m2 IV every 4 weeks in
combination with cyclophosphamide for the treatment of ovarian cancer.
A commonly used method for calculating carboplatin dosage is the Calvert formula,
which is based on the patient's glomerular filtration rate (GFR) and the relationship
between the area under the plasma concentration-time curve (AUC) of ultrafiltrable
platinum and the degree of hematologic toxicity. This formula is expressed as follows:
Total dose (mg) = target AUC (mg/ml/min) x [GFR (mUmin) +25]

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Using the Calvert formula, carboplatin dose is calculated as mg, not mg/m2. A target
AUC of 5 mg/ml/min (range, 4-6 mg/ml/min) is a usual dosage range for patients
previously treated with chemotherapy.
The toxicity of carboplatin differs significantly from that of cisplatin. Myelosuppression, especially thrombocytopenia, is the dose-limiting toxicity of carboplatin.
Nausea and vomiting are much less severe, and nephrotoxicity is uncommon.
Antimetabolites
Antimetabolites have been used over the past 40 years in the treatment of cancer.
These compounds are structural analogs of the naturally occurring metabolites involved in
DNA and RNA synthesis. As the constituents of these metabolic pathways have been
understood, a large number of structurally similar drugs have been developed that alter the
critical pathways of nucleotide synthesis.
The antimetabolites exert their cytotoxic activity by either competing with normal
metabolites for the catalytic or regulatory site of a key enzyme or by substituting for a
metabolite that is normally incorporated into DNA and RNA. Because of this mechanism
of action, the antimetabolites are most active when the cells are in S phase, and little effect
is seen on cells G0. Consequently, these drugs are most effective in tumors that have a
high growth fraction.
Antimetabolites have a nonlinear dose-response curve, such that, after a certain dose,
no more cells are killed despite increasing doses (fluorouracil [5-FU] is an exception).
Unlike the alkylating agents, the antimetabolites uncommonly produce severe, prolonged
myelosuppression, and they do not increase the risk of secondary malignancies. The
antimetabolites can be divided into folate analogs, purine analogs, pyrimidine analogs,
adenosine analogs, and substituted ureas.
Folate analogs
Methotrexate forms a strong, reversible bond with the enzyme dihydrofolate
reductase, thereby preventing the reduction of folic acid to its active form, tetrahydrofolic
acid. Therefore, de novo synthesis of purine and pyrimidine precursors are blocked and
DNA cannot be formed. Currently, the drug has a broad range of clinical applications and
is utilized most frequently in combination with other chemotherapeutic agents.
Methotrexate can be given by oral, intravenous (infusion or push), intrathecal, intraarterial, or intramuscular routes. Numerous dosing schedules are given with combination
chemotherapy. The half-life of methotrexate is approximately 2 hours. Methotrexate is not
metabolized and is excreted unchanged in the urine. Therefore, to achieve maximal
efficacy, doses must be given that will produce intracellular concentrations that will
saturate methotrexate binding sites (plasma levels of l0-6 M).
Very high doses of methotrexate (>1g/m2 have been used in patients with a variety of
tumors. In these patients, administration of leucovorin (folinic acid, citrovorum factor)
over the following 24-36 hours provides a rescue from associated toxicities. If signs of

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renal toxicity occur, aggressive hydration, urine alkalinization, and leucovorin therapy
should be given until plasma methotrexate levels are < l0-6 M.
Since methotrexate has a significant renal clearance, dose adjustments should be
considered based on creatinine clearance. High doses of methotrexate are contraindicated
in patients with a creatinine clearance < 50ml/min. Methotrexate accumulates in thirdspace effusions and, preferably, these effusions should be drained prior to therapy.
Purine analogs
Fludarabine (FAMP [Fludara]) is a fluorinated nucleotide analog that interferes
with DNA synthesis by inhibiting ribonucleotide reductase. It is indicated for CLL and has
activity in other lymphoproliferative disorders. The dosage of fludarabine is 25 mg/m2/d
IV over 30 minutes for 5 consecutive days, and repeated every 28 days. It has an extensive
volume of distribution and is excreted by the kidney. Fludarabine given prior to cytarabine
(ara-C) increases the intracellular concentration of ara-CTP up to 15-fold, potentially
increasing the cytotoxicity of ara-C. Fludarabine should not be given with pentostatin
(deoxycoformycin [Nipent]) because of the risk of severe pulmonary toxicity.
Mercaptopurine (6-MP [Purinethol]) is a chemical analog of purine base
hypoxanthine. The active drug accumulates, resulting in a false feedback inhibition of de
novo purine synthesis. 6-MP is useful ill the treatment of acute lymphocytic leukemia
(ALL) in adults and children. It is given as 1.5-2.5 mg/kg/d p.o. (100-200mg for the
average adult) until response or toxic effects are observed. The dose may be increased up
to 5 mg/kg/d. Myelosuppression is the dose-limiting toxicity; if a rapid fall in blood counts
is seen, the drug should be discontinued. Nausea, vomiting, anorexia and hepatic
insufficiency with cholestasis are less common toxicities.
Thioguanine (6-TG, Thioguanine]) is used primarily in combination with
ara-C for acute myelogenous leukemia (AML). It is given as 2 mg/kg/d p.o. twice daily for
5 days. It is excreted renally, and doses should be reduced in patients with liver and renal
impairment. Myelosuppression is the dose-limiting toxicity. Nausea, vomiting and
cholestasis occasionally occur.
Adenosine analogs
Pentostatin (deoxycoformycin [Nipent]) is structurally similar to adenosine and is a
potent and irreversible inhibitor of adenosine deaminase, resulting in the accumulation of
adenosine metabolites, which inhibit DNA synthesis. Initial trials demonstrated that
pentostatin has profound lymphocytotoxic effects. Hairy-cell leukemia has shown
exceptionally dramatic responses to the drug. Short courses of therapy have produced
durable remissions in > 90% of patients.
Pentostatin is given as 4 mg/m2/wk IV every other week or for 3 consecutive weeks.
Higher doses result in severe renal and neurologic toxicity. For the first course, patients
should be hospitalized. Aggressive fluids should be administered (at least 2l/d of urine
output), and the patient should be premedicated with allopurinol. Sedatives should be used
with caution, as pentostatin can increase CNS toxicity. Pentostatin is nephrotoxic, and if

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renal function is compromised, doses should be reduced. The drug causes profound
leukopenia and lymphopenia with a granulocyte nadir at 15 days; this can be associated
with severe infections.
Cladribine (2-CdA [Leustatin]) is an adenosine antimetabolite that is resistant to
metabolic inactivation by the enzyme adenosine deaminase. The accumulated drug is
incorporated into DNA, creating DNA strand breaks. It is highly effective in lymphoid
malignancies, such as hairy-cell leukemia, Waldenstrom's macroglobulinemia, CLL, and
low-grade lymphomas. The most frequently used dosage to treat hairy cell leukemia is
0.1 mg/kg/(l (4 mg/m2/d) via continuous IV infusion for 7 days. Most patients have t drop
in their granulocyte count, which is maximal in the first 1-2 weeks and recovers by the
fourth weeks CD4 and CD8 counts also decline with therapy. Fever, rash, and infection are
common. Infections usually manifest in the lungs or venous access sites, with the
organisms infrequently identified.
Pirimidine analogs
Cytarabine (ara-C [Cytosar and others]) is an analog of deoxycytidine that is
phosphorylated to its active metabolite, ara-CTP. Ara-CTP inhibits DNA polymerase and
is incorporated into DNA, resulting in strand breaks.
Ara-C is most active in the hematologic malignancies in combination with other
drugs. It is commonly combined with daunorubicin in the remission induction and
consolidation therapy of AML (7 + 3 regimen). This results in a 60-80% complete
remission rate.
The usual dose of ara-C is given in Table 5. High-dose ara-C (3 g/m2 every 12 hours
for 4-12 doses) can be utilized in consolidating and inducing remissions in relapsed
patients. ln addition, ara-C is used in several multidrug regimens for the treatment of NHL.
Some activity is also seen in ALL and CML. Since the CNS can be a sanctuary site for
leukemia, ara-C is effectively used intrathecally as a prophylactic antineoplastic agent. It
can simply be given as 100 mg in preservative-free saline.
Somnolence, confusion, and seizures are generally seen with rapid infusion at high
doses. Up to 30% of patients can develop cerebellar toxicity, manifested by ataxia,
dysarthria, nystagmus, tremor, and confusion. Methotrexate combined with ara-C enhances
toxicity; therefore, concurrent use of these drugs should be undertaken cautiously.
Floxuridine (FUDR and others) is a fluoridated deoxyribose metabolite of 5-FU,
that, when converted to its active form, inhibits thymidylate synthase (TS). Floxuridine is
used primarily as an intra-arterial chemotherapeutic agent for locoregional management of
cancers metastatic to the liver. its advantage over 5-EU is significant first-pass extraction
by the liver.
Intra-arterial administration of FUDR requires a surgically placed catheter in an artery
supplying a well-defined tumor. Doses range from 0.1 to 0.6 mg/kg/d infused over several
days to weeks. Infusion pumps allow patients to receive therapy over long periods. The
patient should be heparinized to prevent clot formation and should receive H2-antagonists
to prevent peptic ulcer disease. Consider hospitalizing the patient during therapy.

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During therapy, a chemical hepatitis with increased liver function tests is seen, as well
as frequent fever. Numerous catheter-related problems can occur, including arterial
occlusion, leakage, embolism, perforated vessels, and infection, which may necessitate
interrupting therapy. Long-term complications include sclerosing cholangitis.
Fluorouracil (5-FU [Adrucil and others]) is a fluorinated pyrimidine antimetabolite
of the DNA precursor uracil. Fluorouracil is activated by enzymatic conversion to a
nucleoside (FdUMP), after which it acts as a false antimetabolite. 5-FU interrupts DNA
synthesis by inhibiting TS and by incorporation into DNA and RNA. 5-FU has maximal
cytotoxic effect on cells in the S phase and has been found to be effective in treating
numerous solid tumors.
5-FU is given by a wide variety of routes and dosing schedules. The regimens include
a loading dose, weekly IV bolus, and continuos infusions lasting from days to weeks.
Dosing of 5-FU should be based on lean body weight.
The conventional regimen is 300-500 mg/m2 (maximum, 800mg) iv daily for 4 days
either as a bolus or continuous infusion. This is followed by a maintenance dose of 12-15
mg/kg/wk. This regimen has been associated with severe, life-threatening bone marrow
toxicity. A less toxic regimen 15mg/kg/wk for 4 weeks followed by 20mg/kg/wk until
toxicity develops. Continuous infusion of 5-EU at 1-2 gld for 5 days is also utilized; this
regimen does not enhance cytotoxicity but lessens hematologic toxicity.
GI toxicities, such as stomatitis, ulcers, esophagitis, and diarrhea, are common and are
dose limiting. These are signs of impending severe toxicity and are an indication to
interrupt therapy until resolution. GI toxicities are more common with the continuous
infusion of 5-FU, whereas myelosuppression commonly occurs with bolus injection.
Gemcitabine (Gemzar) is an antimetabolite structurally similar to ara-C. It was
originally developed as an antiviral agent but was found to have significant solid tumor
activity. Gemcitabine is triphosphorylated by the tumor cell and accumulates in high
intracellular concentrations. It acts by inhibiting DNA polymerase and ribonucleotide
reductase. Gemcitabine does not appear to be susceptible to multidrug resistance.
Gemcitabine is approved for first-line therapy of locally advanced and metastatic
pancreatic cancer, for which it shows modest antitumor activity and improves the patients
quality of life. The drug is also effective in breast, ovarian, lung, and colon cancer.
Gemcitabine is given as 1,000 mg/m2 IV over 30 minutes, once weekly for up to 7 weeks
(or until toxicity necessitates reducing or withholding a dose), followed by a week of rest.
Subsequent cycles consist of infusions once weekly for 3 consecutive weeks out of every
4 weeks.
Natural products
A wide variety of compounds possessing antitumor activity have been isolated from
natural substances, such as plants, fungi, and bacteria. Likewise, selected compounds have
semisynthetic and synthetic designs based on the active chemical structure of the parent
compounds, and these, too, have cytotoxic effects. These drugs have a major role in the
current armamentarium of anticancer.

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Antitumor antibiotics
Bleomycin (Blenoxane) consists of a group of 13 antitumor copper-chelating
glycopeptides that are derived from the fermentation of Streptomyces verticillus
Bleomycin preferentially intercalates DNA at guanine-cytosine and guanine-thymine
sequences, resulting in spontaneous oxidation and formation of free oxygen radicals that
cause strand breakage.
Bleomycin has appreciable activity in a variety of malignancies, including squamous
cell carcinoma of the head and neck, skin, cervix, vulva and penis. A favorable response is
also seen in Hodgkin's disease, lymphoma, and testicular cancer. Since bleomycin is not
myelosuppressive, it is most often given in combination with other agents. Bleomycin is
also utilized as a sclerosing agent for malignant plural effusions.
Pulmonary damage and fibrosis are the most serious toxicities associated with
bleomycin. The propensity for lung damage results from the fact that lung tissue contains
negligible hydrolase for bleomycin inactivation and relatively high oxygen tension for free
radical formation. Supplemental oxygen may cause severe pulmonary damage. Patients
undergoing surgical procedures should not have oxygen concentrations exceeding an FI02
of 30%. Pulmonary toxicity appears to be dose related, with an increased incidence when
the total dose is > 400 units.
Febrile episodes with chills are relatively common and usually diminish with
subsequent doses. Rarely, anaphylaxis with hypotension occurs. A majority of patients will
experience hyperpigmentation, hyperkeratosis, and peeling of the skin.
Dactinomycin (actinomycin D [Cosmegen]) is a phenoxazine pentapeptidecontaining antibiotic isolated from Streptomyces parvullus. It can be used as a single agent
or in combination therapy to achieve a high cure rate in gestational trophoblastic tumors.
The usual adult dose is 0.5 mg IV daily for 5 consecutive days. Dactinomycin is extremely
damaging to soft tissue, and extravasation should be avoided. Once administered, the drug
does not undergo metabolism, but rather, is excreted unchanged in the bile. Dactinomycin
has a long half-life of 36 hours and does not cross the blood-brain barrier.
Anthracyclines
The anthracycline antibiotics are products of the fungus Streptomyces percetus. They
are chemically very similar, with a basic anthracycline structure containing a glycoside
bond to an amino sugar, daunosamiuc. The anthracyclines have proved to be very active
compounds in a variety of malignancies.
Daunorubicin (Cerubidine) is most commonly used in combination with ara-C to
induce remission of acute nonlymphocytic leukemia in adults. Daunorubicin is also active
in ALL, especially in patients who relapse after vincristine and prednisone therapy or for
remission induction in pediatric ALL. This drug has marginal activity in solid tumors.
Idarubicin (demethoxydaunorubicin ([Edamycin]) is approved for use in remission
induction of AML in combination with ara-C. Overall survival in patients with AML
appears to be improved with idarubicin, as compared with daunorubicin. Idarubicin has
also demonstrated activity in the blast phase of CML and ALL. In addition, idarubicin has

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produced responses in breast cancer but has been less efficacious than doxorubicin in
advanced breast cancer.
Doxorubicin is effective in a large variety of tumors. It is usually given in
combination therapy. Numerous solid tumors are responsive, including neuroblastoma,
soft-tissue and bone sarcomas, breast cancer, ovarian cancer, bladder cancer, thyroid
cancer, small-cell lung cancer (SCLC), and gastric cancer. The hematologic malignancies,
including AML, ALL, Hodgkin's disease and NHL, also respond to doxorubicin.
Doses and toxicities of anthracyclines. These drugs have local vesicant properties
and should be infused into a large vein to avoid extravasation. Upon IV infusion the drugs
rapidly clear from the plasma. Much of the anthracycline is bound to tissue, and 500/o is
excreted in the bile. Doses must be reduced in the presence of elevated bilirubin levels.
The anthracyclines have numerous drug interactions, and these should be reviewed prior to
administration.
Cardiac toxicity is not uncommon with the anthracyclines and can present with both
acute and chronic manifestations that are dose dependent. Chronic toxicity includes
cardiomyopathy secondary to injury to the myocadium form a cumulative anthracycline
bolus dose >550mg/m2.
Myelosuppression is the dose-limiting toxicity with bolus administration and
mucositis is dose limiting with continuous infusion. Alopecia virtually always occurs with
doxorubicin.
Antibiotics
All are fermentation products primari1y from streptomyces microorganisms. Except
for bleomycin, which appears to function as a minienzyme causing DNA breakage, the
others act either by alkylation or a process called intercalation (Figure 9.2).

Figure 9.2. Diagrammatic model of the intercalation of adriamycin into DNA

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Intercalation is the process of sliding the flat ring structure (chromophore) between the
nucleotide pairs of the DNA helix and then being anchored to the DNA structure by the
sugar moieties. The antibiotics either directly inhibit DNA synthesis, DNA directed RNA
or DNA transcription, or cause chromosome breaks. In contrast, bleomycin, a mixture of
glycopeptides, binds iron to produce oxygen free radicals that lead to DNA strand breakage
in the G2 phase.
Microtubule agents
Vinca alkaloids
The Vinca alkaloids are derived from the periwinkle plant, Vinca rosea. Vinorelbine
(Navelbine) is a new semisynthetic vinca alkaloid with established antiturnor activity that
is derived from vinblastine (Velban). Although these drugs have minor structural
differences, there are significant differences in their antitumor activity and toxicities.
The Vinca alkaloids, upon entering the cell, bind rapidly to the tubulin. The binding
occurs in the S phase of the cell cycle at a site different from that associated with paclitaxel
and colchicine. As a consequence, the polymerization of microtubules is blocked, resulting
in impaired mitotic spindle formation in the M phase.
Vincristine (Oncovin and others) is effective in numerous malignancies.
The usual dose of vincristine is 0.4-1.4mg/m2 IV weekly, with a maximum dose of
2mg/wk. A dose reduction of 50% should be used in patients with a bilirubin > 3mg/dL.
Clearance of vincristine is altered when it is given with asparaginase, and therefore,
vincristine should be given 12-24 hours prior to asparaginase.
Vinblastine (Velban) is used for the treatment of Hodgkin's disease, NHL, testicular
cancer, choriocarcinoma, and breast cancer in combination with other drugs. It has also
been used in mycosis fungoides and AIDS-related KS. Vinblastine has been given in
several dosing schemes. The usual dose is 4-12 mg/m2 IV every 1-2 weeks, titrated to
myelosuppression. Like vincristine, the dose of vinblastine should be reduced by 50~) in
the presence of liver dysfunction. Both vincristine and vinblastine must be protected from
light during administration.
Vinorelbine (Navelbine) has recently been approved for the treatment of NSCLC as a
single agent or in combination with cisplatin. The usual dose is 30 mg/m2 IV over
10 minutes repeated weekly. Local tissue necrosis can occur with extravasation. Chemical
phlebitis from peripheral IV infusion can be alleviated by a more rapid infusion rate.
Toxicities of vinorelbine and vinblastine Granulocytopenia is the major doselimiting toxicity of both vinorelbine and vinblastine. Repeat doses should not be given
until full hematologic recovery occurs. The WBC nadir occurs at 5-10 days with recovery
in 7-14 days. Peripheral neuropathies are mild with these drugs. In contrast, the doselimiting toxicity of vincristine is the occurrence of significant neuropathies, which
manifest as paresthesias of the hands and feet, footdrop, constipation, and paralytic ileus.

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Taxanes. Paclitaxel (Taxol) is derived from the pacific yew, Taxus brevifolia. The
drug has a novel 14-member ring, the taxane. Unlike the vinca alkaloids, which cause
microtubule disassembly, paclitaxel promotes microtubule assembly and stability. It has
shown significant activity in refractory ovarian cancer.
Plant Alkaloids
Plant alkaloids are drugs derived from plants such as the periwinkle (eg, vincristine
and vinblastine-vinca alkaloids) or the may apple (eg, etoposide-a podophyllotoxin). Vinca
alkaloids affect the cell in the M phase or mitotic portion of the cell cycle and appear to
cause metaphase arrest by blocking formation of the mitotic spindle. The vincas bind to
tubulin to block microtubule polymerization. In contrast, the new agent, paclitaxel, causes
excess polymerization, or clumping, of microtubule proteins. The epipodophyllotoxins act
to inhibit a DNA enzyme called topoisomerase Ii, which leads to protein-linked DNA
double strand breaks. Most of the cytotoxic effect is in the G2 phase of the cell cycle.
Plant Alkaloids:
Epipodophyllotoxins:
Taxanes:
Vinca alkaloids
Etoposide
Paclitaxel
Vinblastine
Teniposide
Docetaxel
Vincristine
Vindesine
Vinorelbine
Considerable antitumor effects have also been observed in metastatic breast cancer.
Paclitaxel has demonstrated favorable responses in NSCLC and locoregionally recurent
squamous cell carcinoma of the head and neck. The efficacy of paclitaxel in other tumor
types is still under investigation.
The optimal dosing and administration of paclitaxel are still being evaluated.
Paclitaxel has been given at 135-250 mg/m2 by an IV infusion ranging from 3-96 hours. It
is known to be effective in relapsed ovarian cancer at a dose of 135 mg/m2IV over 24
hours every 3 weeks. Administration of paclitaxel has been associated with a severe acute
hypersensitivity reaction manifested by hypotension, dyspnea, bronchospasm, and
urticaria. This reaction may be attributable to the polyoxyethylated castor oil (Cremophor
EL) vehicle used to solubilize paclitaxel. For this reason, patients should be premedicated
with a corticosteroid (such as dexamethasone), diphenhydramine, and an H2 antagonist.
Docetaxel (Taxotere) is a semisynthetic derivative from the leaf extracts of Taxus
baccata. This drug was developed because of supply problems with paclitaxel and has
undergone clinical trials to determine its antitumor efficacy. Docetaxel has the same
mechanism of action as paclitaxel, and actually is more potent in enhancing microtubule
assembly. In vitro, it is more active than paclitaxel against human tumor cell lines. Clinical
responses have been observed in breast, ovarian, and pancreatic cancers and NSCLC, and
the drug is approved for the treatment of breast cancer in patients who relapse after
anthracycline-based therapy.
Docetaxel is given at a dosage of 60-100mg/m2 IV over I h every 21 days. Docetaxel
has toxicities similar to those of paclitaxel, although, unlike paclitaxel therapy, some
patients treated with docetaxel have developed edema and effussions. These toxic effects

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can largely be alleviated by premedication with dexamethasone (8 mg bid) for 5 days prior
to therapy.
Camptothecin analogs
Irinotecan (CPT-11 [Camptosar]) is a semisynthetic analog of the alkaloid
camptothecin, derived from the Chinese ornamental tree, Camptotheca acuminata It
inhibits topoisomerase I and interrupts the elongation phase of DNA replication. Irinotecan
is approved for use in metastatic colorectal cancer that has recurred or progressed after 5FU therapy. Responses have also been seen in SCLC, NSCLC, and ovarian and cervical
cancers. Treatment may continue indefinitely in patients with a response or stable disease.
Dose limiting toxicities include severe myelosuppression and diarrhea. Cautions
should be exercised when giving irinotecan to patients who have previously received
pelvic or abdominal irradiation. The toxicity of diarrhea is significant; 87% of patients
experience diarrhea during therapy, and National Cancer Institute (NCI) grade 3 and 4
diarrhea (> 6 stools/day) is seen in 30% of patients.
In order to have the best chance for cure, chemotherapy must be given that can
achieve a fractional cell kill in a logarithmic fashion (ie, I-log-kill is 90% of cells, 2-logkill 99% of cells). From these concepts, chemotherapy models have been developed
utilizing alternating non-cross-resistant therapies, induction-intensification approaches, and
adjuvant chemotherapy regimens.
Principles of combination chemotherapy
Using kinetic principles, a set of guidelines for designing modern combination
chemotherapy regimens have been derived. Combination chemotherapy accomplishes
three important objectives not possible with single-agent therapy: (1) It provides maximum
cell kill within the range of toxicity tolerated by the host for each drug; (2) it offers a
broader range of coverage of resistant cell lines in a heterogeneous tumor population; and
(3) it prevents or slows the development of new drug-resistant cell lines.
Selection of drugs for combination regimens
The following principles have been established to guide drug selection in combination
regimens:
Drugs known to be active as single agents should be selected for combinations.
Preferentially, drugs that induce complete remissions should be included.
Drugs with different mechanisms of action should be combined in order to allow for
additive or synergistic effects on the tumor.
Drugs with differing dose-limiting toxicities should be combined to allow each drug to
be given at full or nearly full therapeutic doses.
Drugs should be used in their optimal dose and schedule.
Drugs should be given at consistent intervals. The treatment-free interval between
cycles should be the shortest possible time for recovery of the most sensitive normal
tissue.
Drugs with different patterns of resistance should be combined to minimize crossresistance.

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The development of effective combination anticancer therapy was stimulated by the

success of combinations of antimicrobial drugs in patients with infectious diseases in
instances where single agents failed. This development is one of the major advances in
cancer treatment over the past 20 years. It must be noted that most combinations are
chosen empirically, although there are a few basic rules that are usually followed:
1. Select drugs that are active when used as single agents.
2. Select drugs that act synergistically or that enhance the activities of the other agents
either by different modes of actions or by pharmacologic mechanisms.
3. Select drugs that have minimally overlapping toxicities.
4. Maximize the dose and schedule of the various agents with respect to specific tumor
cell and drug kinetics.
Many combinations now in use increase the response rate over single agents by
factors of two to four times.
Dose intensity
Kinetic principles predict that, for drug-sensitive cancers, the factor limiting the
capacity to cure is proper dosing. Reduction in dose is associated with a decrease in cure
rate before a significant reduction in the complete remission rate occurs. A dose reduction
of approximately 20% can lead to a loss of up to 50% of the cure rate. Conversely, a 2-fold
increase in dose can be associated with a 10-fold (1-log) increase in tumor cell kill in
animal models.
Definitions of response
Tumors can be classified according to their general sensitivity to chemotherapy (Table
2). Response to chemotherapy is defined precisely as complete response, partial response,
stable disease or minimal response, and progression.
Complete response (CR) is defined as the disappearance of all evidence of disease and
no appearance of new disease for a specified interval (usually 4 weeks).
Partial response (PR) is defined as a reduction by at least 50%1o in the sum of the
products of the two longest diameters of all lesions, maintained for at least one course of
therapy with no appearance of new disease.
Minimal response or stable disease (SD) is any response less than a partial response
and is usually not reported in clinical trials.
Progression or progressive disease (PD) is defined as growth of existing disease or
appearance of new disease during chemotherapy.
Table 9.1. Classification of tumors according to general sensitivity to chemotherapy
Group I. Cancers in which drugs have been responsible for some patients achieving a
normal life-span:
Acute leukemia in children
Hodgkin's disease
Histiocytic lymphoma
Skin cancer

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Testicular carcinoma
Embryonal carcinoma
Rhabdomyosarcoma
Ewing's sarcoma
Wilms' tumor
Burkitt's lymphoma
Retinoblastoma
Choriocarcinoma
Group 2. Cancers in which responders to chemotherapy have demonstrated improvements
in survival:
Ovarian carcinoma
Breast carcinoma
Adult acute leukemias
Multiple myeloma
Endometrial carcinoma
Prostate cancer
Lymphocytic lymphomas
Neuroblastoma
Adrenocortical carcinoma
Malignant insulinoma
Stomach cancer
Cervical cancer
Group 3. Cancers responsive to drugs for which clinically useful improvements in survival
of responders have not been clearly demonstrated:
Head and neck cancers
Gl cancers
CNS cancer
Endocrine gland tumors
Malignant melanoma
Osteogenic sarcomas
Soft-tissue sarcomas

Group 4. Cancers only marginally responsive or unresponsive to chemotherapeutic

agents:
Hypernephroma
Bladder carcinoma
Esophageal cancer
Epidermoid carcinoma of the lung
Pancreatic carcinoma
Hepatocellular carcinoma
Thyroid carcinoma

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II. Biologic therapy:

Interferons, interleukins, and monoclonal antibodies
As our understanding of the immune system has advanced, the use of molecules with
the ability to modulate activities based on immune function has become a reality. In the
last decade, two classes of compounds have emerged that have been clearly shown to play
a role in the therapy of some human tumors.
Biologic therapy refers to antitumor treatment utilizing the actions of natural hostdefense mechanisms and/or mammalian-derived substances. Its origins date to over a
century ago when William B. Coley first described spontaneous regression of sarcoma in
patients who experienced severe infections. Over the past 2 decades, advances in tumor
immunology and molecular genetics, coupled with development of technology for the
large-scale production of pure biologic reagents, have paved the way for clinical studies to
test these molecules for antitumor efficacy.
Cytokines
Cytokines are soluble proteins produced by cells that affect the growth and
metabolism of either the same (autocrine) or another (paracrine) cell, through interaction
with specific receptors expressed on the surface of the corresponding cell. To date, more
than 50 cytokines have been isolated, although only 7 are currently approved by the FDA
(Table 9.1).
This discussion will be limited to interferons and interleukin-2 (IL-2). The bone
marrow-protective cytokines, granulocyte colony-stimulating factor and granulocytemacrophage GSF (GM-CSF). Other cytokines under investigation such as IL-1, IL-4, IL-6,
IL-12, and macrophage GSF (M-CSF), will not be discussed here.
Interferons
Interferons (IFN's) are glycoproteins originally described in 1957 by Isaac and
Lindemann as the products of virally infected cells, which protect against viral infection.
They have direct antiviral activity, increase expression of major histocompatibility
complex (MHC) and tumor-associated antigens.
The interferons are a class of compounds produced normally by human cells. Their
major role was initially thought to be in the defense of cells against viral infections. There
are three major types of interferons (INF, and ). These compounds are biochemically
and biologically different; the spectrum of their biologic effects is enormous including a
complex array of immunologic effects, antiangiogenesis and cell cycle regulation. INF is
the most widely tested and has clear activity in hairy cell leukemia, chronic myelogenous
leukemia (CML) multiple myeloma, and certain non-Hodgkin's lymphomas. INF also
has limited but real activity in renal cell carcinoma, melanoma, Kaposi's sarcoma and
carcinoid tumors. The side effects of treatment with INF include fever, chills, and
myalgias acutely, and anorexia and fatigue with chronic administration.

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Interleukins
Interleukin 2 (IL-2) is the second biologic response modifier to clearly show clinical
anticancer activity. The major biologic effects of IL-2, originally identified as a T cell
growth factor, appear to be dependent upon the support of T cell proliferation. When
administered alone or in combination with autologous T cells expanded in vitro, IL-2 has
considerable antiproliferative activity in a number of preclinical systems.
IL-2 also can produce clinical remissions in patients with malignant melanoma.
However, when administered in an intermittent high-dose schedule as originally
developed, IL-2 produces significant side effects including hypotension, oliguria,
dermatitis, and ipotentially severe capillary leak syndrome. Even at lower doses, IL-2
therapy must be administered under careful supervision.
Hematopoietic Growth Factors
A group of substances normally secreted by lymphocytes and macrophages has
proven to be useful in reducing side effects of cytotoxic chemotherapy. These substances
are the hematopoietic growth factors. Granu locyte-macrophage colony-stimulating factor
(GM-CSF), granulocyte colony-stimulating factor (G-CSF), and erythropoietin (EPO) are
normally produced by cells of the macrophage-lymphocyte system (especially G-CSF) or
renal tubular cells (especially EPO). These compounds are critical for the stimulation of
granulocyte and macrophage maturation (G-CSF, GM-CSF) or erythrocyte formation. It is
clearly demonstrable that G-CSF and GM-CSF will hasten recovery of granulocyte
suppression following cytotoxic chemotherapy. These drugs permit more rapid
hematologic reconstitution following high-dose chemotherapy and bone marrow
transplantation; their use with more standard doses of chemotherapy has also been shown
to reduce duration of neutropenia and hospitalization. Administration of EPO, for example,
which is effective in stimulating red cell production, will raise hemoglobin concentrations
suppressed by cytotoxic chemotherapy. This may reduce the need for blood transfusion
and may be a useful addition to the agents available for the support of patients undergoing
cancer therapy. A major continuing problem is thrombocytopenia that occurs following
cytotoxic therapy. Recombinant human thrombopoietin is currently undergoing active
clinical investigation for the amelioration of chemotherapy-induced thrombocytopenia.
Monoclonal antibodies
Since Kohler and Milstein first described monoclonal antibody producton in 1975, the
use of antibodies developed against human tumor-associated antigens for tumor diagnosis
and identification has become well established. Despite extensive effords, an effective
therapeutic antitumor application remained elusive until 1997, when was introduced
Rituximab for therapeutic use. Major efforts to develop therapeutical monoclonal
antibodies are underway with many antibodies in various stages of clinical trials.

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Therapeutic use
Rituximab (Rituxan, IDE-C2B8) is a chimeric anti-CD20 monoclonal antibody
comprised a human IgG1k constant region with mouse variable region sequences derivated
from mouse anti-mouse CD20 monoclonal antibody IDEC-C2B8.
It is approvved for the treatment of relapsed or refractory low-grade or folicular nonhodgkin lymphomas (LMNH).
Trastuzumab (Herceptin) is a chimeric monoclonal antibody that binds to
HER-2/neu a transmembrane glycoproteine receptor with intrinsec kinase activity.
HER-2/neu is overexpressed in 25-30% of human breast cancers and is associated
with a poor prognosis and poor response to chemotherapy. Signifiacnt responses to
trastuzumab have been reported in patient with HER-2/neu- overexpressing breast cancers.
Campath-IH is a chimeric monoclonal that targets the CD52 antigen, wich is pesent
on almost all normal and malignant lymphocytes. This antibody is very potent at inducing
complement- mediated cell lysis and can maredly deplete circulating CD52-psitive cells.
Significant eficacy of CAPATH has been seen in chronic lymphocytic leukemia
(CLLL) where up to 30% of patients with Fludarabine (Fludara) refractory disease can
achieve partial responses.
III. HORMONAL THERAPY
Some tumors, most notably breast and prostatic cancers, originate from tissues whose
growth is under hormonal control. Hormonal manipulation of these tumors was recognized
as the first effective systemic treatment for metastatic disease. Control of these tumors by
hormonal manipulation has been accomplished using several different modes of therapy. In
some cases, the tissue producing the hormone stimulating tumor growth may be removed
surgically. Examples of this type of therapy would be removal of the ovaries (the principal
site of estrogen production) in premenopausal women with breast cancer or removal of the
testes (the principal site of testosterone production) in men with prostatic cancer. Various
hormonal or hormonal-like agents may also be administered that inhibit tumor growth by
blocking or antagonizing the naturally occurring substance stimulating tumor growth.
Examples of this type of therapy include the use of exogenous estrogens, an antiestrogen
(eg, tamoxifen), or a progesterone (eg, megestrol acetate) in the management of breast
cancer, or the use of estrogens in prostatic cancer. Other substances may block the
synthesis of the natural hormone stimulating tumor growth. Examples of such substances
include the use of aminoglutethimide in breast cancer, which blocks the peripheral (nonovary) production of estrogens in post-menopausal women. In this setting, the main source
of estrogens in this population of patients is the conversion of endogenous androgens to
estrogens by the aromatase enzymes. Similarly the use of leuprolide in prostatic cancer
blocks the production of testosterone by reducing the cyclical release of FSH and LH from
the pituitary.
Overall, 30% to 40% of patients with metastatic breast cancer will respond to
hormonal therapy (Bonadonna, 1999). It is routine procedure to measure hormone
receptors (estrogen and progesterone) in breast cancer tissue to predict which patients are
most likely to respond to hormonal therapy (and which patients should receive cytotoxic
therapy instead). The majority of patients with disseminated prostatic cancer respond (to
some extent) to hormonal therapy.

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Hormonal Agents
Beatson demonstrated in 1895 that oophorectomy would slow the progression of
breast cancer. Since that observation, a variety of hormonal agents have been proven to be
useful in the therapy of human cancers. The mechanisms by which hormonal therapy can
favorably affect the growth of cancers may depend upon withdrawal or inhibition of
secretion of endogenous hormones necessary for the sustenance of the growth of the cancer
(e.g., estrogens, androgens), or by direct interference with the biochemical effects of
endogenous hormones.
Estrogens, progestins, and androgens derived from the ovaries have been shown to be
important in the progression of breast cancer and endometrial cancer. Removal of the
ovaries or suppression of their function through the administration of gonadotropinreleasing hormone (GNRH) agonists play a role in the suppression of those cancers.
Prostate cancer and breast cancer in the male are dependent upon the secretion of
androgens from the testes. Orchiectomy or inhibition of testicular antigen synthesis
through the use of luteinizing hormone-releasing hormone (LH-RH) analogues play an
important role in the control of those cancers.
Adrenal-derived androgens and estrogens appear to be important in supporting the
growth of prostate cancer and breast cancer A number of agents such as aminoglutethimide
(AG) and ketoconazole have been shown to inhibit enzymes necessary for the synthesis of
adrenal androgens and estrogens. In addition, AG and other newer aromatase inhibitors
such as anastrazole alter the peripheral conversion of androgens to estrogens
(aromatization); because of the enhanced tolerance of the newer aromatase inhibitors, they
have become important additions to the hormonal managenent of advanced breast cancer.
Another class of hormonal agents were originally classified as antihormones
Tamoxifen, which is a nonsteroidal antiestrogen, and flutamide a nonsteroidal
antiandrogen, are the prototypes of this class of compounds. They exert their
antiproliferative effects by a variety of mechanisms including, in the case of tamoxifen,
alterations in the activation of the estrogen receptor gene, blockade estrogen-stimulated
progesterone receptor synthesis and stimulation of other growth regulating gene products
such as TGF beta. Tamoxifen has been prove to be safe and beneficial in both the surgical
adjuvant therapy breast cancer and in the treatment of advanced disease. It is currently
being evaluated as a chemopreventive agent for women at high risk for developing breast
cancer. Tamoxifen, however, possesses both agonist and antagonist effects; while king the
effects of estrogen on the breast, it is an estrogen mimic with respect in the uterus. This can
lead to hyperplasia and an increased risk of endometrial cancer after long-term tamoxifen
exposure. Other side effects include weight gain dashes, and an increased risk of deep
venous thrombosis. Flutamide competes with natural androgen for binding to the androgen
receptor Flutamide is a modest active agent in advanced prostate cancer; it is sometimes
used in combination with either orchiectomy or LH-RH analogues in a so-called total
androgen deprivation approach to the treatment of prostate cancer. The superiority of this
approach site orchiectomy alone for advanced prostate cancer remains unclear.
Progestational agents are also effective in some forms of cancer. Endometrial cancer
is suppressed in 40% to 50% of cases by exogenous administration of progesterone or
progesterone analogues. Progestational agents are also effective in advanced breast cancer,
particularly in women whose tumors have previously responded to hormonal manipulation;

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these agents also have some activity in advanced prostate cancer. Although the cytotoxic
mechanism of action of progestine is unclear, these drugs produce a characteristic
spectrum of toxicity including weights gain, fluid retention, hot flashes, cholestasis, and an
increased risk of thromboembolic.
IV. GENE THERAPY
The application of molecular biology and genetics to medicine has resulted in a
detailed understanding of the processes within mammalian cells that govern the
proliferation, differentiation, and cellular response to genotoxic stress, key determinants in
the natural history of neoplastic diseases and their response to therapy. Gene therapy
strategies for altering the natural history of tumor cells once the transformation event has
occurred have involved the use of viral proteins, cationic lipids, replication-incompetent
retroviral, adenoviral, and herpes viral vectors, and lentiviral vectors.
The explosive growth in our understanding of tumor biology coupled with increasing
ease and sophistication of molecular genetiques has opened the door for the transfer of
specific oncogenes, antisense oligonucleotides, tumor-suppresor genes or cytokine into
tumors in vivo or ex vivo using a variety of delivery systems, including retroviral vectors,
liposomes and mechanical delivery. Many of these approaches are being evaluated
currently in clinical trials.
Vectors that are either replication-incompetent, which will therefore not produce an
infection from cell to cell within a solid tumor nodule, and those vectors that are
conditionally replication-competent, which will replicate and spread an infection within the
tumor cells, have been developed. Gene delivery systems have been used for the ex vivo
modification of tumor cells and normal cells that are to be returned to the patient's body for
therapy. Vectors have also been used for the injection of genetic modification vectors
directly into tumors, into the lumen of vessels for regional therapy within tissues, and into
body cavities, such as the peritoneal and pleural spaces. Therapeutic gene delivery strategies in cell and animal models have been developed for the suppression of oncoprotein
function, for the restoration of tumor-suppressor gene function, for the activation of
nontoxic prodrugs into cytotoxic drugs within tumor cells, and for the sensitization of
tumor cells to radiation therapy and chemotherapy. The normal cells of the body have
become targets for genetic modification to protect normal tissues from the effects of
chemotherapy and radiation, for the interruption of the development of tumor vasculature
and for the activation of the cellular immune response to the tumor cells. The engineering
of autologous and allogeneic cells that participate in the immune response to a tumor, as
well as the modification of the tumor cell itself, has led to a number of clinical
immunoenhancement strategies that are either under development at the preclinical level or
are under evaluation in clinical trials. Finally, information about the structure and function
of cellular and viral proteins that contribute to transformation, as well as information about
the structure of peptides and proteins that inhibit oncoprotein action, are being combined
with synthetic combinatorial approaches for the development of small-molecular-weight
chemicals thus can bind to and block the action of oncoproteins. These inhibitors of
oncoprotein action are being applied to the development of new vector systems, as well as
to the development of new anticancer drugs.

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Vectors and gene delivery systems

The most commons used vectors include the retroviral vectors and the adenoviral
vectors. Classically, both of these have been replication-incompetent. The retroviral vectors
have been used for the permanent modification of target cells. An example is the use of
these vectors to permanently introduce transgenes into tumor cells for tumor-cell vaccines.
From the technical gene delivery point of view, this has been success-fill. The adenoviral
vectors have also been used to deliver transgenes to tumor cells, not only for the
development of vaccines, but for the sensitization of target tumor cells to the action of
chemotherapy and radiation therapy. The adenoviral transgenes have also been used for
replacement of nonfunctional tumor-suppressor genes.
Recent developments have been the clinical experience acquired from the use of these
vectors clinically. Most surprising was the discovery that these vectors could be injected
directly into tumors repetitively without hypersensitivity reactions. Despite the almost
universal development of neutralizing antibodies, the transgenes of these vectors have
continued to be expressed. Presumably, this is due to the restricted access of intravascular
antibodies to the inner reaches of the tumor cell. Doses of up to 1 trillion plaque-forming
units have been delivered.
There have been many technical developments in adenoviral vectors. Frank
McCormick first produced a conditionally replication-competent vector in which the loss
of function mutation within the tumor cells creates a permissive environment for the
replication of the vector in which the E1 gene is driven by its native promoter. Many
second-generation adenoviral vectors with tumor specific promoters have been introduced
and are under study.
A second modification that has been introduced recently was an adenoviral vector in
which the capacity of the vector had been increased to include almost the size of the entire
adenoviral vector genome. This has permitted the introduction of genomic clones of
transgenes and tissue specific expression of these genes over months in target cells.
Cosmid cloning systems have been developed for the production of vectors that are free of
wild type vector. Finally, hybrid adenoviral vectors have been developed in which the
genetic material of the retroviral vector has been included.
The herpes viral vectors are being engineered to produce conditionally replicationcompetent vector that have a tropism for the CNS and that can replicate within tumor cells.
Simplified vectors, called amplicons, have also been produced as conditionally replicationcompetent vectors.
Oncoprotein inhibitors and tumor suppressor
Most of the clinical experience with tumora-suppressor gene replacement strategies
has been acquired with p53 vectors. The most interesting findings relate to the fact that
repetitive administration of these vectors can be carried out without limiting
hypersensitivity side effects, as long as intratumoral injections are used. Doses of up to
1 trillion plaque-forming units can be delivered, and transgenes continue to be expressed in
the face of increasing titers of neutralizing antibodies. There is also an impression that
doses greater than 10 billion plaque-forming units are required fl reliably detect the
transgene products at the protein level.

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Activation of the cellular immune response

Both retroviral vectors and adenoviral vectors have been used to deliver transcription
units, witch produce lymphokines, growth factors, antigen presentation elements and other
protein products designed to enhance the cellular immune response against tumor cells.
Some of the most exciting experiments have involved the design of peptide transcription
units, which produce short protein fragments, which are shown to be able to bind to the
pocket of class I human leukocyte antigen (HLA) molecules. These molecules have been
shown to direct the T-cell-dependent cellular immune response against tumor cells that
bear the peptides on their surface.
Modification of dendritic cells also produces effects that appear to promote the
development of T-cell-dependent cellular immunity against the tumor cell. The
modification of the dendritic cells, as well as their precursors, has been a focus of many
groups and is under evaluation at present. Vaccine therapy, which is based on the
modification of tumor cells and subsequent injection of the modified tumor cells into
patients, has been the focus of most of these trials.
Inhibition of tumor angiogenesis
Interest in the design and testing of vectors that block the development of the tumor
vasculature has been driven by the discovery of natural products that inhibit the
development of tumor neovasculature. In addition, the use of computational and
combinatorial synthetic chemical techniques has produced inhibitors of the angiogenesis
receptor and the hope that small-molecular-weight inhibitors of tumor vascular
development, which do not act on the vasculature of established tissues, can be developed
and brought into clinical use. These compounds may be suitable for administration in
tablets or infusions. This is an area in which development may be directed to the normal
cells, in order to change the systemic conditions that shift the balance against the tumor
cells and in favor of the normal cells of the body.
Peptidomimetic inhibitors of oncoprotein action
Most of the existing anticancer drugs are natural products that have been isolated from
plants and microorganisms. These often are very complex, polycyclic hydrocarbon
molecules that have limited solubility and pharmacokinetics, which result in the
accumulation of the drugs within the CNS or other tissues, producing toxicity.
The development of the capability of simulating the detailed domains of biologically
active proteins with small-molecular-weight chemicals, based on the knowledge of their
protein x-ray crystallographic structure, has created the opportunity to design drugs that
may bind to and inhibit key functional domains of cellular or viral oncoproteins.

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Summary
The use of systemic cancer treatment includes drugs that are directly cytotoxic to
tumor cells by a wide variety of diferent mechanisms compounds that may affect the
hormonal milieu in wich the tumor proliferates or biologic agents that enhance the
patients immunologic response to the tumor. The use of each of these clases of systemic
therapies provides curative treatment options for patients with several forms of
disseminated hematologic malignancies as well as postsurgical adjunctive therapy that
improves the cure rate for early stages of the breast, ovarian and colo-rectal cancer and
effective palliative treatment for all the common solid tumors in humans.
Systemic treatments can best be understood through an appreciation of several critical
concepts in tumor biology that form the foundation of Medical Oncology as well as an
understanding of clinical and molecular pharmacology of specific drugs currently in use.
*

During the past two decades, rapidly advancing knowledge of natural histories of
cancers and specific characteristics of their stages have developed from biologic, cellular
and molecular level of investigations and the interdigitation of these three levels of
comprehension. These new understandings have provided more specific methods designed
to prevent cancer formation in the clinical phase. The concept of irreversibility of action by
initiating agents has led to major efforts to limit human exposure to these agents (e.g.
limiting radiation exposure from diagnostic radiology procedures, limiting of ultraviolet
light from sunlight and limitation of exposures to known human chemical carcinogens in
the workplace, in pharmaceutical products and dietary sources). Additional efforts at
removing exposures to promotion agents have led to educational efforts to limit exposures
to cigarette smoke, use of smokeless tobacco and reduction of excess dietary fat. A search
for agents designed to modify the stage of promotion has led to the new science of cancer
chemoprevention exemplified by the use of vitamin A and its chemical analogs (e.g.13
cis-retinoic acid and inhibition of continued development of upper airway cancers). An
understanding of karyotypic instability present in the stage of progression and its
relationship in the some circumstances to actions by oncogenic viruses has led to
development of immunization methods (e.g. hepatitis B vaccination and attempts to
prevent hepatic cancers). Attempts have been made to inhibit the formation and growth of
metastases by interfering with altered blood coagulation process as well as by development
of anti-angiogenetic therapy. Finally, adjuvant chemotherapy treatments have been actively
designed in attempts to inhibit formation of metastases in patients with early clinical
cancers. New knowledge concerning the natural histories of how cancers evolve should
enable design of novel approaches to cancer control.
In the current era, we are witnessing rapid emergence of molecular insights into
genes and their cognate proteins that drive tumor inception, proliferation and
dissemination. Consequently, our understanding of the treatment for these disease is
likewise undergoing change. As we enter the 21st century there is justified optimism that
the exciting advances in the molecular and cellular biology, immunology and biochemistry
of cancer will greatly improve our ability to more effectively diagnose and treat human
malignancies and even prevent some of these dreaded diseases.

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