Download 01. Epidemiology of cancer. Methods of diagnosis and treatment

Cancer
Uglyar T.Y.
What is cancer?
• Caner is defined as the continuous uncontrolled
growth of cells.
• A tumor is a any abnormal proliferation of cells.
• Benign tumors stays confined to its original
location
• Malignant tumors are capable of invading
surrounding tissue or invading the entire body
• Tumors are classified as to their cell type
• Tumors can arise from any cell type in the body
What Is Cancer?
• Cancer – a large group of diseases characterized
by the uncontrolled growth and spread of
abnormal cells
• Neoplasm – new growth of tissue that serves no
physiological function
• Tumor – clumping of neoplasmic cells
• Malignant - cancerous
• Benign - noncancerous
• Biopsy – microscopic examination of cell
development
Cancer is an umbrella term covering a plethora of
conditions characterized by unscheduled and
uncontrolled cellular proliferation.
• Almost any mammalian organ and cell type can succumb to oncogenic
transformation, giving rise to a bewildering array of clinical outcomes.
• The causes of cancer are many and varied, and include genetic
predisposition, environmental influences, infectious agents and ageing.
These transform normal cells into cancerous ones by derailing a wide
spectrum of regulatory and downstream effector pathways. It is just
this complexity that has hampered the development of effective and
specific cancer therapies.
• Any attempt to provide a comprehensive overview of cancer-related
knowledge would be futile — therefore the next two lectures will
focus on topics undergoing particularly rapid progress.
Cancer continued; three cancer types
• Carcinomas; constitute 90% of cancers, are
cancers of epithelial cells
• Sarcomas; are rare and consist of tumors of
connective tissues (connective tissue,
muscle, bone etc.)
• Leukemias and lymphomas; constitute 8%
of tumors. Sometimes referred to as liquid
tumors. Leukemias arise from blood
forming cells and lymphomas arise from
cells of the immune system (T and B cells).
What Causes Cancer?
• External Factors – chemicals, radiation,
viruses, and lifestyle
• Internal Factors – hormones, immune
conditions, and inherited mutations
• Theories
– Cellular change/mutation theories
– Carcinogens
– Oncogenes/ protooncogenes
Risks For Cancer
• Lifetime risk – the probability that an
individual, over the course of a lifetime, will
develop cancer or die from it
• Relative risk – measure of the strength of the
relationship between risk factors and a
particular cancer
• Smoking – 30% of all cancer deaths, 87% of
lung cancer deaths
• Obesity – 50% higher risk for breast cancer
in postmenopausal women, 40% higher risk
in colon cancer for men
Biological Factors
• Some cancers such as breast, stomach,
colon, prostate, uterus, ovaries and lung
appear to run in families
• Hodgkin’s disease and certain leukemia's
show similar patterns
• University of Utah research suggests that a
gene for breast cancer exists
• A rare form of eye cancer appears to be
transmitted genetically from mother to
child
Reproductive And Hormonal
Risks For Cancer
• Pregnancy and oral contraceptives increase
a woman’s chances of breast cancer
• Late menarche, early menopause, early first
childbirth, having many children have been
shown to reduce risk of breast cancer
Social And Psychological Factors
• Stress has been implicated in increased
susceptibility to several types of cancers
• Sleep disturbances, diet, or a combination
of factors may weaken the body’s immune
system
Chemicals In Foods
• Sodium nitrate when ingested forms a
potential carcinogen, nitrosamine
• Sodium nitrate is still used because it is
effective in preventing botulism
• Pesticide and herbicide residues
Viral Factors
• Herpes-related viruses may be involved in the
development of leukemia, Hodgkin’s disease,
cervical cancer, and Burkitt’s lymphoma
• Epstein-Barr virus, associated with
mononucleosis, may contribute to cancer
• Human papillomavirus (HPV), virus that causes
genital warts, has been linked to cervical cancer
• Helicobacter pylori causes ulcers which are a
major factor in the development of stomach
cancer
Medical Factors
• Some medical treatments actually increase
a person’s risk for cancer
• Diethylstilbestrol (DES) used 1940 to 1960
to control bleeding during pregnancy, the
daughters of mothers that used DES were
found to have an increased risk for cancers
of the reproductive organs
• Estrogen supplementation
• Chemotherapy used to treat one form of
cancer may increase risk for another type
of cancer
Properties of cancer cells
Normal cells show
contact inhibition
Cancer cells lack
contact inhibition
Properties of cancer cells
They keep growing
And growing
And growing
And growing
Cancer: Benign
• Benign: localized and of
small size
• Cells that closely resemble,
and may function, like
normal cells
• May be delineated by a
fibrous (Basal lamina)
capsule
• Become problems due to
sheer bulk or due to
secretions (e.g. hormones)
Cancer : Malignant
Malignant tumors: high rate of division, properties may vary compared
to cells of origin. Most malignant cells become metastatic
Invade surrounding tissue and establishment of secondary areas of
growth: Metastasis
Metastasis
Carcinoma: derived from endoderm or ectoderm
Oncology
• Biology of abnormal cancer cells
• They have continuous or inappropriate, usually
faster growth or larger growth patterns
• They have no specific morphology and often do
not resemble their parent cells = anaplastic
• They do not respond to signals for apoptosis =
programmed cell death
Apoptosis
• Apoptosis is a tightly regulated form of cell death,
also called the programmed cell
death. Morphologically, it is characterized by
chromatin condensation and cell shrinkage in the
early stage. Then the nucleus and cytoplasm
fragment, forming membrane-bound apoptotic
bodies which can be engulfed by phagocytes. In
contrast, cells undergo another form of cell death,
necrosis, swell and rupture. The released
intracellular contents can damage surrounding
cells and often cause inflammation.
p53 in apoptosis
Following DNA damage, e.g. by radiation, p53 levels rise, and
proliferating cells arrest in G1. This allows time for DNA repair
prior to the next round of replication. This arrest is mediated by
stimulation of expression of p21CIP1, the cyclin kinase inhibitor.
Very high p53 levels, or susceptible cell types, e.g. lymphocytes,
are triggered to undergo apoptosis. Bcl-2 acts between p53 and the
caspase:
The role of caspase
• During apoptosis, the cell is killed by a class of
proteases called caspases. More than 10 caspases
have been identified. Some of them (e.g., caspase
8 and 10) are involved in the initiation of
apoptosis, others (caspase 3, 6, and 7) execute the
death order by destroying essential proteins in
the cell. The apoptotic process can be
summarized as follows:
1. Activation of initiating caspases by specific signals
2. Activation of executing caspases by the initiating
caspases which can cleave inactive caspases at
specific sites.
3. Degradation of essential cellular proteins by the
executing caspases with their protease activity.
Capsase activation
• Comparison between active and inactive forms of
caspases. Newly produced caspases are
inactive. Specifically cleaved caspases will
dimerize and become active.
P53 can bind to DNA!
Stabilized by Zn2+.
DNA
p53
What does p53 do?
• Suppresses tumors in response to DNA
by inducing cell cycle arrest or apoptosis
How can you inhibit gene
expression?
How is p53 Activated?
1) Regulation of p53 by MDM2
P53 tumor suppressor protein can be stabilized and
activated by two separate mechanisms in
response to DNA-damage-induced
phosphorylation.
2) p53 nuclear export is inhibited, to ensure that it is
activated in response to DNA damage.
The discovery of p53
•
Studies of SV40-transformed cells show that a 55kDa protein is coprecipitated with the large-T
antigen (Chang et al. 1979; Kress et al. 1979; Lane
and Crawford 1979; Linzer and Levine 1979;
Melero et al. 1979). This association was shown to
be the result of an in vivo association between the
two proteins (Lane and Crawford 1979). It was then
postulated that this protein could be encoded by
the cellular genome. (It should be kept in mind that
no middle-T was found for SV40 and that the
molecular weight of this protein was similar to that
of polyoma middle-T antigen). Linzer and Levine
(Linzer and Levine 1979) found that the 54-kDa
protein was overexpressed in a wide variety of
murine SV40 transformed cells, but also in
uninfected embryonic carcinoma cells. A partial
peptide map from this 54-kDa protein was identical
among the different cell lines, but was clearly
different from the peptide map of SV40 large-T
antigen (Kress et al. 1979; Linzer and Levine 1979).
It was then postulated that SV40 infection or
transformation of mouse cells stimulates the
synthesis or stability of a cellular 54-kDa protein.
Oncology
• Cancer grading and staging
• Cancer is graded upon the resemblance to normal cells
= G
(The higher the number, the worse the grade of cancer) i.e. G1,
G2, G3, G4
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Staging is based upon
the presence of a primary tumor = T
involvement in lymph nodes = N
and appearance of metastasis = M
Numbers of the stage range from
x = none to 3 or 4 for each letter
Is this a high grade or low grade
cancer?
1. High
2. Low
0%
Lo
w
Hi
gh
0%
Oncology
• Types of cancer cells are named for their site of
origin:
• Adenocarcinoma
• Carcinoma in situ (CIS)
• Squamous
• Basal cell
• Astrocytomas
• Melanomas
• Sarcomas
• Lymphomas
Oncology
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Symptoms of Cancer
Cachexia – weight loss,unexplained
Anorexia
Anemia
Impaired immune response
Pain – when the cancer is large enough to
compress nerves or organs
• Lymphadema – when the tumor blocks lymph or
circulatory flow
• Motor or sensory deficits
Oncology
• Cancer statistics
• Lung cancer has annual
new cases (incidence)
of 173,770 people
per year: 93,110 males and
80,660 females
• Annual mortality: 160,440 per year
consisting of 92,000 males and
68,510 females
Oncology
• Cancer statistics
• 28% of all cancer deaths are due to lung cancer
• This is the leading cause of cancer death in
both men and women
• There are more deaths from lung cancer than
prostate, breast, and colorectal cancers
combined
Oncology
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Cancer statistics
Risks for lung cancer:
Smoking (75-80% of cases)
Occupational exposure
Nutrition/Diet
Genetic factors
Oncology
• Cancer statistics
• Prostate cancer is number two cause of cancer in
men
• Breast Cancer is number two cause of cancer in
women
• Most common non-malignant or non-fatal cancer
is non-melanoma type skin cancers
Oncology
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Lab tests for cancer
Ultrasounds to determine size
CT scan with contrast– the golden standard
Genetic markers – BRCA 1 and BRCA 2
Tumor markers:
CEA – general carcinogenic antigen
PSA – prostate antigen
CA-125 – ovarian
CA-25,27 – breast
HER 2 NEU – breast tissue needed
Oncology
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Lab tests for cancer
Liver function tests
CBC with diff
Renal function tests
PET scan – looks for metastasis using a
radioactive glucose solution
• PT, PTT, Fibrinogen, Fibrin levels
Oncology
• Lab tests for cancer
• Pathology slide of tumor:
(Should be kept for a period of years)
• Determines type of tumor
• Source of tumor
• Aggression of tumor – whether fast growing,
differentiated, or non-differentiated
• Used to determine tumor growth factors and
susceptibility to certain chemotherapies
Cancer treatment.
By Dr.Huda abd-alkarim.
Assistant prof.& consultant oncologist.
Modalities of treatment:
• 1-local therapy:
– -surgery.
– -radiation therapy.
• 2-systemic treatment:
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chemotherapy.
Hormonal therapy.
Monoclonal antibodies.
Radioactive material.
• 3-supportive care.
• 4-non-conventional therapy.
Surgery:
• Surgery was the first modality used
successfully in the treatment of cancer.
• It is the only curative therapy for many
common solid tumors.
• The most important determinant of a
successful surgical therapy are the absence
of distant metastases and no local
infiltration.
Cont:
• Microscopic invasion of surrounding normal
tissue will necessitate multiple frozen section.
• Resection or sampling of regional lymph node is
usually indicated.
• Surgery may be used for palliation in patients for
whom cure is not possible.
• Has significant role in cancer prevention.
– E.g familial polyposis coli.
Surgery for prevention:
• Patients with conditions that predispose
them to certain cancers or with genetic traits
Associated with cancer can have normal life
span with prophylactic surgery.
-colectomy .
-oophorectomy.
-thyroidectomy.
-removal of premalignant skin lesion .
Radiation therapy:
Radiation therapy:
• Radiation therapy: is a local modality used in the
treatment of cancer .
• Success depend in the difference in the radio
sensitivity between the tumor and normal tissue.
• It involves the administration of ionizing radiation
in the form of x-ray or gamma rays to the tumor
site.
• Method of delivery: External beam(teletherapy).
Internal beam therapy(Brachytherapy).
Cont:
• Radiation therapy is planned and performed
by a team of nurses, dosimetrists,physician
and radiation oncologist.
• A course of radiation therapy is preceded by
a simulation session in which low-energy
beam are used to produce radiograghic
images that indicate the exact beam
location.
Cont:
• Radiation therapy is usually delivered in
fractionated doses such as 180 to 300 cGy per
day,five times a week for a total course of 5-8
weeks.
• Radiation therapy with curative intent is the main
treatment in limited stage Hodgkin’s disease,some
NHL,limited stage ca prostate,gynecologic
tumors&CNS tumor .
• Also can use in palliative &emergency setting.
Complication of radiation:
• There is two types of toxicity ,acute and long term
toxicity.
• Systemic symptoms such as Fatigue,local skin
reaction,GI toxicity,oropharyngeal
mucositis&xerostomia.myelosuppression.
• Long-term sequelae:may occur many months or
years after radiation therapy.
• Radiation therapy is known to be
mutagenic,carcinogenic,and teratogen,and having
increased risk of developing both secondary
leukemia and solid tumor.
Nuclear medicine
Radionuclides:
• For decades have been used systemically to treat
malignant disorders.
• They are administer by specialists in nuclear
medicine or radiation oncologist.
• Radioactive iodine:in the from of 131I is effective
therapy for well differentiated thyroid ca
• Strontium-89. Is used for the treatment of body
metastasis.it is an alkaline earth element in the
same family as calcium
Chemotherapy:
Chemotherapy:
• Systemic chemotherapy is the main
treatment available for disseminated
malignant diseases.
• Progress in chemotherapy resulted in cure
for several tumors.
• Chemotherapy usually require multiple
cycles.
Classification of cytotoxic drug:
• Cytotoxic agent can be roughly categorized
based on their activity in relation to the cell
cycle.
cytotoxic drug
phase nonspecific.
phase specific
Cont :
• What is the difference between phase specific &
phase non specific?…..
• Phase non-specific:
– The drugs generally have a linear dose-response
curve( the drug administration ,the  the fraction of
cell killed).
• Phase specific:
– Above a certain dosage level,further increase in drug
doesn’t result in more cell killing.but you can play with
duration of infusion.
What are the chemotherapeutic
agent?…..
Chemotherapeutic agents:
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Alkylating agents:
Antimetabolites:
Antitumor antibiotic:
Plant alkaloids:
Other agents
Hormonal agent:
Immunotherapy:
Complication of Chemotherapy:
• Every chemotherapeutic will have some
deleterious side effect on normal tissue .
• E.G; Myelosuppression,nausea&vomiting,
Stomatitis,and alopecia are the most
frequently observed side effects.
Criteria used to describe response
are:
• Complete response (complete remission)is the
disappearance of all detectable malignant disease.
• Partial response:is decrease by more than 50% in
the sum of the products of the perpendicular
diameters of all measurable lesions.
• Stable disease:no increase in size of any lesion nor
the appearance of any new lesions.
• Progressive disease:means an increase by at least
25% in the sum of the products of the
perpendicular diameters of measurable lesion or
the appearance of new lesions.
Endocrine therapy:
Endocrine therapy:
• Many hormonal antitumor agents are functional agonist or
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antagonist of the steroid hormone family.
Adrenocorticoids:
Antiandrogen:
Estrogen:
Antiestrogen:
Progestins
Aromatase inhibitor:
Gonadotropin-releasing hormone agonists:
Somatostatin analogues:
Adrenocorticosteroid:
• Are frequently used in combination regimen for
the treatment of lymphocytic leukemia and
lymphoma.
• They function by binding to glucocorticoidspecific receptors present in lymphoid cells and
initiate programmed cell death
• They most commonly used agent are
prednisone,methylprednisone,dexamethosone.
Antiandrogens:
• Flutamide :
Effectively blocks the binding of androgen to
its receptor in the periphral tissue .
It is used in the treatment of disseminated
prostate ca
Biological therapy:
Biologic therapy:
• Immunotherapy:
– Cytokines
– Cellular therapy.
– Tumor vaccine:
• Hematopoietic growth factors.
Oncology
• The waves of the future:
• Stem Cell Research
• Oncogene therapy – now that cancer cells are
being genetically tagged, we can tell which growth
factors are present, and which enzymes turn off
the gene. Soon all gene markers will have a pill
that matches the enzyme, i.e. IRESSA is a
tyramine kinase inhibitor, and stops the tumors
growth that use tyramine kinase
Oncology
• Stem Cell Induction – there are new drugs out
for stem cell induction to immunosuppress the
patient, even in deadly cancers, i.e. Multiple
Myeloma. Recently, the combination of
lenalidomide(Revalamid), bortezomib
(Velcade) and dexamethasone produced a
98% response rate in patients
Oncology
• The waves of the future:
• Cancer vaccines
• Oncology is the science of cancer and
treatment of all cancer patients. It is one of
the most demanding and rewarding fields in
medicine.
• The future is open for a cure.
Oncology