Transcript Concepts in Oncology Therapeutics

Concepts in Oncology
Pathophysiology
Bruce L Hotchkiss, PharmD., BCPS
Assistant Professor of Clinical Pharmacy
Epidemiology
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30-50% of the U.S. Population will
eventually have some type of cancer
Strikes any age
– Kills more children 3-14 yrs of age compared
to any other disease
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4 out of 10 alive at 5 yrs post diagnosis
Emphasis on identifying and avoiding
carcinogenic factors coupled with early
detection and possible chemoprevention.
Cancer Statistics 1999
New Cases / Deaths by Sex
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Male
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Prostate 29% /
Lung
15% /
Colon
10% /
Bladder
6% /
NHL
5% /
Melanoma 4% /
Leukemia 3% /
Renal
3% /
Pancreas 2% /
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3%
31%
10%
3%
5%
4%
5%
Female
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–
–
–
–
–
–
Breast
29% / 16%
Lung
13% / 25%
Colon
11% / 11%
Uterus
6% / 2%
Ovary
4% / 5%
NHL
4% / 5%
Melanoma 3% /
Bladder
3% /
Pancreas 2% / 5%
Thyroid
2% /
The Clinical Cancer Process
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Risk Factor Assessment
• Genetic
• lifestyle
• Environmental
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Initiation
- heredity, acquired
- smoking, Alcohol, Fat, ...
- chemical, irradiation
- i.e. colon CA
• chemoprevention- OC’s, Tamoxifen, NSAIDS
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Precancer
• Polyps, Dysplasia...
• Screening - PAP, Mamo, PSA, Guiaic...
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Invasive Cancer
• Diagnosis
• Staging
• Therapeutic Plan
• Psychosocial support
Cellular Growth Cycle
Characteristics of Cancer
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Uncontrolled growth or division of cells
that are genetically dysfunctional
Loss of differentiated characteristic
Loss of contact inhibition (Invasive)
Metastasis
Malignant Transformation
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Believed to result from two or more
mutations in the same cell
Initiators/ Promoters
Multiple etiologic factors
Carcinogenesis results from an
accumulation of changes in an
assortment of genes
Cells with High growth fractions are
susceptible
Chromosomal Changes
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Point Mutations
Translocations
Amplification
Insertions
Deletions
Frame shift
Chromosomal Changes
Oncogenes and Breakpoint Regions
Oncogenes/ Proto-oncogenes
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Viral Oncogenes - Cells of vertebrates contain DNA
that encodes viral information
Proto-oncogenes
– All cells contain DNA sequences homologous to
viral information
Protein products of genetic alterations
– mutations yield qualitative and quantitative
changes in protein production
– Likely responsible for uncontrolled growth, loss of
contact inhibition
Outside factors (chemical, irradiation) may cause
mutations(point, deletion, insertion, translocation,
amplification) that activate oncogenes and result in
malignant transformation
Insertion of a Viral Oncogene
Multiple Mutations leading to
Metastatic Colon Carcinoma
Malignant Transformation
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Factors other than oncogenes must also
be responsible for malignant
transformation
– Activated oncogenes have not been
detected in the majority of human tumors
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Tumor Suppressor Genes
– Protein products of genes that inhibit
cellular growth under normal conditions
Common Oncogenes, Proto-oncogenes, and
Tumor- Suppressor genes
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Oncogene/ Proto-onc. Cancer
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N-myc
c-myc
erb-B
ras
ABL
RASK
Neuroblastoma
Breast
Breast, Cervical, head
AML
CML
Lung, Ovarian, Bladder
Tumor Suppressor Genes
• p-53
• BRCA-1 &2
• RB
Breast, Lung
Breast/ Ovarian
Retinoblastoma
Oncogenes in cell cycle control
Types of Proteins Involved with
Malignant Characteristics
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Growth factors
Growth factor receptors
Membrane-associated binding proteins
(Integrins)
Cytoplasmic kinases
Nuclear proteins and transcription
factors
Growth factor and Post-receptor
factor control
Tumor Cell Proliferation
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Transformed cell proliferates to form a
clone
– May be recognized and eliminated or may
possess receptors for stimulation
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Cancer cells prone to genetic mishaps
– Thus heterogeneity of biochemical and
morphological characteristics
• Explains why chemo or radRX may not kill all
cells
Etiology of Cancer
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Viruses
– Epstein-Barr virus
• Burkitt’s lymphoma
• Nasopharyngeal carcinoma
– Hepatitis B, Hepatitis C
• Hepatocellular carcinoma
– Human papilloma virus
• Cervical carcinoma
– HTLV1
• Adult T-cell lymphoma
Etiology of Cancer
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Genetic
– Inherited mutations in tumor suppressor
genes
– BRCA-1, BRCA-2 - Breast Cancer
– RB-1 - Retinoblastoma
– APC - Colon CA
Etiology of Cancer
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Environment/ occupation
– Chimney sweeps- scrotal cancer
– Aniline dye- bladder cancer
– Benzene- acute leukemia
– Asbestos- mesothelioma
– Sunlight- skin (melanoma)
– Cigarette- lung cancer
• esp if in conjunction with asbestos, chromate or
uranium exposure
Etiology of Cancer
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Lifestyle
– Cigarette
• 80% of lung cancers in the United States is
related to smoking
– Radiation exposure
• Atomic bomb- leukemia and breast cancer
• Radiation to neck as child- thyroid cancer
– Radon
• 40,000-50,000 cases of lung cancer per year in
U.S.
Etiology of Cancer
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Diet
– High Fat, low residue diets, carcinogens
take longer to pass through and expose
lining of the large bowel for increased time
• Colon, breast, prostate, ovarian
– Alcohol
• oropharynx, esophageal, gastric, liver, breast
and larynx
Etiology of Cancer
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Drug Therapy
– Alkylating agent- leukemia
– Cyclophosphamide therapy- bladder CA
– Long term immunosuppressive agentslymphoma
– Estrogen and tamoxifen- endometrial CA
– Oral contraceptives and post-menopausal
hormone replacement - breast CA
Tumor Growth Kinetics
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Doubling time
– time it take a tumor mass to double in size
– Solid tumors
• Averages 2-3 month
• Range 1 month to several years
– Breast CA , average 100 days
– Hematological malignancies
• May be as short as a day
– Burkitt’s Lymphoma
Tumor Mass
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1 cm tumor has approx. 1 billion cells
From 1 cell to 1 billion = approx.. 30
doublings
– This process takes an average of 5-8 years
to occur
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10 additional doublings to reach 1 Kg
– 1-2 kg mass load considered lethal
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Thus undetectable for much of it’s life
then appears to rapidly progress
Tissues of Origin
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Epithelial
Neuroectoderm
Connective
Lymph
Synovia
Mesothelium
Blood cells
Nerve
Anaplastic Tumor Cells with Mitotic
Irregularities
Characteristics of Benign and
Malignant Tumors
Characteristics
Benign Tumors
Malignant Tumors
Rate of growth
Slow
Unpredictable,
unrestrained
Morphologically
typical of tissue of
origin
Yes
No
Encapsulated
Yes
No
Recurrence after
surgical removal
Rare
Common
Potential to
metastasize
No
Yes, local and
distant
Benign Tumors
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Though they lack most of the other
harmful characteristics of cancer
– May be characterized by uncontrolled
cellular division
– Can lead to death if the tumor continues to
grow in a vital tissue and interrupts normal
function
Tumor Classification/ Staging
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Classified according to their tissue of
origin
– Histological types respond differently to
therapy and prognosis varies significantly
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Staging
– Various Systems
– Clinical, Surgical, Pathologic criteria
– T, N, M
Hematological Malignancies
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Acute Leukemia's
• Acute Lymphoblastic Leukemia (ALL)
• Acute Myeloblastic Leukemia (AML)
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Chronic Leukemia's
• Chronic Lymphocytic Leukemia (CLL)
• Chronic Myelocytic Leukemia (CML)
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Lymphomas
• Hodgkin's
• Non-Hodgkin's (NHL)
• Other
Colon Carcinoma
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Heiteditary
– FAP - Hereditary polyposis
– HNCC-
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Non-Hereditary
Breast Carcinoma
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Atypical Hyperplasia
Lobular carcinoma insitu
Ductal carcinoma insitu
Invasive Breast Carcinomas
Inflammatory/ Pagets Disease of nipple
Prostate Cancer
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Variable Progression rates
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Gleason score (range 2-10)
– Histologic appearance (grade 1-5)
– (Primary + secondary)
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Prostate Specific Antigen (PSA)
– Free vs Bound
Lung Cancer
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Small Cell Lung Cancer
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Non Small Cell Lung Cancer
Cancer Diagnosis
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Screening
– Criteria for test
• Sensitive and specific
• acceptable to target population
– not excessively painful or inconvenient
• low risk
• economically justifiable to society
Current Screening Programs
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Breast
Prostate
Colorectal
Cervical
Testicular
Skin
Diagnosis in Symptomatic
Individuals
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Symptoms from invading, obstructing or
displacing normal structures
Paraneoplastic symptoms
– Result of biologically or immunologically
active substances that are secreated by
the tumor
– Thrombophlebitis, SIADH, Myasthenic
syndrome, Hypercalcemia, DIC, Cushing’s,
Autoimmune hemolytic anemia, Addison’s
Clinically Useful Tumor Markers
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MARKER
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ASSOCIATED CA
– Alpha-fetoprotein (AFP)
– Liver, testes
– Carcinoembryonic antigen (CEA)
– Colon, lung, breast
– Human chorionic gonadotropin (HCG) – Germ Cell tumors
– Calcitonin
– Medullary thyroid CA
– Prostate Specific Antigen (PSA)
– Prostate
– Carcinoma antigen-125 (CA-125)
– Ovary
– Immunoglobulins
– Multiple myeloma