Concepts in Oncology Pathophysiology
Bruce L Hotchkiss, PharmD., BCPS
Assistant Professor of Clinical Pharmacy
Epidemiology
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 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 1999New Cases / Deaths by Sex
Male– Prostate 29% / 3%
– Lung 15% / 31%
– Colon 10% / 10%
– Bladder 6% / 3%
– NHL 5% / 5%
– Melanoma 4% /
– Leukemia 3% / 4%
– Renal 3% /
– Pancreas 2% / 5%
Female– 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 Risk Factor Assessment
• Genetic - heredity, acquired
• lifestyle - smoking, Alcohol, Fat, ...
• Environmental - chemical, irradiation
Initiation - i.e. colon CA
• chemoprevention- OC’s, Tamoxifen, NSAIDS
Precancer• Polyps, Dysplasia...• Screening - - PAP, Mamo, PSA, Guiaic...
Invasive Cancer• Diagnosis • Therapeutic Plan • Staging • Psychosocial support
Characteristics of Cancer
Uncontrolled growth or division of cells that are genetically dysfunctional
Loss of differentiated characteristic Loss of contact inhibition (Invasive) Metastasis
Malignant Transformation
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
Oncogenes/ Proto-oncogenes 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
Malignant Transformation
Factors other than oncogenes must also be responsible for malignant transformation– Activated oncogenes have not been
detected in the majority of human tumors Tumor Suppressor Genes
– Protein products of genes that inhibit cellular growth under normal conditions
Common Oncogenes, Proto-oncogenes, and Tumor- Suppressor genes Oncogene/ Proto-onc. Cancer
• N-myc Neuroblastoma• c-myc Breast• erb-B Breast, Cervical, head• ras AML• ABL CML• RASK Lung, Ovarian, Bladder
Tumor Suppressor Genes• p-53 Breast, Lung• BRCA-1 &2 Breast/ Ovarian• RB Retinoblastoma
Types of Proteins Involved with Malignant Characteristics Growth factors Growth factor receptors Membrane-associated binding proteins
(Integrins) Cytoplasmic kinases Nuclear proteins and transcription
factors
Tumor Cell Proliferation
Transformed cell proliferates to form a clone– May be recognized and eliminated or may
possess receptors for stimulation 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 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
Genetic– Inherited mutations in tumor suppressor
genes– BRCA-1, BRCA-2 - Breast Cancer – RB-1 - Retinoblastoma– APC - Colon CA
Etiology of Cancer
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 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
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 Drug Therapy
– Alkylating agent- leukemia– Cyclophosphamide therapy- bladder CA– Long term immunosuppressive agents-
lymphoma– Estrogen and tamoxifen- endometrial CA– Oral contraceptives and post-menopausal
hormone replacement - breast CA
Tumor Growth Kinetics
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 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 10 additional doublings to reach 1 Kg
– 1-2 kg mass load considered lethal Thus undetectable for much of it’s life then
appears to rapidly progress
Characteristics of Benign and Malignant TumorsCharacteristics Benign Tumors Malignant Tumors
Rate of growth Slow Unpredictable,unrestrained
Morphologicallytypical of tissue oforigin
Yes No
Encapsulated Yes No
Recurrence aftersurgical removal
Rare Common
Potential tometastasize
No Yes, local anddistant
Benign Tumors
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
Classified according to their tissue of origin– Histological types respond differently to
therapy and prognosis varies significantly Staging
– Various Systems– Clinical, Surgical, Pathologic criteria– T, N, M
Hematological Malignancies Acute Leukemia's
• Acute Lymphoblastic Leukemia (ALL)
• Acute Myeloblastic Leukemia (AML)
Chronic Leukemia's• Chronic Lymphocytic Leukemia (CLL)
• Chronic Myelocytic Leukemia (CML)
Lymphomas• Hodgkin's
• Non-Hodgkin's (NHL)
• Other
Breast Carcinoma
Atypical Hyperplasia Lobular carcinoma insitu Ductal carcinoma insitu Invasive Breast Carcinomas Inflammatory/ Pagets Disease of nipple
Prostate Cancer
Variable Progression rates
Gleason score (range 2-10)– Histologic appearance (grade 1-5) – (Primary + secondary)
Prostate Specific Antigen (PSA)– Free vs Bound
Cancer Diagnosis
Screening– Criteria for test
• Sensitive and specific• acceptable to target population
– not excessively painful or inconvenient
• low risk• economically justifiable to society
Diagnosis in Symptomatic Individuals 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
MARKER– Alpha-fetoprotein (AFP)
– Carcinoembryonic antigen (CEA)
– Human chorionic gonadotropin (HCG)
– Calcitonin
– Prostate Specific Antigen (PSA)
– Carcinoma antigen-125 (CA-125)
– Immunoglobulins
ASSOCIATED CA– Liver, testes
– Colon, lung, breast
– Germ Cell tumors
– Medullary thyroid CA
– Prostate
– Ovary
– Multiple myeloma