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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 1999 New Cases / Deaths by Sex Male – – – – – – – – – Prostate 29% / Lung 15% / Colon 10% / Bladder 6% / NHL 5% / Melanoma 4% / Leukemia 3% / Renal 3% / Pancreas 2% / 3% 31% 10% 3% 5% 4% 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 • lifestyle • Environmental Initiation - heredity, acquired - smoking, Alcohol, Fat, ... - chemical, irradiation - i.e. colon CA • chemoprevention- OC’s, Tamoxifen, NSAIDS Precancer • Polyps, Dysplasia... • Screening - PAP, Mamo, PSA, Guiaic... Invasive Cancer • Diagnosis • Staging • Therapeutic Plan • Psychosocial support Cellular Growth Cycle 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 Chromosomal Changes Point Mutations Translocations Amplification Insertions Deletions Frame shift Chromosomal Changes Oncogenes and Breakpoint Regions 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 Insertion of a Viral Oncogene Multiple Mutations leading to Metastatic Colon Carcinoma 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 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 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 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 agentslymphoma – 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 Tissues of Origin 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 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 Colon Carcinoma Heiteditary – FAP - Hereditary polyposis – HNCC- Non-Hereditary 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 Lung Cancer Small Cell Lung Cancer Non Small Cell Lung Cancer Cancer Diagnosis 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 Breast Prostate Colorectal Cervical Testicular Skin 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 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