1. Concepts in Oncology Pathophysiology Bruce L Hotchkiss, PharmD., BCPS Assistant Professor of Clinical Pharmacy

2. Epidemiology n 30-50% of the U.S. Population will eventually have some type of cancer n Strikes any age –Kills more children 3-14 yrs of age compared to any other disease n 4 out of 10 alive at 5 yrs post diagnosis n Emphasis on identifying and avoiding carcinogenic factors coupled with early detection and possible chemoprevention.

3. Cancer Statistics 1999 New Cases / Deaths by Sex n 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% n 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% /

4. The Clinical Cancer Process n Risk Factor Assessment Genetic - heredity, acquired lifestyle - smoking, Alcohol, Fat,... Environmental - chemical, irradiation n Initiation - i.e. colon CA chemoprevention- OC’s, Tamoxifen, NSAIDS n Precancer Polyps, Dysplasia... Screening - - PAP, Mamo, PSA, Guiaic... n Invasive Cancer Diagnosis Therapeutic Plan Staging Psychosocial support

5. Cellular Growth Cycle

6. Characteristics of Cancer n Uncontrolled growth or division of cells that are genetically dysfunctional n Loss of differentiated characteristic n Loss of contact inhibition (Invasive) n Metastasis

7. Malignant Transformation n Believed to result from two or more mutations in the same cell n Initiators/ Promoters n Multiple etiologic factors n Carcinogenesis results from an accumulation of changes in an assortment of genes n Cells with High growth fractions are susceptible

8. Chromosomal Changes n Point Mutations n Translocations n Amplification n Insertions n Deletions n Frame shift

9. Chromosomal Changes

10. Oncogenes and Breakpoint Regions

11. Oncogenes/ Proto-oncogenes n Viral Oncogenes - Cells of vertebrates contain DNA that encodes viral information n Proto-oncogenes –All cells contain DNA sequences homologous to viral information n Protein products of genetic alterations –mutations yield qualitative and quantitative changes in protein production –Likely responsible for uncontrolled growth, loss of contact inhibition n Outside factors (chemical, irradiation) may cause mutations(point, deletion, insertion, translocation, amplification) that activate oncogenes and result in malignant transformation

12. Insertion of a Viral Oncogene

13. Multiple Mutations leading to Metastatic Colon Carcinoma

14. Malignant Transformation n Factors other than oncogenes must also be responsible for malignant transformation –Activated oncogenes have not been detected in the majority of human tumors n Tumor Suppressor Genes –Protein products of genes that inhibit cellular growth under normal conditions

15. Common Oncogenes, Proto-oncogenes, and Tumor- Suppressor genes n Oncogene/ Proto-onc. Cancer N-myc Neuroblastoma c-mycBreast erb-BBreast, Cervical, head rasAML ABLCML RASKLung, Ovarian, Bladder n Tumor Suppressor Genes p-53Breast, Lung BRCA-1 &2Breast/ Ovarian RBRetinoblastoma

16. Oncogenes in cell cycle control

17. Types of Proteins Involved with Malignant Characteristics n Growth factors n Growth factor receptors n Membrane-associated binding proteins (Integrins) n Cytoplasmic kinases n Nuclear proteins and transcription factors

18. Growth factor and Post-receptor factor control

19. Tumor Cell Proliferation n Transformed cell proliferates to form a clone –May be recognized and eliminated or may possess receptors for stimulation n Cancer cells prone to genetic mishaps –Thus heterogeneity of biochemical and morphological characteristics Explains why chemo or radRX may not kill all cells

20. Etiology of Cancer n 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

21. Etiology of Cancer n Genetic –Inherited mutations in tumor suppressor genes –BRCA-1, BRCA-2 - Breast Cancer –RB-1 - Retinoblastoma –APC - Colon CA

22. Etiology of Cancer n 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

23. Etiology of Cancer n 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.

24. Etiology of Cancer n 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

25. Etiology of Cancer n 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

26. Tumor Growth Kinetics n 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

27. Tumor Mass n 1 cm tumor has approx. 1 billion cells n From 1 cell to 1 billion = approx.. 30 doublings –This process takes an average of 5-8 years to occur n 10 additional doublings to reach 1 Kg –1-2 kg mass load considered lethal n Thus undetectable for much of it’s life then appears to rapidly progress

28. Tissues of Origin n Epithelial n Neuroectoderm n Connective n Lymph n Synovia n Mesothelium n Blood cells n Nerve

29. Anaplastic Tumor Cells with Mitotic Irregularities

30. Characteristics of Benign and Malignant Tumors

31. Benign Tumors n 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

32. Tumor Classification/ Staging n Classified according to their tissue of origin –Histological types respond differently to therapy and prognosis varies significantly n Staging –Various Systems –Clinical, Surgical, Pathologic criteria – T, N, M

33. Hematological Malignancies n Acute Leukemia's Acute Lymphoblastic Leukemia (ALL) Acute Myeloblastic Leukemia (AML) n Chronic Leukemia's Chronic Lymphocytic Leukemia (CLL) Chronic Myelocytic Leukemia (CML) n Lymphomas Hodgkin's Non-Hodgkin's (NHL) Other

34. Colon Carcinoma n Heiteditary –FAP - Hereditary polyposis –HNCC- n Non-Hereditary

35. Breast Carcinoma n Atypical Hyperplasia n Lobular carcinoma insitu n Ductal carcinoma insitu n Invasive Breast Carcinomas n Inflammatory/ Pagets Disease of nipple

36. Prostate Cancer n Variable Progression rates n Gleason score (range 2-10) –Histologic appearance (grade 1-5) –(Primary + secondary) n Prostate Specific Antigen (PSA) –Free vs Bound

37. Lung Cancer n Small Cell Lung Cancer n Non Small Cell Lung Cancer

38. Cancer Diagnosis n Screening –Criteria for test Sensitive and specific acceptable to target population –not excessively painful or inconvenient low risk economically justifiable to society

39. Current Screening Programs n Breast n Prostate n Colorectal n Cervical n Testicular n Skin

40. Diagnosis in Symptomatic Individuals n Symptoms from invading, obstructing or displacing normal structures n 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

41. Clinically Useful Tumor Markers n MARKER –Alpha-fetoprotein (AFP) –Carcinoembryonic antigen (CEA) –Human chorionic gonadotropin (HCG) –Calcitonin –Prostate Specific Antigen (PSA) –Carcinoma antigen-125 (CA-125) –Immunoglobulins n ASSOCIATED CA –Liver, testes –Colon, lung, breast –Germ Cell tumors –Medullary thyroid CA –Prostate –Ovary –Multiple myeloma