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

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 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

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 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

Tissues of Origin

Epithelial Neuroectoderm Connective Lymph Synovia Mesothelium Blood cells Nerve

Anaplastic Tumor Cells with Mitotic Irregularities

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

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– 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