Oncology Review

Vic V. Vernenkar, D.O. Dept. Of Surgery St. Barnabas Hospital

Definitions

Neoplasms: abnormal growth of tissue characterized by excessive cell division unresponsive to normal control mechanisms. Impair normal function by local tissue invasion and destruction, mets to distant sites. Differentiates it from benign.

Definitions

Carcinoma-in-situ: cytologic characteristics of malignancy, but no BM invasion. There are 4 mechanisms in the dissemination of cancer cells: tissue infiltration, lymphatic invasion,vascular invasion, direct implantation.

The Metastatic Process

Inefficient, multistep process. Called the metastatic cascade. Detachment and invasion: pass in to lymphatic or venous system. Transport: to a distant site of growth. Has to survive a bunch of host defenses on the way. Arrest and extravasation: Stuck up in target organ. Digestion of BM to invade. Establishment of new growth.

Cancer Spread

Supraclavicular: breast, lung, stomach (Virchows), pancreas. Axillary: lymphoma (#1), breast, melanoma. Periumbilical: pancreas (SMJ node). Ovarian: stomach (Krukenberg tumor), colon. Bone mets: Breast (#1), prostate. Skin mets: breast, melanoma.

Tumor Markers

CEA- Colon cancer elevated in 60% preop. Also elevated in cirrhosis, COPD, pancreatitis, cholecystitis, diverticulitis, UC, breast cancer too. AFP- Liver cancer (also a oncofetoprotein) Elevated in cirrhosis, other non-malignant things. 80% sens for hepatocellular ca, 60% sens for testicular cancer. CA 19-9 Pancreatic cancer

Tumor Markers

CA125- Ovarian ca. Not useful as diagnostic tool, produced by other cancers like lung, colon. Also non-malignant like cirrhosis, gynecomastia. Beta-HCG- Testicular cancer, choriocarcinoma PSA- Prostate cancer correlates with tumor burden.

Tumor Markers

NSE- Small cell lung cancer, neuroblastoma BRCA I (5% of breast ca) chr 17- 85% lifetime risk of breast cancer BRCA II chr 13 same risk. Half-lives- CEA 8 days, PSA 18 days, AFP 5 days

Oncogenesis

Cancer Transformation: inheritable alteration in genome, loss of growth regulation. Latency Period: Dose dependent.Time between exposure and clinical detected tumor. Initiation: carcinogen acts irreversibly with DNA. Promotion of cancer cells,a slow reversible process. Occurs during latency period. Progression of cancer cells to clinically detected tumor.

Oncogenesis

Neoplasms can arise from carcinogenesis (smoking), viruses (EBV), or immunodeficiency (HIV). Retroviruses contain oncogenes: EBV associated with Burkitts Lymphoma (8:14 translocation) and nasopharyngeal cancer (cmyc). Protooncogenes are human genes with malignant potential.

Definitions

Oncogenes are genes capable of causing cancer. Proto-oncogenes code for a number of protein products (growth factors, kinases, etc). The expression is well controlled, playing a role in normal growth and development. The genes are activated by mutation, amplification, or translocation. Activation can lead to the loss of normal regulation and differentiation, increased proliferation.

Proto-oncogenes

ras- proto-oncogene: a G protien defect. SRC proto-oncogene: tyrosine kinase deficiency. Sis proto-oncogene: platelet derived growth factor receptor defect. Erb B proto-oncogene- epidermal growth factor receptor defect. Myc (c-myc, n-myc, l-myc) proto-oncogenesnuclear factors. HER-2/neu over expression in 15-30% of pts with breast cancer.

Proto-oncogenes

LiFraumeni syndrome: defect in p53 gene. Patients get childhood sarcomas, breast cancer, brain tumors, leukemia, adrenal cancer. Medullary thyroid cancer: associated with Ret proto-oncogene on chr 10. Patients with Ret oncogene defect plus family history- 90% get medullary cancer of thyroid, need total thyroidectomy. MENIN a product of MEN1 gene also associated with medullary cancer of thyroid.

Tumor Suppressor Genes

Retinoblastoma (RB1)- chr 13: involved in cell cycle. P53- chr 17: involved in cell cycle (normal gene induces cell cycle arrest and apoptosis, abnormal gene allows unrestrained cell growth. APC- chr 5; involved with cell adhesion and cytoskeleton function. BRCA I and II

Carcinogens

Coal tar: larynx, skin, bronchial CA Beta-naphthylamine (used in dye industry)- urinary tract, bladder CA. Benzene- leukemia Asbestos- mesothelioma

Radiation Therapy

Nucleus is main target. M phase: most vulnerable stage of cell cycle for XRT. Most damage done by formation of O2 radicals, with maximal effect at high O2 levels. The units of radiation is the Gy or 1 joule of absorbed energy per kilo of tissue. 100 rad = 1Gy.

Radiation Therapy

Main target is DNA, O2 radicals cause damage of DNA and other molecules. XRT can itself also cause damage by causing small breaks in DNA. Risk of long-term injury depends on type and amount of tissue irradiated, total dose, amount of dose given with each fraction, rather than duration of therapy.

Radiation Therapy

Higher energy radiation has skin preserving effect as deep tissues effected. Fractionated doses allow repair of normal cells (90% in 4-6h), reoxygenation of tumor, redistribution of tumor cells in cell cycle. Very radiosensitive tumors: seminomas, lymphomas. Very radioresistant: epithelial, sarcomas.

Radiation Therapy

Kidneys, lung, liver, lymphocytes have increased sensitivity to radiation. Large tumors are less responsive to radiation due to lack of oxygen in the tumor. Brachytherapy: source of radiation in or next to tumor, delivering high concentrated doses of radiation.

Chemotherapy Agents

Cell cycle specific agents: Antimetabolites (5-FU, methotrexate) exhibit plateau in cell killing ability. Cell cycle non-specific agents: linear response to cell killing.

Chemotherapy Agents

Tamoxifen (blocks estrogen receptor) decreases short-term risk of breast cancer by 45%, risk of blood clots, endometrial cancer. Taxol: promotes microtubule formation and stabilization that cannot be broken down; cells are ruptured. From Pacific Yew Tree. Significant activity in Ovarian cancer. Arimidex (anastrozole) an aromatase inhibitor, blocks conversion of steroids to estrogen.

Chemotherapy

Bleomycin and busulfan- cause pulmonary fibrosis. Cisplatin (platinum alkylating agents) is nephrotoxic, neurotoxic, ototoxic. Carboplatin- bone (myelosupression).

Chemotherapy

Vincristine, a plant alkaloid (microtubule inhibitor)- peripheral neuropathy, neurotoxic. Vinblastine, a plant alkaloid - bone (myelosuppression). Both from Periwinkle plant, both arrest mitosis in metaphase. Etoposide(VP-16): inhibits topoisomerase which normally unwinds DNA.From mandrake plant, a plant alkaloid.

Chemotherapy

Alkylating agents: transfer alkyl groups, forming covalent bonds. Cyclophosphamide - side effects are gonadal dysfunction, SIADH, hemorrhagic cystitis. Melphalan, another alkylating agent used fro multiple myeloma. Chlorambucil, for CLL. Isosphamide

Chemotherapy

Levamisole-antihelminthic drug which stimulates immune system. Methotrexate (antimetabolite)- inhibits dihydrofolate reductase, which inhibits purine and DNA synthesis. Side effects are nephrotoxicity. Leukovorin rescue- decreases folate; reverses effects of methotrexate.

Chemotherapy

5-Flourouracil (antimetabolite)- inhibits thymidalate synthesis, which inhibits purine and DNA synthesis. Leukovorin increases the toxicity of 5FU. Doxorubicin (adriamycin)- DNA intercalater, O2 radical formation. Cardiac toxicity secondary to O2 radicals at >500mg/m2.

Chemotherapy

DTIC is the most active single therapeutic agent in metastatic melanoma, response rates are 15-25%. As adjuvant chemo however, not shown to be beneficial. Interferon response rates for melanoma are 10-20%, partial and short-lived.

Chemotherapy

Least myelosuppression: bleomycin, vincristine, busulfan, cisplatin. GCSF (granulocyte colony stimulating factor) used for neutrophil recovery after chemo. Side effects: Sweets syndrome (acute febrile neutropenic dermatitis).

Resection for Prevention

Colon: FAP Breast: BRCA I and II with strong family history. Thyroid: RET proto-oncogene or MENIN gene with family history of MEN or thyroid cancer.

Colon Cancer

Genes involved are APC, p53, DCC, and K-ras. APC involved in cell adhesion and cytoskeleton function- thought to be the initial mutation in the development of colon cancer. Colon cancer does not go to bone.

Clinical Trials

Phase I- is it safe and at what dose? Phase II- is it effective? Phase III- is it better than existing therapy? Phase IV- implementation and marketing.

Types of Therapy

Induction: Sole treatment, often used for advanced disease or when no other treatment exists. Primary (neoadjuvant) chemotherapy: given first, followed by another (secondary) treatment. Adjuvant: Combined with another modality, given after other treatment is used. Salvage: for tumors that fail to respond to initial chemotherapy.

Odds and Ends

Colon mets to liver: 25% 5-year survival if successfully resected. Most successfully cured mets with surgery: colon cancer in liver, sarcoma to lung, melanoma to lung, but survival is still low overall for all of them.

Odds and Ends

Ovarian ca: one of the few tumors for which surgical debulking improves chemotherapy (not seen in other tumors). Curable solid tumors with chemotherapy: Hodgkins disease (MOPP, MOPP/ABV), low grade, intermediate non-Hodgkins lymphoma (CHOP). Most lymphomas are B-cell. Metastatic testicular cancer (Cisplatin, VP-16, Bleomycin).

Odds and Ends

MOPP is nitrogen mustard, vincristine (oncovin), procarbazine, prednisone. ABV is adriamycin, bleomycin, vinblastine. CHOP is cyclophosphamide, adriamycin, vincristine (oncovin), prednisone. HIV related malignancies: Kaposis sarcoma, non-Hodgkins lymphoma.

Blots

Southern Blot: Used to isolate and analyze DNA. Northern Blot: Used to characterize mRNA. Western Blot: Proteins are identified