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Oncology Review
Vic V. Vernenkar, D.O.
Dept. Of Surgery
St. Barnabas Hospital
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Definitions
Neoplasms: abnormal growth of tissue
characterized by excessive cell division
unresponsive to normal controlmechanisms.
Impair normal function by local tissue
invasion and destruction, mets to distantsites. Differentiates it from benign.
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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,vascularinvasion, direct implantation.
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The Metastatic Process
Inefficient, multistep process. Called themetastatic cascade.
Detachment and invasion: pass in to lymphaticor venous system.
Transport: to a distant site of growth. Has tosurvive a bunch of host defenses on the way.
Arrest and extravasation: Stuck up in targetorgan. Digestion of BM to invade.
Establishment of new growth.
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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.
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Tumor Markers
CEA- Colon cancer elevated in 60% preop. Also
elevated in cirrhosis, COPD, pancreatitis,
cholecystitis, diverticulitis, UC, breast cancertoo.
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
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Tumor Markers
CA125- Ovarian ca. Not useful asdiagnostic tool, produced by other cancers
like lung, colon. Also non-malignant likecirrhosis, gynecomastia.
Beta-HCG- Testicular cancer,choriocarcinoma
PSA- Prostate cancer correlates withtumor burden.
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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, AFP5 days
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Oncogenesis
Cancer Transformation: inheritable alterationin genome, loss of growth regulation.
Latency Period: Dose dependent.Timebetween 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.
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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 (c-
myc). Protooncogenes are human genes with
malignant potential.
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Definitions
Oncogenes are genes capable of causingcancer.
Proto-oncogenes code for a number of proteinproducts (growth factors, kinases, etc). Theexpression is well controlled, playing a role innormal growth and development.
The genes are activated by mutation,amplification, or translocation. Activation canlead to the loss of normal regulation anddifferentiation, increased proliferation.
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Proto-oncogenes
ras- proto-oncogene: a G protien defect.
SRC proto-oncogene: tyrosine kinasedeficiency.
Sis proto-oncogene: platelet derived growthfactor receptor defect.
Erb B proto-oncogene- epidermal growth factor
receptor defect. Myc (c-myc, n-myc, l-myc) proto-oncogenes-
nuclear factors.
HER-2/neu over expression in 15-30% of pts
with breast cancer.
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Proto-oncogenes
LiFraumeni syndrome: defect in p53 gene.Patients get childhood sarcomas, breast cancer,brain tumors, leukemia, adrenal cancer.
Medullary thyroid cancer: associated with Retproto-oncogene on chr 10. Patients with Retoncogene defect plus family history- 90% getmedullary cancer of thyroid, need totalthyroidectomy.
MENIN a product of MEN1 gene also associatedwith medullary cancer of thyroid.
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Tumor Suppressor Genes
Retinoblastoma (RB1)- chr 13: involved in cell
cycle.
P53- chr 17: involved in cell cycle (normal geneinduces 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
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Carcinogens
Coal tar: larynx, skin, bronchial CA
Beta-naphthylamine (used in dye
industry)- urinary tract, bladder CA.
Benzene- leukemia
Asbestos- mesothelioma
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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.
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Radiation Therapy
Main target is DNA, O2 radicals causedamage of DNA and other molecules.
XRT can itself also cause damage bycausing small breaks in DNA.
Risk of long-term injury depends on typeand amount of tissue irradiated, total dose,amount of dose given with each fraction,rather than duration of therapy.
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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.
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Radiation Therapy
Kidneys, lung, liver, lymphocytes haveincreased sensitivity to radiation.
Large tumors are less responsive toradiation due to lack of oxygen in thetumor.
Brachytherapy: source of radiation in ornext to tumor, delivering high concentrateddoses of radiation.
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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.
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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.
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Chemotherapy
Bleomycin and busulfan- cause
pulmonary fibrosis.
Cisplatin (platinum alkylating agents) isnephrotoxic, neurotoxic, ototoxic.
Carboplatin- bone (myelosupression).
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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 mandrakeplant, a plant alkaloid.
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Chemotherapy
Alkylating agents: transfer alkyl groups, forming
covalent bonds.
Cyclophosphamide - side effects are gonadaldysfunction, SIADH, hemorrhagic cystitis.
Melphalan, another alkylating agent used fro
multiple myeloma.
Chlorambucil, for CLL.
Isosphamide
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Chemotherapy
Levamisole-antihelminthic drug whichstimulates immune system.
Methotrexate (antimetabolite)- inhibitsdihydrofolate reductase, which inhibitspurine and DNA synthesis. Side effectsare nephrotoxicity.
Leukovorin rescue- decreases folate;reverses effects of methotrexate.
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Chemotherapy
5-Flourouracil (antimetabolite)- inhibitsthymidalate synthesis, which inhibits
purine and DNA synthesis. Leukovorin increases the toxicity of 5FU.
Doxorubicin (adriamycin)- DNAintercalater, O2 radical formation. Cardiactoxicity secondary to O2 radicals at>500mg/m2.
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Chemotherapy
DTIC is the most active single therapeutic
agent in metastatic melanoma, response
rates are 15-25%. As adjuvant chemohowever, not shown to be beneficial.
Interferon response rates for melanoma
are 10-20%, partial and short-lived.
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Chemotherapy
Least myelosuppression: bleomycin,
vincristine, busulfan, cisplatin.
GCSF (granulocyte colony stimulatingfactor) used for neutrophil recovery after
chemo. Side effects: Sweets syndrome
(acute febrile neutropenic dermatitis).
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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.
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Colon Cancer
Genes involved are APC, p53, DCC, and
K-ras.
APC involved in cell adhesion andcytoskeleton function- thought to be the
initial mutation in the development of colon
cancer. Colon cancer does not go to bone.
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Clinical Trials
Phase I- is it safe and at what dose?
Phase II- is it effective?
Phase III- is it better than existingtherapy?
Phase IV- implementation and marketing.
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Types of Therapy
Induction: Sole treatment, often used foradvanced disease or when no other treatmentexists.
Primary (neoadjuvant) chemotherapy: givenfirst, followed by another (secondary) treatment.
Adjuvant: Combined with another modality,given after other treatment is used.
Salvage: for tumors that fail to respond to initialchemotherapy.
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Odds and Ends
Colon mets to liver: 25% 5-year survival if
successfully resected.
Most successfully cured mets withsurgery: colon cancer in liver, sarcoma to
lung, melanoma to lung, but survival is still
low overall for all of them.
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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. Metastatictesticular cancer (Cisplatin, VP-16, Bleomycin).
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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: Kaposissarcoma, non-Hodgkins lymphoma.
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Blots
Southern Blot: Used to isolate and
analyze DNA.
Northern Blot: Used to characterizemRNA.
Western Blot: Proteins are identified