oncology review

7/29/2019 Oncology Review

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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

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