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 control mechanisms.
• Impair normal function by local tissue invasion
  and destruction, mets to distant sites.
  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,vascular invasion, direct implantation.

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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.

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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 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

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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.

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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, AFP 5 days

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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.

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Oncogenesis

• Neoplasms can arise from carcinogenesis
  (smoking), viruses (EBV), or immunodeficiency
  (HIV).
• Retroviruses contain oncogenes EBV associated
  with Burkitts Lymphoma (814 translocation) and
  nasopharyngeal cancer (c-myc).
• Protooncogenes are human genes with malignant
  potential.

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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.

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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-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 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.

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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

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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 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.

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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 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.

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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) is
  nephrotoxic, 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 mandrake plant, a plant
  alkaloid.

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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

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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.

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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.

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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.

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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).

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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 and cytoskeleton
  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 existing therapy?
• Phase IV- implementation and marketing.

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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.

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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.

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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. Metastatic testicular 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 Kaposis sarcoma,
  non-Hodgkins lymphoma.

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Blots

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