The Process of Carcinogenesis

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The Process of Carcinogenesis

• Lynn Marzinski RN, MSN, AOCN
• Oncology Clinical Nurse Specialist
• The Cancer Institute-Wornall

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Introduction

• Normal growth is rigidly controlled
• Genes promote growth - Oncogenes
• Genes inhibit growth Suppressors
• Damaged cells are repaired
• When unable to be fixed cell dies
• Apoptosis
• Limit to number of times a cell can replicate
• Telomere located at end of chromosome
• Not completely copied with each replication
• When they get too short, cell cannot replicate

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Apoptosis

• Programmed cell death
• Activation of endogenous proteases
• Digest the cell from inside out
• Cell membrane develops bubbles
• Apoptotic bodies
• Causes phagocytosis
• No inflammatory response
• Cytoplasm is not released
• May stimulate apoptosis as a means of cancer
  treatment

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What is Cancer

• Large group of diseases characterized by
• Abnormal Cell Structure
• Uncontrolled growth
• Ability to spread
• Ability to invade normal tissue
• Measured by grade and stage

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Carcinogenesis

• Clonal Selection
• Mutation occurs affecting cell survival
• Oncogenes are activated
• Suppressor genes are inactivated
• DNA repair genes are inactivated
• Cells become immortal
• Reproduces uncontrollably
• Does not undergo apoptosis
• Lacks telomeres no end to ability to replicate
• May develop telomerase (replicates telomeres)

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Stages of Carcinogenesis

• Initiation
• Primary change produced by carcinogen
• Promotion
• Secondary effect by agent that would not cause
  cancer by itself
• Progression
• Tumor progresses

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Mechanism of Action Initiators and Promoters
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Classification of Carcinogenesis

• According to etiologic factors
• Chemical
• Familial
• Physical
• Viral
• According to environmental factors
• Occupational
• Dietary
• Lifestyle
• Environmental

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Chemical Carcinogenesis

• Carcinogens are rich in electrons (free radicals)
  that bind to DNA causing mutations
• 1915 First laboratory carcinogenesis
• Coal tar applied to rabbit skin
• 1761 Discovery tobacco contains carcinogens
• 1775 Soot causes testicular cancer in chimney
  sweeps
• 1930 First synthetic carcinogen discovered
• There are now thousands
• 1950 Tobacco rediscovered as carcinogen
• Chemotherapy is carcinogenic
• Alkylating agents worst

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Familial Carcinogenesis

• Up to 15 of all tumors have hereditary component
• Breast Cancer -13
• BRCA1 breast and ovarian cancer
• BRCA2 breast cancer
• Colorectal Cancer 5
• Dysplastic Nevi syndrome melanoma
• 35 familial cancer syndromes have been published
• Loss of tumor-suppressor gene

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Physical Carcinogenesis

• Damage to genes is physical
• Ionizing radiation
• Leads to permanent mutations in DNA
• Radon much publicized but little data
• Ultraviolet radiation
• Induces DNA change that leads to malignant
  transformation
• Asbestos inhalation
• Synergistic with tobacco smoke
• Mechanism of action unknown
• Causes mesotheliomas and bronchogenic cancers

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Viral Carcinogenesis

• Earliest viral oncogene found in 1911
• Caused Sarcoma in chickens
• Viral infections DO NOT produce malignancy
  multi-step process
• Human T-cell leukemia virus type 1 (HTLV1)
  implicated in adult T-cell leukemia
• Hep B - Hepatocellular cancer
• Hep C - Hepatoma
• Epstein-Barr virus Burkitts lymphoma
• Human Papillomaviruses (HPV) cervical and other
  genital cancers

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Bacterial Carcinogenesis

• Mucosa-Associated Lymphoid Tissue (MALT) cancer
• Helicobacter pylori (H. pylori)
• Treat the H.pylori and you get rid of MALT
• Chronic H. pylori gastritis associated with an
  increased risk of gastric carcinoma.

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Cell Cycle
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Cell Life Cycle

• Gap 0 Resting phase cell not dividing
• Gap 1 (G1) RNA and enzyme synthesis
• 2 hours to Several Days
• Synthesis (S) DNA is produced
• 8 to 30 hours
• Gap 2 (G2) RNA and mitotic protein production
• lasts a few hours only
• Mitosis (M) Cell division occurs
• 30 to 90 minutes cell very vulnerable at mitosis

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Tumor Characteristics

• Generation Time Amount of time for a cell to
  move through the entire cell cycle
• Doubling time Amount of time it takes the cells
  in a tumor to increase by 100
• Growth fraction Percentage of cells actively
  dividing at any given point in time
• Tumor burden Number of cells in tumor
• Heterogenicity The amount of similarity between
  cells within a tumor
• Differentiation The amount of similarity between
  tumor cells and the parent tissue

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Tumor Growth Patterns

• Tumors grow exponentially at first
• As tumors get larger, the growth rate slows due
  to lack of oxygen and nutrients
• As tumors get very large, many cells are not
  proliferating, and some have died due to lack of
  oxygen and nutrients
• Chemotherapy kills the same percentage of cells
  with each treatment

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Metastasis

• Spread of tumor cells
• Via bloodstream
• Via lymphatics
• Site distant from tumor
• Many Factors contribute to metastasis
• Angiogenesis
• Motility
• Lack of cell adhesion
• Ability to degrade barriers and move across them
• Ability to hide from Immune System
• Natural Killer Cells

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Metastatic Cascade

• Scan Figure2-7, pg 31 cancer nsg

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Principles of Cancer Treatment

• Cure - Disease gone forever
• Control - Extend life of patient disease will
  never go away completely
• Palliation - Provide comfort, relief of symptoms,
  and improve quality of life
• Prophylaxis - No disease but person at high risk
  for disease development

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Treatment Modalities

• Surgery
• Radiation
• Chemotherapy
• Biotherapy

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History of Cancer Treatment

• Nitrogen mustard gas
• NCI developed (1937)
• Alkylating agents
• Folic acid antagonists
• Antitumor antibiotics
• Cisplatin Multidrug Rx
• Toxicity multimodal Rx
• Taxanes, 5HT3 antagonists
• Biologic agents
• Gene therapy

• WW I
• W.W.II
• 1950s
• 1960-1970s
• 1980s
• 1990s

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Drug Development

• Laboratory Research
• Animal studies
• Human studies
• Phase 1 trials-determine toxicity
• Phase 2 trials-determine efficacy in diseases
• Phase 3 trials-compare to standard treatment
• Drug is approved for use by FDA
• Phase 4 trials- determine other uses for drug

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Chemotherapy Effect on Cellular Reproduction

• Some drugs are Cell-Cycle Specific
• Work in a certain phase of cell growth cycle
• Work best given continuously or frequently
• Antimetabolites, plant alkaloids, miscellaneous
• Some drugs are Cell-Cycle Non-Specific
• Work in all phases of cell cycle
• Used to treat slow-growing tumors
• Cell kill proportional to amount of drug given
• Alkylating agents, Antitumor antibiotics,
  Nitrosoureas, hormones

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Factors Affecting Response

• Tumor Burden
• Combination vs Single Agent Therapy
• Hormone Receptor Status
• Administration Schedule
• Dose Category
• Drug Resistance
• Supportive Therapies

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Rationale for Using the Highest Dose Possible
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Cures
Dose
Lethal Bone Marrow Toxicity
Lethal Toxicity to Other Organs
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Single Drug Treatment

• Less toxicity to normal tissue BUT.
• Less toxicity to cancer cells
• Overall lower response rate
• There ARE exceptions
• Fludarabine for CLL
• Rituxan for NHL
• Targretin for Cutaneous T-cell Lymphoma
• Temodar for Glioblastoma

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Combination Therapy

• Most often used
• Each drug effective against the cancer
• Minimally overlapping toxicities
• Drugs have different mechanisms of action
• Drugs may maximize the other drugs effect
  (synergy)
• Decrease possibility of drug resistance
• Increase percent of cells killed at one time

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Types of Administration

• Bolus therapy - IV push or piggyback
• Infusional therapy (runs over a number of hours)
• Multiple agents in different bags
• Multiple agents in same bag
• Sequential infusions
• Combined modality therapy - chemo given with
  radiation to increase response rate

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Dose Category

• Standard doses
• High dose
• Pt will need supportive therapies
• Dose intensification
• 10 to 200 times higher than standard dose
• Given in single dose, divided doses, or
  continuous IV over several days
• Toxicities differ depending on length of time of
  administration

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Standard Doses

• Day 0 Rituxan 375 mg/m2 IV
• Day 1 Cytoxan 750 mg/m2 IV
• Vincristine 1.4 mg/m2 IV
• Adriamycin 50 mg/m2 IV
• Given every 21 days
• M2 is a way of determining BODY SURFACE AREA
  which is how chemotherapy is dosed

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Example of BMT Preparative Regimen
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Drug ResistanceChemo becomes ineffective

• Intrinsic resistance occurs prior to exposure to
  antineoplastics
• P-glycoprotein
• Topoisomerase
• Acquired malignant cells become resistant after
  being exposed to antineoplastic agent

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Tumor Response

• Complete response (CR) Absence of all tumor for
  at least one month
• Partial Response (PR) gt 50 reduction in
  measurable tumor for at least one month
• Stable disease (SD) lt 50 reduction or lt 25
  increase in cancer size
• Progression gt 25 growth of tumor
• Subjective response

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Measurement Criteria

• Performance Scale
• Karnofsky (in book)
• ECOG (0 to 5 where 5 dead)
• Tumor Assessment
• X-rays, CT scans, MRI
• Physical examination
• Tumor Markers

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Small Cell Carcinoma
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