Cancer Pathophysiology

Cancer

Learning Outcomes:

• Define cancer and cancer terminology
• Identify incidence and mortality rates
• Review cell cycle and examine this process as it relates to carcinogenesis
• Compare benign and malignant tumors including cancer cell characteristics
• Gain a better understanding of etiology and risk factors for cancer
• Describe nomenclature as it relates to neoplasms
• Describe classification and staging of malignant tumors
• Gain a better understanding of cancer treatment, including side effects and management

Definition

Cancer is the uncontrolled growth of abnormal cells in the body

• Cancerous cells are made of less well-differentiated cells that lost ability to control cell proliferation and differentiation into a mature cell

Statistics

• Nearly 1 in 2 Canadians will develop cancer at some point in their lives
• 1 in 4 Canadians will die from cancer at some point in their lives
• Cancers of the lung, breast, colon, and prostate account for half of all new cancer cases
• Breast cancer more common for women and prostate cancer more common for men
• Lung cancer is leading cause of cancer death

Cell cycle

• 5 phases of the cell cycle
    * G zero
    * G1
    * S (synthesis)
    * G2
    * M (mitosis)
• Synthesis - DNA is synthesized and chromosomes are replicated
• Mitosis - cell divides and 2 daughter cells are formed
• G phases- cell is metabolically active or growing enzymes/proteins to prepare for DNA synthesis or mitotic division
• After mitosis- daughter cells either go into state of dormancy (G zero phase) where they are not actively proliferating OR if a stimulus for cell division exists, cell enter G1 to begin cell reproductive cycle again
• G1 determines overall length of cell cycle because cell spends hours or days in this phase
• Differentiation: the process by which proliferating cells become specialized
    * Categories of differentiation and proliferation cells: cells that never/rarely divide, cells that continue to proliferate then die (PROGENITOR CELLS)
      * Lastly is stem cells that can enter the cell cycle and produce progenitor cells when required
• Cancer cells can complete cell cycle faster by decreasing time spent in G1 phase
    * Also less likely to enter or remain in G zero phase than normal cells

Cell Cycle Checkpoints

• G1-S: monitors whether DNA in chromosomes is damaged by radiation or chemicals
• G2-M: prevents entry into mitosis if DNA replication is not complete

Carcinogenesis Intro

• Process by which normal cells are transformed into cancer cells
• Caused by mutation of the genetic material of normal cells- upsets normal balance between proliferation and cell death
• Results in uncontrolled cell division and tumor development in body

Carcinogenesis Stages

• Initiation
    * Exposure of cells to appropriate doses of carcinogenic agent that makes them susceptible to malignant transformation
• Promotion
    * Unregulated and accelerated growth of the mutated cells and dysplasia
    * Dysplasia usually indicates early neoplastic process
• Progression
    * Where tumor cells acquire malignant changes and autonomous growth tendencies that promote invasiveness and metastatic capabilities
• Carcinoma in situ
    * Transformation of a neoplastic lesion to one in which cells undergo no maturation and can be considered “cancer like”
    * Remains localized and hasn’t invaded past the basement membrane into the tissues below surface
• Invasive cancer
    * Cancer that has invaded beyond basement membrane and has potential to metastasize or spread to other body parts

Carcinogenesis- How it occurs?

• Proto-oncogenes
    * Encourage cell division
    * When mutated they become oncogenes- stimulate excess division
    * IMPORTANT* oncogenes result form activated or turning on of proto-oncogenes
      * How it contributes to cancer:
        * Develop cancer by instructing cells to make proteins or go signals that stimulate excessive cell growth and division
          * Causing a cell’s growth-signaling pathway to become hyperactive
• Tumor suppressor genes (TSG)
    * Inhibit cell division
    * When mutated it inactivated these genes causing inhibition of cell division that normally prevents excessive growth
    * IMPORTANT* cause cancer when they are inactivated/turned off
      * How it contributes to cancer:
        * When TSG does not function properly, cells with DNA damage continue to divide and accumulate more DNA damage that eventually lead a cell to grow and divide uncontrollably
        * Like having a brake pedal that does not work
        * ***people who inherit increased risk of developing cancer are often born with one defective copy of TSG
          * Because genes come in pairs (one from each parent), inherited defect in one copy will not lead to cancer because other normal copy is still functional
        * Defective TSG called APC gene causes familial adenomatous polyposis- condition where people develop thousands of colon polyps sometimes leading to colon cancer

DNA Sequencing

• 3 systems that help avoid runaway cell division

1. DNA repair system

• Instruct a cell to repair damaged DNA
• Mutations in DNA repair system:
    * A change in single base along the base sequence of a gene (like a typo error)
    * One or more bases added or deleted
    * Large segments of DNA molecule repeated, deleted or moved
    * Mutations can lead to failure in repair
• When a mistake occur during DNA replication- repair proteins recruit enzyme EXO1 (exonuclease that chops off the mutant strand)

Apoptosis

• When old cells become damaged over time they’re eliminated by apoptosis
• Tumor suppressor p35 protein initiates cell suicide
• Tumor suppressor gene and p35 protein are most frequently mutated genes in human cancer

NK Cells

• Can target tumors and cancer cells and kill them

Metastasis

• Spread of cancer from original location to other parts of body
• Occurs in 2 ways:
    * Malignant cells directly invade or extend into adjacent organs or sites
    * Individual cancer cells move away from primary tumor and enter body or lymph circulation
• Most common sites are lungs, bones and liver

Angiogenesis

• Process of forming new blood vessels
• Begins when tumor becomes large enough where it needs to increase supply of nutrients & oxygen
• Low oxygen (hypoxia) triggers tumor and environment to release signals that result in growth of BV into the tumor

Tumor Angiogenesis

• The proliferation of a network of vessels that penetrates into cancerous growths, supplying nutrients & oxygen and removing waste products
• Steps:
    * Cancerous tumor cells release molecules that send signals to surrounding normal host tissue
    * Signaling activates certain genes in host tissue that make proteins to encourage growth of new blood vessels

Angiogenesis Inhibitors

• Endostatin
    * Molecules that directly inhibit the growth of endothelial cells
• Thalidomide
    * Prevents endothelial cells from forming new blood vessels
• Avastin (first to be FDA approved)
    * Molecules that interfere with steps in angiogenesis signaling cascade
    * Delays tumor growth
• Interferon-alpha
    * Naturally occurring protein
    * Inhibits the production of growth factors from starting the angiogenesis signaling cascade

Etiology

• Even though cancer is genetic, only 5-10% if inherited
• Chances of getting cancer increase with age
• Cancer screening
• High risk individuals for prostate cancer should start testing from age 45
• High risk: person w/ known gene mutation that increases risk for BC, first degree relative of someone with gene mutation, is assessed as having 25% or greater lifetime risk of breast cancer based on family hx, has had radiation therapy of the chest
• Carcinogens: substances directly responsible for damaging DNA, promoting or aiding cancer
    * Include UV light, radiation, chemical, bacteria, viruses or medical treatments
• Lifestyle factors (alcohol, smoking, obesity, inactivity,

Nomenclature

• Neoplastic: abnormal growth of new tissue
• Benign: noncancerous tumor growth
    * Composed of well differentiated cells, resembling cells of tissue of origin
    * Characterized by slow progressive rate of growth that can stop or regress
    * Lost ability to suppress genetic program for cell proliferation but retained program for cell differentiation
    * Remain localized to site of origin, lack capacity to infiltrate, invade or metastasize to distant sites
    * Develop surrounding rim of compressed connective tissue (fibrous capsule)- responsible for sharp line of demarcation between benign tumor and adjacent tissues (known as encapsulated, is a factor for surgical removal)
    * Named by adding suffix “oma”
• Malignant: cancerous tumor growth
    * Less well differentiated, lost ability to control cell proliferation/differentiation into mature cell
    * Anaplasia: loss of cell differentiation in cancerous tissue
    * Poorly differentiated: poorly resembles cell it arose from
    * Undifferentiated: malignant cells are immature, embryonic and no resemblance to cell it arose from
    * Grow rapidly in disorganized/uncontrolled manner to invade surrounding tissues and blood vessels
    * Rob normal tissue of essential nutrients and release enzymes, toxins and cytokines that destroy normal tissue
    * Have cells that break loose and form metastases
    * Have suffix “carcinoma” or “sarcoma”

Staging Malignant Tumors

• Stage I: small, localized, curable
• Stage II: locally advanced
• Stage III: locally advanced, lymph node involvement
• Stage IV: inoperable, metastatic
• IA: no symptoms
• IIB: symptoms like fever, night sweats and weight loss
• TNM classification: tumor, nodes, metastases
    * Only lymph nodes draining area of the primary tumor are considered in classification

Molecular Tests

• Tumor markers - PSA, CEA, AFP CA125 and Estrogen receptors- occur in blood or tissue useful in patient diagnosis or management
• PSA- prostate specific antigen measures levels of PSA in blood, high levels can be marker for prostate cancer
    * Can also be high in men with infection/inflammation of prostate or benign prostate hyperplasia
• CEA- carcinoembryonic antigen
    * Type of protein that can be found in many different cells of body but usually associated with some tumors
    * Benign and malignant conditions can increase CEA level
    * Colon and rectum cancer most commonly increase CEA
    * ***best use of CEA is as a tumor marker- especially for cancers of GI tract
    * Rising CEA indicates progression or recurrence of cancer
• AFP- normal fetal serum protein synthesized by liver, yolk sac and GI
    * Major component of fetal plasma normally in pregnant women
    * Rise is usually only seen in diseases like benign liver diseases and hepatocellular carcinoma
• CA 125- antigen present on 80% of ovarian carcinomas
    * Circulates in serum of patients w/ ovarian carcinomas, used as marker to monitor disease
    * Decrease =good therapy, increase =recurrence
• ER+- have receptors for estrogen on surface, growth requires presence of estrogen
    * ER+ tumors more affected by hormonal treatment and less aggressive

Radiation Therapy

• Immediately kills cells, delays or stops cell cycle progression or causes damage to cell’s DNA causing cell death after replication

Chemotherapy

• Cells mainly affect by chemo
    * Blood cell forming bone marrow, hair follicles, lining of the mouth and digestive system
• Chemotherapeutic drugs most effective against frequently dividing cells or all phases of cell cycle except G zero

Classifications

• Cell cycle phase nonspecific drugs are active on cells in dividing or resting state
    * Effective on large tumors that have few active cells dividing at time of admin
    * Usually given as single bolus injections
• Cell cycle phase specific drugs are given in minimal concentrations through continuous dosing methods

Hormonal Therapy

• Admin of drugs designed to disrupt hormonal environment of cells
• Used for cancers that are responsive to or dependent on hormones for growth
• Can treat hormone receptors positive breast cancers
    * By lowering amount of estrogen in body
    * Or by blocking action of estrogen on breast cancer cells
• Estrogen makes hormone receptor positive breast cancers grow
• Hormonal therapies are not effective against hormone-receptor-negative breast cancers

Biotherapy

• Biologic response modifiers can trigger immune system to indirectly affect tumors

Targeted Therapy

• Drugs that selectively attack malignant cells while leaving normal cells unharmed
• “Molecularly targeted drugs/therapies”
• Interfere with cancer cell division, processes of apoptosis or angiogenesis
• Thalidomide

BMT and PBSCT

• Restore stem cells that have been destroyed by high doses of chemo or radiation
• 3 types of transplants
    * Autologous- patients receive their own stem cells
    * Syngeneic- patients receive stem cells from identical twin
    * Allogeneic- patients receive stem cells from brother, sister or parent

Side Effects of Treatment

Intergumentary

• Alopecia
    * Hair loss occurs 10-21 days after drug treatment, is temporary will regrow when drug discontinued
• Hair thinning
• Local or systemic hypersensitivity reactions
    * Review pt’s allergy hx, monitor for hypersensitivity of anaphylaxis, test doses as ordered, maintain good hygiene, avoid perfume lotions
• Extravasation
    * Inadvertent leakage of chemo drug from a vessel into surrounding tissue
    * Assess for immediate/delayed pain, tightness, blister or sloughing of tissues
    * Prompt admin of antidotes to minimize tissue damage

MSK

• Aches/pain
    * Pain meds
• Fatigue
    * Conserve energy & plan rest periods

Nervous System

• Neurotoxicity
    * Monitor for signs of weakness, numbness, tingling extremities and foot drop
• Ototoxicity
    * Some chemo drugs can cause hearing changes, monitor for tinnitus, hearing loss and vertigo
• Sleep pattern disturbances
    * Vitamins, corticosteroids and neuroleptics for N/V can negatively impact sleep
• Anxiety and depression
    * Set small achievable daily goals, participate in enjoyable and divisional activities and share feelings
• Memory changes
    * “Chemo fog”
    * Use calendars and lists, provide pill boxes or dosettes

Endocrine System

• Hypercalcemia
    * Monitor serum calcium levels, polyuria and mental status changes
• Hyperglycemia
    * Patients on steroids for cancer can develop high BS
• Hyperkalemia
    * Rapid amount of cellular destruction causes contents of cell to move into blood stream (tumor lysis syndrome)
• Hypernatremia
    * Caused by dehydration, loss of fluids. Monitor serum sodium levels, symptoms of thirst, dry mucous membranes, poor skin turgor, restlessness and lethargy
• Hyperuricemia
    * Monitor serum and urine uric acid levels, daily I/O, rigorous hydration if indicated

Cardiovascular System

• Cardiac toxicity
    * Drugs- cyclophosphamide and doxorubicin
    * Baseline ECG, echo, cardiac enzymes before chemo, monitor for changes

Digestive System

• Hepatotoxicity
    * Monitor liver function tests, assess for jaundice, tenderness over liver, urine and stool color changes
• Anorexia
    * Eat small frequent meals high in protein, monitor weight
• N/V and constipation
• Diarrhea
• Mucositis/Stomatitis
    * Symptoms appear 3-5 days after local radiation or systemic chemo
    * Can be painful enough to require analgesic IV drip

Urinary System

• Renal toxicity
    * Assess baseline, encourage oral intake, monitor I/O and weight changes
• Cystitis
    * Some chemo can cause inflammation and bleeding of bladder lining
    * Increase fluid intake, empty bladder frequently, administer antidote

Pulmonary System

• Pulmonary toxicity
    * Individuals over 70 at greater risk
    * Assess baseline resp function, monitor resp status

Reproductive System

• Reduced fertility
• Fetal death

Lymphatic and Hematological

• Neutropenia
    * Abnormally low count of neutrophils in blood stream (> 2000 cells/cubic mm)
    * Monitor CBC, infection, sepsis, frequent temperatures, health teaching
• Thrombocytopenia
    * Reduction in number of circulating platelets below 30,000 per cubic mm
    * Monitor CBC, assess for bruising, purpura, petechiae, nose bleeds, bleeding gums or tarry stools
    * Platelet transfusions can be required
• Anemia
    * Abnormal or low hematocrit and hemoglobin below 80g/L
    * Monitor CBC, assess paleness, chest pain, SOB, heart palpitations, dizziness, lethargy