Module Thirteen: Cancer and Cancer Chemotherapy
PHARMACOLOGY FOR DENTAL HYGIENE DEHY34
Contact and Instuctor: Jim Middleton


I. General background on Cancer
 A. The "War on Cancer"
  1. declared by Richard Nixon in 1971; he was confident that a cure would be found in time for the nation's bicentennial in 1976 (he was also confident he’d be President until that year, whoops!)
  2. 1991 report indicated that "our ability to treat and cure most cancers has not materially improved"
  --meaning, the average cancer patient has a 50:50 chance of a 5 year survival rate once diagnosed today; the same odds existed in 1971
  --the 1% decrease in mortality reported from 1991 to 1994 is now thought to be due more to earlier detection, not better treatments
  --since 1950, the overall cancer incidence has increased by 44%, with breast cancer and male colon cancer up by 60% and prostate cancer up by 100%
  3. NCI has spent $39 billion since 1971 and hospital therapies have cost over $1 trillion
  4. Cancer is an "obligate anaerobic glucose feeder" aided by immune suppression and toxin overloads--resistance to therapy seems to develop; unless the underlying causes are addressed, the returning cancer has a greater virulence
  5. Approximately 80% of cancers are thought to be environmental in nature
   a. aflatoxins from foods contaminated with aspergillus fungus (possible with peanuts, soybeans, corn, wheat and rice in warm, moist areas) – liver cancer
   b. hair dyes – bladder cancer
   c. asbestos, diesel fuel fumes, metallic ores – lung cancer

 B. The American Diet
  1. Most popular grocery items (1992)
   a. Marlboros
   b. Coke Classic
   c. Pepsi
   d. Kraft processed cheese
   e. Diet Coke
   f. Campbell's soup
   g. Budweiser
   h. Tide
   i. Folger's coffee
   j. Winstons

  2. Annual average consumption of low nutrient foods:
   a. 60 pounds of cakes, cookies, and donuts
   b. 23 gallons of ice cream
   c. 7 pounds of potato chips
   d. 200 sticks of gum
   e. 365 servings of soda
   f. 90 pounds of fat
   g. 134 pounds of refined sugar

 --sources of preservatives, free radicals, and loads of sugar

  3. Toxins
   a. there are 5 million registered chemicals in the world
   b. mankind comes in contact with 70,000
   c. at least 20,000 are known carcinogens
   d. 1.2 billion pounds of pesticides on our crops annually
   e. 90 billion pounds of toxic waste in 55,000 toxic waste sites
   f. administers 9 million pounds of antibiotics to our farm animals

 C. Nutritional and other considerations for preventing and beating cancer
    1. bolster spirits--depression is a major inhibitor of the body's immune system
    2. Avoid any refined sugars or sweet foods
  --sugars feed cancer; avoid or seriously curtain intake of anything that tastes sweet, including fruit, foods with a high "glycemic index," including carrot juice and rice cakes
    3. "Eat the rainbow" with colorful vegetables
  --green vegetables, beets, tomatoes, peppers, squash, broccoli

  4. Get adequate protein
  --average adult needs 30-50gm/day, cancer patient should go with 80-120gm/day; this is to rebuild and strengthen the immune system

  5. Load on the antioxidants
  --Vitamins A,C,E and selenium can help reduce the severity of side effects of radiation.  Cancer cells don't benefit from antioxidants; healthy cells do.  During radiation, it will be the cells that are unprotected by the antioxidants that will suffer less damage.   Selenium also reduces the toxic effects of Adriamycin on cardiac muscle.

  6. Exercise: a half-hour of exercise every other day cuts the risk for breast cancer by 75% -- exercise increases the oxygenation of blood and tissues; cancer, being anaerobic, doesn't like that
  --similarly, exercise raises body temperature slightly; cancer is sensitive to increases in temperature, especially over 107°; possibly the slight increase can help kill cancer cells in their earliest stages of development

  7. Botanicals used to fight cancer include Pau D'arco, ginseng, green tea, mistletoe (be really careful with this one!), polyphenols, carotenoids, bioflavenoids, echinacea, astragalus, chaparral and blood root (careful careful careful again), garlic and various mushroom extracts (again, watch out)

  8. There are 2 times in human life where a foreign body is allowed to live within it--cancer and pregnancy.  Both times show the presence of Tumor Necrosis Factor inhibitor (TNF-i) that tells the body not to attack the tumor or the fetus; Nashville researchers are developing a dialysis-type device to filter out the TNF-i factor in the blood of cancer patients.

 D. Immune system considerations
  1. Of the thousands of known cells involved in immunity, we understand about five

  2. Thymus gland was considered a useless vestige as late as the 1970s--it is now known to be the origin for the T helper cells--T cells release Interleukin 2, an important step in immune activation

  3. The macrophages release TNF--Tumor Necrosis Factor--as the name implies, TNF is what kills cancer cells; in a weakened immune system, the cancer cell wall is able to mutate so that it is no longer noticed by the immune system--within 3 to 4 generations, the cells are no longer viewed as a threat and the cancer grows

 E. Three major modes of treating cancer
  1. surgery
  2. radiation therapy
  3. chemotherapy
   The first two, surgery and radiation therapy, are primarily for “solid tumors” where chemotherapy is most often reserved for disseminated cancers.

OK, now that all having been said, let's look at some of the presently accepted forms of traditional chemotheapy and the theories behind their use and value.  Remember, too, that when it comes to fighting cancer, the nurse is as important an entity as any chemical that is being prescribed, and often more effective.

II. Cellular kinetics/location of action
 A. Cell cycles
  --similar in both normal and cancer cells
  --activated when the cell has a need to divide and replicate
  1. 4 sequential phases
   G0 is when the cell is in “sleep” or “quiescent” phase
   a. G-1:  a few hours to a few days
   b. S: DNA synthesis, 10-20 hours
   c. G-2: 2-10 hours, components made for segreation of chromosomes and cell divison
   d. M: mitosis, 30 minutes-1 hour
  2. Cancer chemotherapy works on these various phases (cycle-specific agents), or on cells in the cycle or in a resting phase (cycle-nonspecific agents)

 B. Cancer cell growth
  1. increased growth rates without cells being able to properly function; the relentless growth of cancer cells is due to a lack of feedback mechanisms in those cells that would regulate proliferation ; theory is that oncogenes are activated, especially in tumors of the breast, colon, lung, and bone
  2. lack the cell adhesive properties of normal cells which may lead to metastasis, or spread of the cancer
  3. cancer growth is rapid at first but reaches a plateau when its blood and nutrient supply no longer keeps pace
   Gompertzian growth kinetics
   --a cell burden of 109 is usually the smallest tumor "burden" that is physically detectable; this represents a tumor of 1 billion cancer cells weighing 1gm and is the size of a small grape; clinical symptoms begin to appear at this point

   If you can kill 99.9% of the cells would reduce a 1010 cell burden to 107 cancer cells; this is the goal of each course of chemotherapy.  Eventually, it is hoped that the body's immune system can kick in and set the condition into remission.

   In order to destroy the cancer and “cure” the patient, 100% of the cancer has to be destroyed.

   To further complicate matters, cancerous tumors are heterogeneous vs homogeneous.  This means that the tumor often will have several subsets of colonies or “mini tumors” that will demonstrate an increasing ability to be resistant to drug therapy as time progresses.

III. Chemotherapy
 A. Goals
  1. most effective against smaller tumors with rapidly proliferating cells and efficient blood supply

  2. surgical removal of hard, localized tumors with chemotherapy afterwards to find micrometastases

  3. combination cancer therapies have a greater cancer cell kill ratio than with a single agent
   a. each drug has to be effective on its own
   b. each drug needs to have a different mechanism of action
   c. each drug needs to demonstrate a different type of toxicity–overlapping toxicities are not a good thing

 B. Combination Chemotherapy
  1. initially for acute lymphoblastic leukemia and Hodgkin's disease; now many routines have been developed to attack the cancer and its growth:
 for example
   --MOPP for Hodgkin's disease
   Mustargen - Oncovin (vincristine) - procarbazine - prednisone

  Mustargen-- an alkylating agent that interferes with DNA; bone marrow suppression
  Oncovin-- inhibits mitosis, neurotoxicity is rate limiting
  Procarbazine-- weak MAO inhibitor that works during the S phase of the cell cycle; bone marrow suppression comes at a different time from the mustargen
  Prednisone-- lympholytic properties with antifibrotic possibilities against the cell, also useful in improving appetite

 There are over twelve dozen such combinations and protocols that are
 documented. Many others are still experimental.
 

IV. Toxicity
 --most antineoplastic agents work on similar metabolic pathways used by normal and cancer cells; toxicity to healthy cells becomes a problem

 A. Common side effects of chemotherapy
  --alopecia, nausea, vomiting, anorexia, diarrhea, and stomatitis
  --alopecia (hair loss) reversal takes 6-8 weeks
  --rapidly reproducing healthy cells are also attacked; bone marrow, hair follicles, and the GI tract
  The goal in intermittent chemotherapy is to allow the bone marrow and GI tissue to repair itself and regenerate; it is necessary that these tissues regenerate at a rate faster than the cancer grows

 B. adverse reactions
  --leucopenia, thrombocytopenia, and anemia; bone marrow suppression is the major dose limiting property
   Leucopenia can result in even a minor infection becoming fatal; hospitalized patients are especially prone to serious complications if they contract NOSOCOMIAL infections; common bacteria present on uncooked fruits or vegetables or the apparently “healthy salad” can be devastating.
  --concern with platelet counts below 50,000 cells/mm3 ; watch for symptoms of easy bruising and take especial care with venipunctures or IM injections
  –hyperuricemia:  kidney damage due to the purines released by the cell kill-off; purines become uric acid and can precipitate in the kidneys; again 3 liters/day fluid intake is recommended

 C. specific dose-limiting drug effects

  --hepatotoxicity:   methotrexate, mercaptopurine, lomustine, carmustine, doxorubicin

  --hemorrhagic cystitis:   cyclophosphamide

  --cardiac toxicity:   doxorubicin and daunorubicin

  --neurological toxicity:   (tingling to deep tendon reflex loss); vincristine, vinblastine, methotrexate

V. Emetic potential
 A. High Emetic potential
  1. cisplatin (Platinol)
  2. nitrogen mustard
  3. actinomycin D
  4. doxorubicin
  5. daunorubicin
  6. nitrosoureas (BCNU, CCNU)
  7. procarbazine
  8. cyclophosphamide (Cytoxan)
  9. etoposide (VP-16)
  10. mitomicin
  11. methotrexate (high doses)

 B. Low emetic potential
  1. 5-fluorouracil (5-FU)
  2. vincristine (Oncovin)
   –however, constipation can become a problem (encourage fluids and fiber)
  3. vinblastine
  4. methotrexate (lower doses)
   5. bleomycin
  6. chlorambucil
  7. melphalan
  8. cyclophosphamide (oral route)
  9. 6 mercaptopurine

VI. Antiemetic medications
 A. metoclopramide (Reglan)
  --originally for diabetic gastroparesis, found useful in treating chemo-induced nausea in very large infusion doses; was the mainstay before the development of 5HT-3 inhibitors

  5HT3 serotonin receptors are present both peripherally on the vagal nerve terminals and in the chemoreceptor trigger zone (CTZ) in the brain; chemotherapy seems to trigger the increase of serotonin from cells in the small intestine

 B. ondansetron (Zofran) 5HT3 receptor antagonist
  --$58.57/3 tablets (drug cost)
  --4mg, 8mg tablets, 4mg/5ml solution
  --2mg/ml injection

 C. dolasetron (Anzemet) 5HT3 receptor antagonist
  --50mg, 100mg tablets
  --20mg/ml injection

 D. granisetron (Kytril) 5HT3 receptor antagonist
  --1mg tablets
  --1mg/ml injection

 E. dronabinol (Marinol)
  --a CIII controlled substance; an extract from ?9-THC (cannibis); recently reduced from CII status (which had it under the same controls as morphine and oxycodone)

 F. lorazepam (Ativan)
  --benzodiazepine anti-anxiety with a high level of retrograde amnesia; doesn't necessarily reduce nausea, but makes the memory of it much less
  --0.5-2mg tablets, 1mg/ml injection

VII. Specific antineoplastic agents

 A. Antimetabolite drugs
  --have a structure similar to  necessary building block for the formation of DNA, interfering with the production of the tumor cell's DNA

  1. Cytarabine (Cytosar U)
  2. fluorouracil (5-FU)
   a. injection, 50mg/ml
   b. low WBCs seen between days 9 and 14 after the first course of therapy; the count usually normalizes at day 30
   c. myocardial ischemia
   d. stomatitis and esophagopharyngitis; diarrhea, anorexia, naurea, vomiting, enteritis
   e. alopecia, dermatitis, photosensitivity; nail changes, including loss of nails
   f. lab test abnormalities: prothrombin, total proteins, sedimentation rate, thrombocytopenia
   g. mutation in DNA will cause disruption of reproductive genes; contraceptive measures recommended
   h. extra fluids recommended
   i. AVOID EXTRAVASATION

  3. mercaptopurine (Purinethol)
  4. methotrexate (Mexate, MTX)
   a. injection, 25mg/ml
   b. orally, 2.5mg tablets (indication for severe unresponsive arthritis)
   c. ulcerative stomatitis, leukopenia, nausea, fever and chills
   d. renal failure, azotemia; bone marrow suppression
   e. treat toxicity with LEUCOVORIN
   f. DRUG INTERACTION with aspirin
    aspirin both displaces leucovorin from albumin in the blood and decreases the renal excretion of leucovorin–drug levels of leucovorin increase as a result, with an increase in potential liver toxicity

  5. thioguanine

 B. Alkylating agents
  --substitute an alkyl chemical structure for a hydrogen atom in DNA; each strand of DNA becomes cross-linked and prevents cell division
  1. nitrogen mustard (Mustargen)
  2. chlorambucil (Leukeran)
  3. cyclophosphamide (Cytoxan)
   a. 25,50mg tablets
   b. 100,200,500mg vials for injection (powder)
   c. with thiazides, may increase leucopenia
   d. anticoagulant effect of warfarin (Coumadin) is increased
   e. digoxin serum levels may be reduced
   f. use cautiously in renal impairment
    Hemorrhagic cystitis is thought to occur in about 10% of patients started on cyclophosphamide therapy; watch for blood in the urine, dysuria, or burning upon urination

  4. melphalan (Alkeran)
  5. carmustine (BCNU)
  6. lomustine (CCNU)
  7. streptozocin (Zanosar)
  8. cisplatin (Platinol)
   a. 10,50mg vials for injection
   b. cumulative renal toxicity is severe
   c. ototoxicity to tinnitus and deafness
   d. aminoglycosides worsen renal damage if given concurrently
   e. loop diuretics have an added ototoxicity if given concurrently
   f. marked nausea and vomiting
   g. high levels of pre-therapy hydration required, followed by stimulation of diuresis with mannitol, all to prevent renal accumulation and potential damage to the kidneys

 C. Mitotic inhibitors
  --block cell division in metaphase
  1. vinblastine (Velban)
  2. vincristine (Oncovin)
   a. IV needle or catheter must be carefully placed before injection; leakage causes considerable irritation
   b. IV use only; intrathecal injections result in death
   c. from the periwinkle plant (Vinca rosea)
   d. phenytoin (Dilantin) levels may drop
   e. digoxin (Lanoxin) levels may drop
   f. 1mg/ml injection
  3. etoposide (VePesid)

 D. Hormonal drugs
  1. dexamethasone (Decadron)
  2. fluoxymesterone (Halotestin)
   a. 2,5,10mg tablets
   b. an anabolic steroid, therefore is falls under controlled substance status and is in C-III category
   c. inoperable breast cancer--use for 1 to 3 months
   d. as an androgenic drug, used for hypogonadism

  3. diethylstilbesterol (DES)
  4. tamoxifen (Nolvadex)
   a. antiestrogen properties
   b. uses directed to adjuvant therapy in breast cancer; unknown if therapy is beneficial for tumors under 1cm3
   c. treatment of mastalgia (10mg/day for 4 months) and for decreasing the size and pain of gynecomastia
   d. hypercalcemia possible
   e. liver problems
   f. leucopenia and thrombocytopenia possible

  5. leuprolide (Lupron)
  6. hydroxyprogesterone (Delalutin)
  7. megestrol (Megace)
   a. 20mg, 40mg tablets
   b. possibly an anti-luteinizing effect via the pituitary
   c. not recommended during the first 4 months of pregnancy
   d. for advanced carcinoma of the breast or endometrium (ie recurrent inoperable or metastatic disease); not to be used instead of surgery, radiation or chemotherapy
   e. weight gain a frequent side effect
   f. nausea/vomiting possible
   g. at least 2 months of continuous treatment is adequate for determining efficacy
   h. some studies have used doses up to 800mg/day; usual dose is 40-160mg/daily

  8. goserelin (Zoladex)

 E. Antibiotic-type antitumor drugs
  1. doxorubicin (Adriamycin)
   a. for acute leukemia, lymphoma, cancers of breast, lung, and ovary
   b. will discolor urine to a reddish color for 1-2 days following therapy; patient needs to know about this so he doesn’t confuse the coloration with bleeding
   c. the patient should be instructed to report any shortness of breath, development of edema, or excessive fatigue–these are symptoms of heart failure and the drug will need to be discontinued
   d. extravasation of doxorubicin may lead to serious tissue necrosis

 F. Miscellaneous drugs
  1. asparaginase (Elspar)
  2. dacarbazine (DTIC)
  3. hydroxyurea (Hydrea)
  4. Interferon (Roferon A, Intron)
   a. antiproliferative activity, immune boosting activity
   b. hairy cell leukemia
   c. AIDS-related Kaposi's sarcoma
   d. chronic myelogenous leukemia
   e. many unlabeled uses from bladder tumors to cytomegalovirus and herpes conjunctivitis
   f. Warnings of severe depression and suicidal ideations

  5. mitotane (Lysoderm)
  6. procarbazine (Matulane)
  7. placlitaxel (Taxol)
   a. for advanced ovarian cancer not responding to other therapies
   b. from the bark of the Pacific Yew tree found in northwestern US; it creates microtubules within the tumor cell that leads to cell death
   c. severe hypersensitivity reactions have occurred characterized by dyspnea and hypotension, angioedema, and generalized urticaria (2% of patients)
   d. pretreatment of patients includes
    i. corticosteroids
    ii. diphenhydramine
    iii. H-2 antagonists (ie ranitidine, cimetidine)
   e. do NOT give to patients with baseline neutrophil counts of uncer 1500/mm3
   f. drug interactions
    i. cisplatin (Platinol) –increase in myelosuppression when placlitaxel is given after cisplatin vs before
    ii. ketoconazole (Nizoral)-- increase in placlitaxel levels
    iii. doxorubicin (Adriamycin) – increase in doxorubicin blood levels and side effects

VIII. Drugs that reduce toxicity of antineoplastic drugs
 A. Colony stimulating factors–stimulate production of blood cells
  1. erythropoietin–to treat anemia
  2. filgastrim and  sargramostim– to shorten neutropenia and the accompanying risk for infection
 B. Leucovorin for high dose methotrexate
 C. Mesna to prevent hemorrhagic cystitis from ifosfamide



References
Nutritional information and discussion is from the book, Beating Cancer with Nutrition by Patrick Quillin, PhD, RD, CNS, 1997 Nutritional Times Press, Tulsa, OK

Abrams, Ann, Clinical Drug Therapy, 4th edition, Lippincott press 1998, p811-834

Lehne, Richard, Pharmacology for Nursing Care, second edition, W. A. Saunders, 1994

Goodman and Gilman, The Pharmacological Basis of Therapeutics, 7th edition, 1990

Shlafer, Marshal, The Nurse, Pharmacology, and Drug Therapy, 2nd edition, Addison-Wesley, 1997



End of Module Thirteen
January 2002
KCC Pharmacology for Dental Hygiene
Contact and Instructor: Jim Middleton