Pathopharm Chapter 38- Drugs for Neoplasia

Treatment of Cancer

Drug therapy (chemotherapy) - To cure - For palliation - For prophylaxis • Surgery • Radiation therapy Chemotherapy • Transported through blood - Has potential to reach each cancer cell • Some drugs can cross blood-brain barrier • Some drugs distilled directly into body cavities (e.g., bladder) Surgery • Performed to remove tumor - When localized - When pressing on nerves, airways, or other vital tissues • Surgery sometimes not an option - If tumors affect blood cells - If surgery would not extend lifespan or improve quality of life Radiation • Can destroy tumor cells • Ionizing radiation aimed directly at tumor • May follow surgery • Used as palliation for inoperable cancers - Shrinks size of tumor - Relieves pain, difficulty breathing or swallowing

Biologic Response Modifiers

Drugs that are used to enhance the ability of the body defenses to destroy cancer cells • Stimulate or assist patient's immune system to rid itself of cancer cells - Less toxic than other classes of antineoplastics - Includes interferons, interleukins, monoclonal antibodies - Given concurrently with other neoplastics to limit immunosuppressive effects • Inhibit enzyme tyrosine kinase in tumor cells - Imatinib (Gleevec) and sorafenib (Nexavar)

Prevention of Cancer

Many associated with higher risk of cancer • Encourage patients to adopt healthy lifestyle habits - Eliminate use of and exposure to tobacco - Limit alcohol use - Eat healthy diet (low in fat, high in fruits and vegetables) - Choose most foods from plant sources • Exercise regularly; keep weight normal • Use protection from sun • Self-examine body monthly for abnormal lumps and skin lesions • Get periodic screenings - Mammogram - Prostate exam - Fecal occult blood test - Colonoscopy - Pap test and pelvic exam

Growth Fraction

Measure of how many cells are undergoing mitosis in a tissue - it is a Ratio of replicating cells to resting cells • Major factor in determining success of chemotherapy • Chemotherapy most effective against rapidly dividing cells • High growth fraction = many replicating cells • Solid tumors have low growth fraction; thus less sensitive to chemotherapy • Leukemias and lymphomas have high growth fraction; thus chemotherapy more effective • Hair follicles, bone marrow, gastrointestinal tissue have high growth factor—this explains many adverse effects (e.g., hair loss)

Tumor (neoplasm)

Named for tissue where it originates - Suffix - oma, as in lymphoma • May be solid masses or disseminated in blood

Mitotic inhibitors

Primary subdivisions of natural products for antineoplastics: Have common ability to affect cell division • Vinca alkaloids • Taxanes • Topoisomerase inhibitors • Camptothecins

Dosing Schedules

Specific dosing protocols - Depend on type of tumor, stage of disease, overall condition of patient - May be given as single dose or several doses - May be given within days or after several weeks ▪ Gives normal cells chance to recover • Sometimes optimal dose must be delayed - Lets patient recover from drug toxicities - Example: in bone marrow depression

Cyclophosphamide (Cytoxan)

Therapeutic Class: Antineoplastic Pharmacologic Class: Alkylating agent; nitrogen mustard Actions and Uses It is a commonly prescribed nitrogen mustard. It is used alone, or in combination with other drugs, against a wide variety of cancers, including Hodgkin's disease, lymphoma, multiple myeloma, breast cancer, and ovarian cancer. it acts by attaching to D N A and disrupting replication, particularly in rapidly dividing cells. It is one of only a few anticancer drugs that are well absorbed when given orally (P O). it is a powerful immunosuppressant. While this is considered an adverse effect during cancer chemotherapy, the drug is used to intentionally cause immunosuppression for the prophylaxis of organ transplant rejection and to treat severe rheumatoid arthritis and systemic lupus erythematosus (S L E). Administration Alerts • Dilute prior to I V administration. • Monitor platelet count prior to I M administration; if low, hold dose . • To avoid G I upset, take with meals or divide doses . • Pregnancy category C. Pharmacokinetics (P O) Adverse Effects Bone marrow suppression is a potentially life-threatening adverse reaction that occurs during days 9-14 of therapy; the patient is at dangerous risk for severe infection and sepsis during this period. Thrombocytopenia is common, though less severe than with many other alkylating agents. Nausea, vomiting, anorexia, and diarrhea are frequently experienced. it causes reversible alopecia, although the hair may regrow with a different color or texture. Several metabolites of it may cause hemorrhagic cystitis if the urine becomes concentrated; patients should be advised to maintain high fluid intake during therapy. The drug may cause permanent sterility in some patients. Unlike other nitrogen mustards, it exhibits little neurotoxicity. Contraindications: it is contraindicated in patients with hypersensitivity to the drug and for those who have active infections or severely suppressed bone marrow. Interactions Drug-Drug: Immunosuppressant drugs used concurrently with it will increase the risk of infections and further development of neoplasms. There is an increased chance of bone marrow toxicity if it is used concurrently with allopurinol. There is an increased risk of bleeding if given with anticoagulants. If used concurrently with digoxin, decreased serum levels of digoxin occur. Use with insulin may lead to hypoglycemia. Phenobarbital, phenytoin, or glucocorticoids used concurrently may lead to an increased rate of its metabolism by the liver. Thiazide diuretics increase the possibility of leukopenia. Lab Tests: Serum uric acid levels may increase. Blood cell counts will diminish due to bone marrow suppression. Positive reactions to Candida, mumps, and tuberculin skin tests are suppressed. Pap smears may give false positives. Herbal/Food: St. John's wort may increase the toxic effects of it . Treatment of Overdose: There is no specific treatment for overdose

Methotrexate

Therapeutic Class: Antineoplastic Pharmacologic Class: Antimetabolite, folic acid analog Actions and Uses it is an antimetabolite available by the oral, parenteral, and intrathecal routes. By blocking the synthesis of folic acid (vitamin B9), it inhibits replication, particularly in rapidly dividing cells. It is prescribed alone or in combination with other drugs for choriocarcinoma, osteogenic sarcoma, leukemias, head and neck cancers, breast carcinoma, and lung carcinoma. Its primary use as an antineoplastic agent is in combination therapy to maintain induced remissions in those persons who have had surgical resection or amputation for a primary tumor. In addition to its role as an antimetabolite, methotrexate has powerful immunosuppressant properties. While immunosuppression is considered an adverse effect in patients with cancer, this action of methotrexate can be used to advantage in treating patients with severe rheumatoid arthritis, ulcerative colitis, S L E, and psoriasis. Administration Alerts • Avoid skin exposure to the drug. • Avoid inhaling drug particles . • Dilute prior to I V administration. • Pregnancy category X. Adverse Effects it has many adverse effects, some of which can be life threatening. Nausea and vomiting are severe at high doses. Black Box Warning: it carries multiple black box warnings. it is combined with nonsteroidal anti-inflammatory drugs (N S A I D s) may cause severe and sometimes fatal myelosuppression, which is the primary dose-limiting toxicity of and sometimes fatal myelosuppression, which is the primary dose-limiting toxicity of this drug. The drug is hepatotoxic and may cause liver cirrhosis with prolonged use. Ulcerative stomatitis and diarrhea require suspension of therapy because they may lead to hemorrhagic enteritis and death from intestinal perforation. Potentially fatal opportunistic infections, including Pneumocystis pneumonia, may occur during therapy. Pulmonary toxicity may result in acute or chronic interstitial pneumonitis at any dose level. Severe, sometimes fatal, dermatologic reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome (S J S) have been reported. Low doses of methotrexate have been associated with the development of malignant lymphomas. High doses can result in renal failure. Contraindications: The use of it as an antineoplastic is contraindicated in thrombocytopenia, anemia, leukopenia, concurrent administration of hepatotoxic drugs and hematopoietic suppressants, alcoholism, or lactation. Methotrexate is teratogenic and is contraindicated in pregnant patients. Patients with alcoholism or other chronic liver disease should not receive methotrexate. Immunosuppressed patients or those with blood dyscrasias should not receive methotrexate. Interactions Drug-Drug: Bone marrow suppressants such as chemotherapy agents or radiation therapy may cause increased effects; the patient will require a lower dose of methotrexate. Concurrent use with N S A I D s may lead to severe methotrexate toxicity. Aspirin may interfere with excretion of methotrexate, leading to increased serum levels and toxicity. Concurrent administration with live oral vaccines may result in decreased antibody response and increased adverse reactions to the vaccine. Lab Tests: Serum uric acid levels may increase. Blood cell counts will diminish due to bone marrow suppression. Herbal/Food: Food delays the oral absorption of methotrexate. Echinacea may increase the risk of hepatotoxicity. More than 180 mg per day of caffeine (3 to 4 cups of coffee) may decrease the effectiveness of methotrexate when taken for arthritis. Treatment of Overdose: Leucovorin (folinic acid), a reduced form of folic acid, is sometimes administered with methotrexate to "rescue" normal cells or to protect against severe bone marrow damage. It is most effective if administered as soon as possible after the overdose is discovered. In addition, the urine may be alkalinized to protect the kidneys from methotrexate toxicity.

Doxorubicin (Adriamycin)

Therapeutic Class: Antineoplastic Pharmacologic Class: Antitumor antibiotic Actions and Uses it attaches to D N A, distorting its double helical structure and preventing normal D N A and R N A synthesis. It is administered only by I V infusion. it is a broad- spectrum cytotoxic antibiotic, prescribed for solid tumors of the bone, G I tract, thyroid, lung, breast, ovary, and bladder, and for various leukemias and lymphomas. It is structurally similar to daunorubicin. it is considered to be one of the most effective single drugs against solid tumors. A novel delivery method has been developed for both doxorubicin and daunorubicin. The drug is enclosed in small lipid sacs, or vesicles, called liposomes. The liposomal vesicle is designed to open and release the antitumor antibiotic when it reaches a cancer cell. The goal is to deliver a higher concentration of drug to the cancer cells, thus sparing normal cells. An additional advantage is that its liposomal has a half-life of 50 to 60 hours, which is about twice that of regular doxorubicin. Doxorubicin liposomal is approved for use in patients with Kaposi's sarcoma, refractory ovarian tumors, and relapsed multiple myeloma. Administration Alerts • Extravasation can cause severe pain and extensive tissue damage. Skin contact or extravasation should be treated immediately with local ice packs to reduce absorption of the drug . • For infants and children, verify concentration and rate of I V infusion with the health care provider. • Avoid skin contact with the drug. If exposure occurs, wash thoroughly with soap and water. • Pregnancy category D. Adverse Effects it has many adverse effects, some of which are serious. The most serious dose-limiting adverse effect of it is cardiotoxicity. Like many anticancer drugs, it may profoundly lower blood cell counts. Acute nausea and vomiting are common and often require antiemetic therapy. Complete, though reversible, hair loss occurs in most patients. Black Box Warning: Severe myelosuppression may occur, which is the major doselimiting toxicity with doxorubicin. It may manifest as thrombocytopenia, leukopenia (especially granulocytes), and anemia. it exhibits significant cardiotoxicity, which may be either acute or chronic. Cardiac adverse effects can be life threatening and may include sinus tachycardia, bradycardia, delayed heart failure, acute left ventricular failure, and myocarditis. Heart failure may occur months or years after the termination of chemotherapy. Acute, infusion-related reactions may occur, including anaphylaxis. Severe local necrosis may result if extravasation occurs. Secondary malignancies, especially acute myelogenous leukemia, may occur 1 to 3 years following therapy. Contraindications: Contraindications include pregnancy, lactation, myelosuppression, thrombocytopenia, pre-existing cardiac disease, obstructive jaundice, lactation, or previous treatment with complete cumulative doses of doxorubicin or daunorubicin. Interactions Drug-Drug: If digoxin is taken concurrently, patient serum digoxin levels will decrease. Use with phenobarbital may lead to increased plasma clearance of doxorubicin and decreased effectiveness. Use with phenytoin may lead to decreased phenytoin level and possible seizure activity. Hepatotoxicity may occur if mercaptopurine is taken concurrently. Use with verapamil may increase serum doxorubicin levels, leading to doxorubicin toxicity. Lab Tests: Serum uric acid and aspartate aminotransferase (A S T) levels may increase. Blood cell counts will diminish due to bone marrow suppression. Herbal/Food: Green tea may enhance the antitumor activity of it. St. John's wort may decrease the effectiveness of it . Treatment of Overdose: The primary result of overdosage is immunosuppression. Treatment includes prophylactic antimicrobials, platelet transfusions, symptomatic treatment of mucositis, and possibly hemopoietic growth factor (G-C S F, G M-C S F).

Tamoxifen

Therapeutic Class: Antineoplastic Pharmacologic Class: Estrogen receptor blocker Actions and Uses it is an oral antiestrogen that is a preferred drug for treating metastatic breast cancer. It is effective against breast tumor cells that require estrogen for their growth (E R-positive cells). Whereas tamoxifen blocks estrogen receptors on breast cancer cells, it actually activates estrogen receptors in other parts of the body, resulting in typical estrogen-like effects such as reduced low-density lipoprotein (L D L) levels and increased mineral density of bone. it is approved for the palliative treatment of advanced, metastatic, E R-positive breast cancer in men and postmenopausal women. A unique feature of it is that it is one of the few antineoplastics that is approved for prophylaxis of breast cancer, for high-risk patients who are at risk of developing the disease. In addition, it is approved as adjunctive therapy in women following mastectomy to decrease the potential for cancer in the opposite breast. Administration Alerts • Give with food or fluids to decrease G I irritation. • Do not crush or chew drug. • Avoid antacids for 1-2 h following P O dosage of it. • Pregnancy category D. Adverse Effects Nausea and vomiting are common adverse effects of tamoxifen. Hot flashes, fluid retention, and vaginal discharges are relatively common. it causes initial "tumor flare," an idiosyncratic increase in tumor size, but this is an expected therapeutic event. Hypertension and edema occur in about 10% of patients taking the drug. Black Box Warning: The most serious problem associated with its use is the increased risk of uterine cancer. The benefits of it outweigh the risks in women who are taking it to treat breast cancer. The benefit versus risk is not as clear in women who are taking it to prevent breast cancer. There is also a slightly increased risk of thromboembolic disease, including stroke, pulmonary embolism, and deep vein thrombosis with the use of it . The risk of a embolism, and deep vein thrombosis with the use of tamoxifen. The risk of a thromboembolic event is believed to be about the same as for oral contraceptives. Contraindications: Contraindications to the use of it include anticoagulant therapy, pre-existing endometrial hyperplasia, history of thromboembolic disease, pregnancy, and lactation. Precautions should be observed in patients with blood disorders, visual disturbances, cataracts, hypercalcemia, and hypercholesterolemia. Interactions Drug-Drug: Anticoagulants taken concurrently with it may increase the risk of bleeding. Concurrent use with cytotoxic drugs may increase the risk of thromboembolism. Estrogens will decrease the effectiveness of it . Lab Tests: Serum calcium levels may increase. Herbal/Food: Unknown. Treatment of Overdose: Seizures, neurotoxicity, and dysrhythmias may occur with overdose. The patient is treated symptomatically.

Vincristine

Therapeutic Class: Antineoplastic Pharmacologic Class: Vinca alkaloid, mitotic inhibitor, natural product Actions and Uses it is specific for the M-phase of the cell cycle where it kills cancer cells by preventing their ability to complete mitosis. It exerts this action by inhibiting microtubule formation in the mitotic spindle. Although it must be given I V, its major advantage is that it causes minimal immunosuppression. It has a wider spectrum of clinical activity than vinblastine and is usually prescribed in combination with other antineoplastics for the treatment of Hodgkin's and non-Hodgkin's lymphomas, leukemias, Kaposi's sarcoma, Wilms' tumor, bladder carcinoma, and breast carcinoma. Administration Alerts • Extravasation may result in serious tissue damage. Stop the injection immediately if extravasation occurs, apply local heat, and inject hyaluronidase as ordered. Observe the site for sloughing. • Avoid eye contact, which can cause severe irritation and corneal changes. • Pregnancy category D. Adverse Effects The most serious dose-limiting adverse effects of it relates to nervous system toxicity. Children are particularly susceptible. Symptoms include numbness and tingling in the limbs, muscular weakness, loss of neural reflexes, and pain. Severe constipation is common and paralytic ileus may occur in young children. Reversible alopecia occurs in most patients. Black Box Warning: Myelosuppression may be severe and predispose to opportunistic infections. Extravasation can cause intense pain, inflammation, and tissue necrosis. If extravasation occurs, treatment with warm compresses and hyaluronidase is recommended; cold compresses will significantly increase the toxicity of vinca alkaloids. Contraindications: Contraindications to the use of it include obstructive jaundice, men and women of child-bearing age, active infection, adynamic ileus, radiation of the liver, infants, pregnancy, and lactation. Interactions Drug-Drug: Asparaginase used concurrently with or before vincristine may cause increased neurotoxicity secondary to decreased hepatic clearance of vincristine. Doxorubicin or prednisone may increase bone marrow toxicity. Calcium channel blockers may increase its accumulation in cells. Concurrent use with digoxin may decrease digoxin levels. When it is given with methotrexate, the patient may need lower doses of methotrexate. it may decrease serum phenytoin levels, leading to increased seizure activity. Lab Tests: Serum uric acid levels may increase. Herbal/Food: Unknown. Treatment of Overdose: Overdose with it may cause life-threatening symptoms or death. Symptoms are extensions of the drug's adverse effects. Supportive treatment may include administration of leucovorin (folinic acid).

Hormones and Hormone Antagonists

• Antineoplastic drugs slow growth of reproductive-related tumors - Breast, prostate, uterine • Less cytotoxic than other antineoplastics • Prototype drug: tamoxifen • Mechanism of action: blocks estrogen receptors on breast cancer cells • Primary use: patients with breast cancer - Also given to high-risk patients to prevent disease Also given to high-risk patients to prevent disease • Adverse effects: nausea and vomiting - Association with increased risk of endometrial cancer and thromboembolic disease - Hot flashes, fluid retention, vaginal discharges common

Cell Cycle

• Cell cycle - G0 phase: resting stage (spend most of the time here)- go through metabolism, impulse conduction, contraction or secretion.-everyday stuff. - G1 phase: synthesizes material needed to duplicate D N A (like RNA, proteins, etc) - S phase: Duplicates D N A - G2 phase: known as premitotic phase - M phase: mitosis occurs - Cell returns to G0 phase

Cancer (carcinoma)

• Characterized by rapid, uncontrolled cell division • Cells lose normal functions and invade normal tissues • Metastasis: cancer cells travel to another location Causes: Some known carcinogens • Chemical - Tobacco (responsible for one third of all cancers) - Asbestos (lung cancer) - Benzene (leukemia) associated with plastic • Physical - X-rays (leukemia) - Ultraviolet (U V) light from sun (skin cancer) • Biological - Viruses (associated with 15% of all cancers) ▪ Examples: herpes simplex viruses, Epstein-Barr, papillomavirus, cytomegalovirus - Factors that suppress immune system ▪ H I V ▪ Drugs given after transplants - Oncogenes (genetic predisposition) - Damage to tumor suppressor gene

Serious Toxicity limits therapy

• Difficult to kill cancer cells without killing normal cells • Adverse effects of therapy - Alopecia - Mucositis (painful ulcerations, GI bleeding, diarrhea) - Nausea and vomiting ▪ Drugs with high emetic potential pretreated with antiemetics (Zofran, Compazine, Reglan, Ativan) • Adverse effects of therapy - Bone marrow depression (anemia, leukopenia, thrombocytopenia) ▪ Treated with bone-marrow transplantation, platelet infusions, or growth factors - If neutropenia occurs (less than 1,500 cells/mL), infection risk grows • Vesicants -Agents that Can cause tissue injury if extravasation occurs from the artery or vein during infusion or injection - Know emergency treatment before giving vesicants I V • Long-term consequences - Possible infertility - Increased risk for secondary tumors

Achieving Total Cure

• Total cure = every malignant cell removed or killed - Even one cell could reproduce - Immune system eliminates very small number of cancer cells • Important to diagnose cancer early - Treat with surgery, radiation, chemotherapy Multiple-Drug Strategy • Multiple drugs from different classes Multiple drugs from different classes - Affect different stages in cell cycle - Use different mechanisms of action to increase cell kill • Combinations allow for lower doses - Reduce toxicity - Slow development of resistance

antineoplastic drugs

•Categories include: Alkylating agents - Form bonds with D N A, prevent cell division -Acts by changing the structure of DNA in cancer cells -Use is limited bc it can cause significant bone marrow suppression • Discontinue if R B C, W B C, and platelet counts fall • Use caution with hepatic or renal impairment, recent steroid therapy, leukopenia, or thrombocytopenia • Hydrate patients with I V or oral fluids before starting chemotherapy • Advise patients to avoid crowds and those with respiratory infections • Be alert to possible development of blood dyscrasias • Monitor nutritional intake • Assess for nausea and vomiting - Be prepared to administer antiemetic drugs • Offer ice chips or ice pops to relieve mouth pain • Assess skin integrity • Monitor for signs of hearing loss • Inform patients of potential adverse impact on fertility • Alkylating agents range from pregnancy category C to X • Maintain strict medical asepsis • Antimetabolites - Resemble building blocks of cells - Disrupt metabolism of nucleic acid in cancer cells • Act by disrupting critical pathways in cancer cells - Example: folate metabolism or D N A synthesis • Three types of antimetabolites - Folic acid analogs - Purine analogs - Pyrimidine analogs • Contraindicated in: pregnancy; hepatic, cardiac, and renal insufficiency; myelosuppression; and blood dyscrasias • Avoid pregnancy for at least 6 months after therapy with category X drug • Adverse effects common to other antineoplastics may occur • Monitor for photosensitivity and idiosyncratic pneumonitis • Teach patients to use good oral hygiene and encourage mouth rinses • Monitor I V site frequently for extravasation • Antitumor antibiotics - Antibiotics that can kill some cancer cells • Act by inhibiting cell growth through cytotoxicity - Actions similar to alkylating agents • Narrow spectrum of clinical activity • Cardiotoxicity is major limiting factor - May occur within minutes or years later - Role of the nurse includes • Assess cardiac status—obtain baseline E C G • Assess for pregnancy and lactation • Monitor for same cytotoxic effects as other antineoplastics • Risk of hypersensitivity reactions exists as with other antibiotics • Changes in rectal mucosa contraindicate suppositories or rectal temperatures • Wear protective clothing (gloves, mask, and apron) when preparing drug • Monitor I V site because doxorubicin is a severe vesicant • Give drug through large-bore, quickly running I V; monitor for extravasation • Natural products - From plants, prevent division of cancer cells • Hormones and hormone agents - Slow growth of hormone -dependent tumors - Structural variety but common effect - Kill cancer cells by preventing cell division - Called mitotic inhibitors • Assess allergy to plants or flowers, including herbs or foods • Vincristine (Oncovin) may produce acute bronchospasm and skin rashes • Inquire if female patients are pregnant or breastfeeding • Monitor for same cytotoxic effects as other antineoplastics • Emphasize need to establish nutritional plan to combat constipation - High fluid and fiber intake • Monitor blood pressure • Observe patients for symptoms such as headache, dizziness, or syncope • May produce severe mental depression; assess possibility of suicidal ideation • Biologic response modifiers and monoclonal antibodies - Enhance body's ability to remove cancer cells • Miscellaneous drugs