Pharmacology Chapter 14 Antineoplastic Agents

Contraindications and Cautions of Alkylating agents

*contraindicated during pregnancy and lactation *Caution is necessary when giving with a known allergy to any of them; * bone marrow suppression, which is often the index for redosing and dosing levels; or with suppressed renal or hepatic function, which may interfere with metabolism or excretion of these drugs and often indicates a need to change the dose.

Adverse effects of antineoplastic drugs

*toxic effects on ova and sperm production, affecting the person's fertility. *

Contraindications and Cautions of Antimetabolites

*use during pregnancy and lactation because of the potential for severe effects on the fetus and neonate. *Caution is necessary when administering to any individual with a known allergy to any of them to prevent hypersensitivity reactions; *with bone marrow suppression, which is often the index for redosing and dosing levels; with renal or *hepatic dysfunction, which might interfere with the metabolism or excretion of these drugs and often indicates a need to change the dose; *with known GI ulcerations or ulcerative diseases that might be exacerbated by the effects of these drugs.

Mitotic inhibitors

(Table 14.4) are drugs that kill cells as the process of mitosis begins (see Figure 14.5). These cell cycle-specific agents inhibit DNA synthesis. Like other antineoplastics the main adverse effects of the mitotic inhibitors occur with cells that rapidly multiply: Those in the bone marrow, GI tract, and skin. Mitotic inhibitors include cabazitaxel (Jevtana), docetaxel (Taxotere), eribulin (Halaven), etoposide (generic), ixabepilone (Ixempra), paclitaxel (Abraxane, Onxol, Taxol), teniposide (Vumon), vinblastine (generic), vincristine (generic), and vinorelbine (Navelbine).

Adverse effects of the antimetabolites

*Hematological effects include bone marrow suppression, with leukopenia, thrombocytopenia, anemia, and pancytopenia, secondary to the effects of the drugs on the rapidly multiplying cells of the bone marrow. *Toxic GI effects include nausea, vomiting, anorexia, diarrhea, and mucous membrane deterioration, all of which are related to drug effects on the rapidly multiplying cells of the GI tract. *CNS effects include headache, drowsiness, aphasia, fatigue, malaise, and dizziness. *There is a risk of pulmonary toxicity, including interstitial pneumonitis with these drugs. As with alkylating agents, effects of the antimetabolites may include possible hepatic or renal toxicity, depending on the exact mechanism of action. *Alopecia may also occur

Therapeutic Actions and Indications of Alkylating agents

Alkylating agents produce their cytotoxic effects by reacting chemically with portions of the RNA, DNA, or other cellular proteins, being most potent when they bind with cellular DNA. The oldest drugs in this class are the nitrogen mustards, and modifications of the structure of these drugs have led to the development of the nitrosoureas. These drugs are most useful in the treatment of slow-growing cancers such as various lymphomas, leukemias, myelomas; some ovarian, testicular, and breast cancers; and some pancreatic cancers. See Table 14.1 for usual indications for each of the alkylating agents. These agents are not used interchangeably.

alkylating agents

Because alkylating agents can affect cells even in the resting phase, these drugs are said to be non-cell cycle specific (Figure 14.4). They are most useful in the treatment of slow-growing cancers, which have many cells in the resting phase. Alkylating agents (Table 14.1) include the following drugs: altretamine (Hexalen), bendamustine (Treanda), busulfan (Busulfex, Myleran), carboplatin (generic), carmustine (BiCNU, Gliadel), chlorambucil (Leukeran), cisplatin (Platinol, Platinol-AQ), cyclophosphamide (generic), dacarbazine (DTIC-Dome), ifosfamide (Ifex), lomustine (CeeNU), mechlorethamine (Mustargen), melphalan (Alkeran), oxaliplatin (Eloxatin), procarbazine (Matulane), streptozocin (Zanosar), and temozolomide (Temodar).

of Cancer Cell-Specific Agents

Clinically Important Drug-Drug Interactions Use caution when administering these drugs with other drugs affected by the cytochrome P450 enzyme system. In addition, St. John's wort decreases the effectiveness of many of these drugs and should be avoided. It is also important to avoid any other drugs that are known to prolong the QT interval.

Contraindications and Cautions of hormones and hormone modulators

These drugs are contraindicated during pregnancy and lactation because of toxic effects on the fetus and neonate. Hypercalcemia is a contraindication to the use of toremifene, which is known to increase calcium levels. Use caution when giving hormones and hormone modulators to anyone with a known allergy to any of these drugs to prevent hypersensitivity reactions. Care is necessary in patients with bone marrow suppression, which is often the index for redosing and dosing levels, and in those with renal or hepatic dysfunction, which could interfere with the metabolism or excretion of these drugs and often indicates a need to change the dose.

of Cancer Cell-Specific Agents

Contraindications and Cautions All of these drugs are in pregnancy category D. For the time that these drugs are being taken, women of childbearing age should be advised to use barrier contraceptives. It can enter breast milk, and it should be used during lactation only if the benefits to the mother clearly outweigh the risks to the baby. Several of the drugs are contraindicated with patients who have or who are at risk for prolonged QT intervals (hypokalemia, hypomagnesia, or taking another drug that prolongs the QT interval) because they prolong the QT interval, and sudden deaths could occur. These drugs should not be given to anyone who has a history of hypersensitivity to any component of the drug being given.

Contraindications and Cautions of mitotic inhibitors

These drugs should not be used during pregnancy or lactation because of the potential risk to the fetus or neonate. Use caution when giving these drugs to anyone with a known allergy to the drug or related drugs to decrease the risk of serious hypersensitivity reactions. Care is necessary for patients with the following conditions: Bone marrow suppression, which is often the index for redosing and dosing levels; renal or hepatic dysfunction, which could interfere with the metabolism or excretion of these drugs and often indicates a need to change the dose; and known GI ulcerations or ulcerative diseases, which may be exacerbated by the effects of these drugs; prolonged QT interval when using eribulin which may prolong the QT interval leading to potentially serious arrhythmias.

Pharmacokinetics of mitotic inhibitors

Generally, these drugs are given intravenously because they are not well absorbed from the GI tract. They are metabolized in the liver and excreted primarily in the feces, making them safer for use in patients with renal impairment than the antineoplastics that are cleared through the kidney.

Hormones and Hormone Modulators

Some cancers, particularly those involving the breast tissue, ovaries, uterus, prostate, and testes, are sensitive to estrogen stimulation. Estrogen receptor sites on the tumor react with circulating estrogen, and this reaction stimulates the tumor cells to grow and divide. Several antineoplastic agents are used to block or interfere with these receptor sites to prevent growth of the cancer and in some situations to actually cause cell death. Some hormones are used to block the release of gonadotropic hormones in breast or prostate cancer if the tumors are responsive to gonadotropic hormones. Others may block androgen receptor sites directly and are useful in the treatment of advanced prostate cancers. Hormones and hormone modulators include abiraterone (Zytiga), anastrazole (Arimidex), bicalutamide (Casodex), degarelix (Firmagon), enzalutamide (Xtandi), estramustine (Emcyt), exemestane (Aromasin), flutamide (generic), fulvestrant (Faslodex), goserelin (Zoladex), histrelin (Vantas), letrozole (Femara), leuprolide (Lupron, Eligard), megestrol (Megace), mitotane (Lysodren), nilutamide (Nilandron), tamoxifen (Soltamox), toremifene (Fareston), and triptorelin pamoate (Trelstar) (Table 14.5).

Therapeutic Actions and Indications of antineoplastic antibiotics

break up DNA links, and others prevent DNA synthesis. The antineoplastic antibiotics are cytotoxic and interfere with cellular DNA synthesis by inserting themselves between base pairs in the DNA chain. This, in turn, causes a mutant DNA molecule, leading to cell death (Figure 14.4). See Table 14.3 for Usual Indications for each antineoplastic antibiotic. Like other antineoplastics the main adverse effects of these drugs are seen in cells that multiply rapidly, such as those in the bone marrow, GI tract, and skin. Their potentially serious adverse effects may limit their usefulness in patients with preexisting diseases and in those who are debilitated and, therefore, more susceptible to these effects.

Antineoplastic drugs work by affecting

cell survival or by boosting the immune system in its efforts to combat the abnormal cells

Adverse effects of mitotic inhibitors

frequently encountered with the use of mitotic inhibitors include bone marrow suppression, with leukopenia, thrombocytopenia, anemia, and pancytopenia, secondary to the effects of the drugs on the rapidly multiplying cells of the bone marrow. GI effects include nausea, vomiting, anorexia, diarrhea, and mucous membrane deterioration. Eribulin is associated with prolonged QT intervals. As with the other antineoplastic agents, effects of the mitotic inhibitors may include possible hepatic or renal toxicity, depending on the exact mechanism of action. Alopecia may also occur. These drugs also cause necrosis and cellulitis if extravasation occurs, so it is necessary to regularly monitor injection sites and take appropriate action as needed.

Adverse effects of hormones and hormone modulators

frequently encountered with the use of these drugs involve the effects that are seen when estrogen is blocked or inhibited. Menopause-associated effects include hot flashes, vaginal spotting, vaginal dryness, moodiness, and depression. Other effects include bone marrow suppression and GI toxicity, including hepatic dysfunction. Hypercalcemia is also encountered as the calcium is pulled out of the bones without estrogen activity to promote calcium deposition. Many of these drugs increase the risk for cardiovascular disease because of their effects on the body. Abiraterone can increase the risk of adrenocortical insufficiency.

Therapeutic Actions and Indications of mitotic inhibitors

interfere with the ability of a cell to divide; they block or alter DNA synthesis, thus causing cell death. They work in the M phase of the cell cycle. These drugs are used for the treatment of a variety of tumors and leukemias. See Table 14.4 for Usual Indications for each of these agents.

To counteract the effects of treatment with one antimetabolite—methotrexate—the drug

leucovorin or its isomer levoleucovorin is sometimes given

The goal of cancer therapy

limit the offending cells to the degree that the immune system can then respond without causing too much toxicity to the host

cancer patients are not considered to be "cured" until

they have been cancer-free for a period of 5 years due to the possibility that cancer cells will emerge from dormancy to cause new tumors or problems

Therapeutic Actions and Indications of hormones and hormone modulators

used as antineoplastics are receptor site specific or hormone specific to block the stimulation of growing cancer cells that are sensitive to the presence of that hormone (see Figure 14.4). These drugs are indicated for the treatment of breast cancer in postmenopausal women or in other women without ovarian function. Some drugs are indicated for the treatment of prostatic cancers that are sensitive to hormone manipulation. Table 14.5 shows Usual Indications for each of the hormones and hormone modulators.

Teachings for Patients Receiving Alkylating Agents

• Arrange for blood tests before, periodically during, and for at least 3 weeks after therapy to monitor bone marrow function to aid in determining the need for a change in dose or discontinuation of the drug • Administer medication according to scheduled protocol and in combination with other drugs as indicated to improve effectiveness. • Protect the patient from exposure to infection; limit invasive procedures when bone marrow suppression limits the patient's immune/inflammatory responses • Provide small, frequent meals, frequent mouth care, and dietary consultation as appropriate to maintain nutrition when GI effects are severe. Anticipate the need for antiemetics if necessary (see Box 14.6).

These agents also jeopardize the immune system by causing

bone marrow suppression, inhibiting the blood-forming components of the bone marrow and interfering with the body's normal protective actions against abnormal cells

of Cancer Cell-Specific Agents

Adverse Effects The adverse effects associated with imatinib include GI upset, muscle cramps, heart failure, fluid retention, and skin rash. The severe bone marrow suppression, alopecia, and severe GI effects associated with more traditional antineoplastic therapy do not occur. Several of these drugs prolong the QT interval and need to be used with caution in patients with cardiac problems. Erlotinib and bortezomib are associated with cardiovascular events and pulmonary toxicity. Bortezomib has also been associated with peripheral neuropathy and liver and kidney impairment.

Adverse Effects of Alkylating agents

Adverse effects frequently encountered with the use of these alkylating agents are listed below; see Table 14.1 for a list of adverse effects specific to each agent. Amifostine (Ethyol) and mesna (Mesnex) are cytoprotective (cell-protecting) drugs that may be given to limit certain effects of cisplatin and ifosfamide, respectively (Box 14.3). Hematological effects include bone marrow suppression, with leukopenia, thrombocytopenia, anemia, and pancytopenia, secondary to the effects of the drugs on the rapidly multiplying cells of the bone marrow. GI effects include nausea, vomiting, anorexia, diarrhea, and mucous membrane deterioration, all of which are related to the drugs'effects on the rapidly multiplying cells of the GI tract. Hepatic toxicity and renal toxicity may occur, depending on the exact mechanism of action. Alopecia, or hair loss, related to effects on the hair follicles, may also occur. All drugs that cause cell death can cause a potentially toxic increase in uric acid levels. Allopurinol has been used to help alleviate this problem and in 2004, a new drug, rasburicase, was introduced to manage uric acid l

Adverse Effects of antineoplastic antibiotics

Adverse effects frequently encountered with the use of these antibiotics include bone marrow suppression, with leukopenia, thrombocytopenia, anemia, and pancytopenia, secondary to the effects of the drugs on the rapidly multiplying cells of the bone marrow. Toxic GI effects include nausea, vomiting, anorexia, diarrhea, and mucous membrane deterioration, all of which are related to drug effects on the rapidly multiplying cells of the GI tract. As with the alkylating agents and antimetabolites, effects of antineoplastic antibiotics may include renal or hepatic toxicity, depending on the exact mechanism of action. Alopecia may also occur. Specific antineoplastic antibiotics are toxic to the heart and lungs. Box 14.9 discusses a cardioprotective drug that interferes with the effects of doxorubicin.

Contraindications and Cautions of antineoplastic antibiotics

All of these agents are contraindicated for use during pregnancy and lactation because of the potential risk to the fetus and neonate. Use caution when giving antineoplastic antibiotics to an individual with a known allergy to the antibiotic or related antibiotics, to prevent hypersensitivity reactions. Care is necessary when administering these agents to patients with the following conditions: bone marrow suppression, which is often the index for redosing and dosing levels; suppressed renal or hepatic function, which might interfere with the metabolism or excretion of these drugs and often indicates a need to change the dose; known GI ulcerations or ulcerative diseases, which may be exacerbated by the effects of these drugs; pulmonary problems with bleomycin or mitomycin, or cardiac problems with idarubicin or mitoxantrone, which are specifically toxic to these organ systems.

Therapeutic Actions and Indications of Antimetabolites

Antimetabolites inhibit DNA production in cells that depend on certain natural metabolites to produce their DNA. They replace these needed metabolites and thereby prevent normal cellular function. Many of these agents inhibit thymidylate synthetase, DNA polymerase, or folic acid reductase, all of which are needed for DNA synthesis. They are considered to be S phase specific in the cell cycle. They are most effective in rapidly dividing cells, preventing cell replication, and leading to cell death (Figure 14.5). The antimetabolites are indicated for the treatment of various leukemias and some GI and basal cell cancers (see Table 14.2 for Usual Indications for each agent). Use of these drugs has been somewhat limited because neoplastic cells rapidly develop resistance to these agents. For this reason, these drugs are usually administered as part of a combination therapy.

Clinically Important Drug-Drug Interactions of hormones and hormone modulators

If hormones and hormone modulators are taken with oral anticoagulants, there is often an increased risk of bleeding. Care is also necessary when administering these agents with any drugs that might increase serum lipid levels.

The antineoplastic drugs that are commonly used today include

alkylating agents, antimetabolites, antineoplastic antibiotics, mitotic inhibitors, hormones and hormone modulators, cancer cell-specific agents, protein tyrosine kinase inhibitors (which target enzymes specific to the cancer cells), and a group of antineoplastic agents that cannot be classified elsewhere.

Antineoplastic antibiotics

although selective for bacterial cells, are also toxic to human cells. Because these drugs tend to be more toxic to cells that are multiplying rapidly, they are more useful in the treatment of certain cancers. Antineoplastic antibiotics include bleomycin (generic), dactinomycin (Cosmegen), daunorubicin (DaunoXome), doxorubicin (Doxil), epirubicin (Ellence), idarubicin (Idamycin PFS), mitomycin (generic), mitoxantrone (generic), and valrubicin (Valstar).

Antimetabolites

are drugs that have chemical structures similar to those of various natural metabolites that are necessary for the growth and division of rapidly growing neoplastic cells and normal cells. *include capecitabine (Xeloda), cladribine (generic), clofarabine (Clolar), cytarabine (DepoCyt, Tarabine PFS), floxuridine (generic), fludarabine (generic), fluorouracil (Carac, Efudex, Fluoroplex), gemcitabine (Gemzar), mercaptopurine (generic), methotrexate (Rheumatrex, Trexall), pemetrexed (Alimta), pentostatin (Nipent), pralatrexate (Folotyn), and thioguanine (generic).

Pharmacokinetics of antineoplastic antibiotics

are not absorbed well from the GI tract. They are given IV or injected into specific sites. They are metabolized in the liver and excreted in the urine at various rates. Many of them have very long half-lives (e.g., 45 hours for idarubicin; more than 5 days for mitoxantrone). Daunorubicin and doxorubicin do not cross the blood-brain barrier, but they are widely distributed in the body and are taken up by the heart, lungs, kidneys, and spleen. This can lead to toxic effects in these organs.

Sanctuary sites

are sites the cytotoxic drugs can't reach (e.g. testes and CNS)