Anticancer Drugs Class II // Breast Cancer Case Study – Flashcards

In the United States, cancer-related deaths rank second after heart disease. According to the American Cancer Society, there will be an estimated 1,685,210 new cases of cancer diagnosed in the United States and 595,690 cancer-related deaths in 2016. The term cancer does not refer to a single disease but instead includes a group of disorders. There are many types of cancer; most have multiple subtypes. Each type of cancer differs in clinical presentation, cellular involvement, drug responsiveness, and prognosis, therefore the treatment of cancer must be individualized depending on the specific biology of the involved cells.

Cell cycle-nonspecific (CCNS) drugs (phase-nonspecific drugs) act during any phase of the cell cycle, including the G0 phase. In general, the CCNS drugs include most alkylating drugs, antitumor antibiotics, and hormones.

Cell cycle-specific (CCS) drugs (phase-specific drugs) influence a specific phase or phases of the cell cycle. CCS agents are most effective against rapidly growing cancer cells. The CCS drugs include antimetabolites and vinca alkaloids.

There are four main classes of anticancer drugs: Cytotoxic agents, which kill cells directly. Hormones and hormone antagonists, which suppress action of endogenous hormones. Biologic response modifiers, which are immunomodulating agents and suppress tumor growth. Targeted drugs, which bind with, and destroy, specific molecules within cancer cells or nearby cells (targets) that promote cancer growth. The term chemotherapy applies to cytotoxic drugs only, which are the most frequently used anticancer drugs. Chemotherapy drugs are typically administered via the intravenous route.

Cytotoxic agents directly kill cancer cells. These agents form the largest class of anticancer drugs. They are either cell cycle-specific or cell cycle-nonspecific. Most cytotoxic agents target deoxyribonucleic acid (DNA) or ribonucleaic acid (RNA) in cancer cells. Some cytotoxic agents block cell division, while another drug, asparaginase, disrupts protein synthesis. All cytotoxic drugs except asparaginase disrupt processes being carried out exclusively by cells undergoing replication; therefore, these drugs are most toxic to tissues that have a high mitotic index, such as hair and skin cells.

Hormonal agents are primarily used in cases of prostate and breast cancer. These cancers are often hormonally sensitive, and hormonal agents either suppress or mimic the actions of endogenous hormones, depending on the response of the cancer cells to the hormone. Many hormonal agents do not cause the serious toxicities that are associated with cytotoxic agents such as nausea, vomiting, stomatitis, alopecia and especially bone marrow suppression, which is often a limiting factor in regards to how a cancer patient can be treated.

This broad class of drugs includes hematopoietic drugs and immunomodulating drugs. Often referred to as biologic response modifiers (BRMs) or biomodulators, they alter the body's response to diseases such as cancer. They may also be used with autoimmune, inflammatory, and infectious diseases. Examples are cytokines (e.g., interleukin, interferons), monoclonal antibodies, and vaccines. BRMs may be adjuvants, immunostimulants, or immunosuppressants.

Targeted anticancer drugs are designed to bind with specific molecules (targets) within the cancerous cells or with cells nearby that are known to assist in the cancerous growth process. The goal of targeted therapy is to suppress tumor growth. The primary difference in targeted therapy is that these drugs are more selective than hormones and cytotoxic anticancer drugs and, therefore, destroy cancer cells while leaving normal cells untouched. A few targeted drugs, such as imatinib, have been remarkably successful, producing complete responses with relatively mild adverse effects. Unfortunately, others have had less impressive results with more severe adverse effects. Nonetheless, the concept of targeted therapy has great appeal, and intensive research is underway to improve outcomes and possibilities. This lesson will focus on the action of select targeted therapy drugs, specifically the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib and the BCR-ABL tyrosine kinase inhibitor imatinib.

Through a process known as phosphorylation, tyrosine kinases activate other substances by adding a phosphate group (PO4) to them (Kee, 2015). Tyrosine kinase inhibitors are drugs that inhibit tyrosine kinases through various mechanisms. There are currently six available EGFR tyrosine kinase inhibitors (cetuximab, panitumumab, erlotinib, gefitinib, afarinib, and lapatinib). Two of these (cetuximab and panitumumab) are monoclonal antibodies that bind with the receptor portion of EGFR tyrosine kinase, thereby preventing its activation. The other four (erlotinib, gefitinib, afatinib, and lapatinib) work inside the cell to inhibit tyrosine kinase directly. Tyrosine kinase is activated when an agonist binds to EGFR, which then activates signaling pathways that regulate cell proliferation and survival. Drugs that inhibit EGFR suppress cell proliferation and promote apoptosis (programmed cell death), which is why they are effective in the treatment of cancer.

The preferred drugs for the treatment of chronic myeloid leukemia (CML) are the BCR-ABL tyrosine kinase inhibitors. The BCR-ABL tyrosine kinase inhibitors that are currently five available include imatinib, dasatinib, bosutinib, ponatinib, and nilotinib. Imatinib is the exemplar drug for CML therapy. Despite this therapy, relapses in cancers can occur, due in part to the ability of cells to develop imatinib-resistance. The other drugs in this class (dasatinib, bosutinib, ponatinib, and nilotinib) may be effective for cancers that no longer respond to imatinib.

Gefitinib disrupts cellular processes regulated by epidermal growth factor receptors (EGFRs). EGFRs are transmembranous proteins that bind to epidermal growth factor, which, in turn, activate intracellular tyrosine kinase. Typically, this leads to activation of signaling pathways that regulate cell proliferation and survival. Gefitinib inhibits tyrosine kinase that is linked with EGFR, suppressing cell proliferation and promoting apoptosis. Pharmacokinetics Therapeutic Use

The pharmacokinetics of gefitinib include: Slow absorption from the GI tract Peak plasma levels occuring 3 to 7 hours after dosing Undergoes extensive hepatic metabolism and is excreted in the feces Elminiation half-life of 48 hours

Gefitinib is targeted therapy approved for treatment of non-small cell lung cancer. It is approved for first-line treatment of metastatic, non-small cell lung cancer (NSCLC) due to the fact that cells associated with NSCLC often over-express EGFRs. Gefitinib is approved only for treatment of NSCLC with tumors that have EGFR exon 19 deletions or exon 21 substitution mutations.

Imatinib is targeted therapy approved for the treatment of various types of cancers, including CML. Inhibition of BCR-ABL tyrosine kinase, which suppresses proliferation of CML cells and promotes apoptosis. Selective action only on cells expressing BCR-ABL tyrosine kinase, leading to fewer side effects.

Effective absorption after oral administration 98% bioavailability; highly protein-bound in the blood Primarily metabolized in the liver by CYP3A4 and CYP2D6, with subsequent excretion in the feces Elimination half-life of imatinib of 18 hours; major metabolite elimination half-life of 40 hours

Anticancer drugs interfere with cell replication and cause cell death.

It suppresses tumor growth It is deliberately designed to interact with target cells. It acts on specific molecular targets associated with cancer.

IV

Non-small cell lung cancer

Imatinib suppresses activation of BCR-ABL tyrosine kinase.

Conduct a detailed medication history including prescriptions, over-the counter medicines, antacids, dietary supplements, vitamins, and herbal supplements to avoid drug-drug interactions. Obtain drug and food allergies. Obtain baseline information about the patient"s physical status, including height, weight, vital signs, cardiopulmonary assessment, intake and output, skin assessment, nutritional status, and any underlying diseases. Obtain baseline laboratory values (CBC, uric acid, chemistry panel) before, and as recommended during, treatment. Assess baseline results of pulmonary function tests, chest radiographs, electrocardiographs (ECG), and renal and liver function studies. Assess patient"s and caregiver"s current level of comprehension related to the therapeutic regimen.

Gefitinib is contraindicated in patients with severe hypersensitivity to, or to any other component of, gefitinib. Liver function tests (LFTs) should be monitored as recommended. The dose should be increased if the patient is using strong CYP3A4 inducers. The drug may be held for up to 14 days if the patient develops unmanageable diarrhea, worsening ocular or pulmonary disorders, or worsening rash. The drug should be discontinued if GI perforation or interstitial lung disease occurs.

Imanitib is contraindicated in women who are pregnant, may become pregnant, or are breastfeeding. The drug should be used cautiously in patients with renal or hepatic impairment, cardiac disease, bone marrow suppression, or active infection. Use with caution in children. Health care providers should avoid using alongside strong CYP3A4 inducers.

CYP3A4 inhibitors, such as itraconazole and ketoconazole, can decrease gefitinib metabolism and may increase its plasma level because its bioavailability and action are prolonged. CYP3A4 inducers, such as rifampin, phenytoin, carbamazepine, and St. John's wort may reduce the bioavailability and action of gefitinib because it is metabolized by the liver more rapidly. Drugs that lower gastric pH, such as histamine2 antagonists, proton pump inhibitors, and antacids, can decrease the rate of gefitinib digestion and absorption in the upper GI tract, thus reducing its activity.

CYP3A4 inhibitors, such as ketoconazole and erythromycin, can increase levels of imatinib. CYP3A4 inducers, such as carbamazepine, rifampin, and St. John's wort, can decrease levels of imatinib. Imitanib may decrease the effect of warfarin.

The usual dosage is 250 mg PO once a day, taken with or without food. Dosing should be interrupted for up to 14 days if the patient develops severe rash, unmanageable diarrhea, or ocular complications. Dosing should be discontinued if patient develops interstitial lung disease. Dosage may be increased to 500 mg/day for patients taking a potent inducer of CYP3A4.

Imatinib is supplied in 100- and 400-mg tablets. The drug should be administered with a meal and a large glass of water. For adults with CML, the dosage is 400 mg once daily during the chronic phase, and 600 mg once daily during the accelerated phase or in a blast crisis. For children with CML, the dosage is 340 mg/m2 once daily during the chronic phase.

Nurses who administer anticancer agents receive specialized training. The following precautions should be taken to minimize the nurse"s exposure to chemotherapeutic agents during administration: Use disposable powder-free gloves approved for handling chemotherapy, regardless of the route of administration. Wear two pair of gloves and change gloves every 30 minutes or when torn, punctured, or contaminated. When administering IV chemotherapy, wear gowns with front closure, long sleeves, and elastic or knit closed cuffs, and dispose of gown after each use. When there is risk of aerosol exposure, follow the Occupational Safety and Health Administration (OSHA) respiratory protection standard. Use a face shield with or without a mask if there is a danger of splashing when administering chemotherapy or disposing of body fluids.

Gefitinib is generally well tolerated. The most frequently reported adverse effects of gefitinib are diarrhea and rash. Other adverse effects include the following: dry skin, nausea, vomiting, conjunctivitis, abnormal eyelash growth, acne, pruritus, anorexia, and increase in serum hepatic transaminases.

The most frequently reported adverse effects of imatinib include nausea, diarrhea, vomiting, rash, headache, fluid retention, musculoskeletal pain, muscle cramps, and arthralgia. Occasionally reported adverse effecs include fatigue, fever, abdominal pain, cough myalgia, fatigue, anorexia, dyspepsia, constipation, night sweats, pruritus, dizziness, blurred vision, and somnolence. Severe fluid retention, including pleural effusion, pericardial effusion, pulmonary edema, and ascites occur rarely, as well as hepatotoxicity. Neutropenia and thrombocytopenia are common responses to imatinib therapy; these increase the risk of infection and bleeding. Additionally reported adverse reactions include allergic reations, nasopharyngitis, petechiae, asthenia, epistaxis, respiratory toxicity that manifests as dyspnea and/or pneumonia, severe heart failure, serious skin reactions (e.g., erythema multiforme, Stevens-Johnson syndrome), and hypothyroidism in thyroidectomy patients receiving thyroid hormone replacement therapy.

Careful skin examination at each visit, evaluating for erythema, rash, peeling, or blister formation. It is important to rate the severity of skin reactions. Monitor for evidence of infection (e.g., fever, chills, leukocytosis, leukopenia, and neutropenia). Assess for evidence of thromboembolic events. Monitor for any signs of intestinal perforation (e.g., abdominal pain or distention, diminished or absent bowel sounds, and changes in blood pressure or heart rate). Monitor renal and hepatic function, CBC, chemistry panel, and urinalysis. Administer prescribed pre-medication therapies according to established protocols. Assess for cardiac events, such as new chest pain and ECG changes. Assess for any pulmonary complications, such as dyspnea and cough.

Seek immediate medical attention if any of the following occurs: chest pain, symptoms of stroke (e.g., altered mental status, inability to talk or move one side of the body, sudden numbness or weakness, seizures), severe abdominal pain, or swelling with redness or pain in one leg. If taking erlotinib, report worsened skin rash; severe or persistent diarrhea, nausea, vomiting, or anorexia; onset of or worsening dyspnea or cough; and eye irritation. Monitor daily weights and report a gain of more than 2 pounds in 1 day or 4 pounds in 1 week. Report foaming of urine (an indication of proteinuria). Avoid nonsteroidal antiinflammatory drugs (e.g., aspirin [except low dose aspirin], celecoxib, ibuprofen, naproxen) to prevent excessive bleeding. If receiving bevacizumab infusions, learn to promote venous return and avoid deep vein thrombosis by avoiding dehydration, restrictive clothing, and smoking cigarettes. Women of childbearing age should avoid pregnancy during and up to 12 months after treatment. Breastfeeding women should stop breastfeeding during, and for 60 days after, treatment. Avoid direct sunlight and tanning beds to prevent dermatological side effects. Avoid cigarette smoking while on erlotinib. If on gefitinib and warfarin, continue close international normalized ratio monitoring. Immediately report adverse effects, including fever, chills, persistent sore throat, swelling, weight gain, and increasing shortness of breath. Immediately report symptoms of bleeding, including black stools, coffee ground emesis, and easy bleeding/bruising. Side effects are dose-dependent.

Take with food or 240 mL of water to reduce gastric irritation. Monitor daily weights and report a gain of more than 2 pounds in 1 day or 4 pounds in 1 week. Check hands and feet daily for signs of palmar-plantar erythrodysesthesia (redness, pain, swelling, or blisters) and report these symptoms immediately. Women of childbearing age should avoid pregnancy during and up to 12 months after treatment. Breastfeeding women should stop breastfeeding during, and for 60 days after, treatment. Grapefruit juice can increase blood levels of imatinib, and worsen side effects or adverse effects of imatinib. Avoiding grapefruit juice is recommended. The herbal supplement St. John's wort should be avoided while on imatinib because of decreased effectiveness. Avoid alcohol and nonessential drugs that are cleared by the liver or have liver-toxic effects (e.g. acetaminophen). Immediately report adverse effects, including fever, chills, persistent sore throat, swelling, weight gain, and increasing shortness of breath. Immediately report symptoms of bleeding, including black stools, coffee ground emesis, and easy bleeding/bruising. Immediately report symptoms of liver impairment, including stomach or abdominal pain, yellowing of eyes or skin, dark urine, and unusual fatigue. Side effects are dose-dependent.

Drugs that inhibit CYP3A4 can reduce metabolism of targeted drugs.

Baseline chest x-ray Food and drug allergies Baseline skin assessment Detailed medication history

chest pain

liver function test

Adequate fluid intake reduces gastric irritation.

"I can resume breastfeeding my child 1 month after completing my medication."

Cancer cells have become resistant to imatinib.

A patient with a history of recent radiation therapy who is receiving gefitinib

Weekly for the first month, bi-weekly for the second month, and periodically thereafter

current breastfeeding current antibiotic therapy current dialysis treatment

Instruct the patient to immediately call and report the symptoms to the prescriber.

cytotoxic drug therapy

hormone antagonists

biologic response modifiers

they bind with and prevent activation of EGFR tyrosine kinase

3-7 hours after administration

"You need to have orientation and unit training before your first patient care assignment."

"Alcohol intake can impair liver metabolism of imatinib."

dyspnea

Tamoxifen blocks the actions of estrogen, a female hormone. Certain types of breast cancer require estrogen to grow. Tamoxifen is used to treat some types of breast cancer in men and women. It is also used to lower a woman's chance of developing breast cancer if she has a high risk (such as a family history of breast cancer). About 80% of all breast cancers are "ER-positive." That means the cancer cells grow in response to the hormone estrogen.

Do not take tamoxifen if you are pregnant. It could harm the unborn baby. Avoid becoming pregnant while you are using this medicine, and for at least 2 months after your treatment ends. You should not use tamoxifen if you are allergic to it. You should not use tamoxifen to reduce your risk of breast cancer if you are also taking a blood thinner such as warfarin (Coumadin, Jantoven). Tamoxifen can increase you risk for endometrial cancer.