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Cancer and ChemotherapyChapter 21 Cancer and Chemotherapy © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Topics Pathophysiology of Cancer Malignancy Drugs for Cancer Preparing and Handling Cytotoxic Drugs Preventing Chemotherapy-Related Medication Errors © Paradigm Publishing, Inc.
Pathophysiology of Cancer and MalignancyAbout Cancer and Chemotherapy Agents Cancer is the second leading cause of death in the U.S. About 1.5 million people diagnosed with cancer each year 1 out of every 2 people in the U.S. will develop cancer Medications to treat cancer (chemotherapy) are complex Narrow window between safe use and toxicity Chemotherapy administered in a hospital or outpatient chemotherapy infusion center by IV Technicians prepare most of these drugs Oral chemotherapy is expanding patient care into community practice United States (U.S.) intravenous (IV) © Paradigm Publishing, Inc.
Pathophysiology of Cancer and MalignancyAbout Cancer Cancer is a group of diseases characterized by the uncontrolled growth of dysfunctional cells Two major classes of the genes in the cancer process: oncogenes and tumor-suppressor genes Oncogenes promote cancer formation Tumor-suppressor genes turn off or downregulate the proliferation of cancer cells All cells, including oncogenes, develop from proto- oncogenes (code for growth factors or their receptors) © Paradigm Publishing, Inc.
Pathophysiology of Cancer and MalignancyAbout Cancer (continued) Alterations of proto-oncogenes can activate the oncogenes that promote abnormal cell growth Activation can occur via exposure to chemicals, viruses, radiation, or hereditary factors Example: erb-B2 (or HER-2neu); codes for a growth factor receptor found in some breast cancers Mutations or deletions of tumor-suppressor genes can also result in uncontrolled cell growth Example: The normal gene product of p53 induces apoptosis (cell death) in abnormal or aging cells © Paradigm Publishing, Inc.
Pathophysiology of Cancer and MalignancyCell Proliferation and Gompertzian Kinetics Mathematical model to show an approximation of tumor cell proliferation Early cancer growth is exponential Takes about 30 divisions of cells to make 1 gram (about 1 cm3) of tumor mass This is the smallest clinically detectable tumor At this stage, tumor is most sensitive to chemotherapy agents that attack and destroy rapidly dividing cells centimeter (cm) © Paradigm Publishing, Inc.
Pathophysiology of Cancer and MalignancyCell Proliferation and Gompertzian Kinetics (continued) A lethal tumor burden (size) is 1 kg mass (about 1012 cells) Tumor burden relates to chemotherapy response The smaller the tumor burden, the more effective chemotherapy will be Cell-kill hypothesis: each cycle of chemotherapy kills a certain percentage of cancer cells Tumor cell count never reaches zero from treatment When number of cancer cells is low enough, normal defense mechanisms take over and kill remaining cells © Paradigm Publishing, Inc.
Pathophysiology of Cancer and MalignancyTumor Cell Growth A tumor must reach a certain size before it can be detected Chemotherapy drugs can kill only a percentage of cancer cells after this point Chart adapted from Schorge et al., Williams Gynecology, © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer About Chemotherapy Chemotherapy is the use of drugs to treat disease; the term most often refers to drugs used to treat cancer Chemotherapy drugs are cytotoxic drugs (toxic to cells), hormonal therapies, or targeted therapies for cancer Multiple factors affect tumor response to chemotherapy Tumor size (tumor burden), cell resistance to the drug, amount of chemotherapy given, condition of patient Chemotherapy is usually given in combination regimens Combination chemotherapy maximizes effectiveness of regimen while minimizing toxicity and resistance © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer The Cell Cycle and Use of Multiple Drugs Multiple agents are often used to act on phases of the cell cycle to increase effectiveness and kill more cancer cells © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer The Cell Cycle The process of division of normal and cancer cells Cancer cells most sensitive to drugs that affect cell cycle Cell cycle–specific chemotherapy regimens administered as continuous infusions or in repeated bolus doses These drugs are schedule-dependent Examples: continuous infusion of fluorouracil or cytarabine; repeated bolus doses of weekly bleomycin Cell cycle–nonspecific drugs work at any point in the cell cycle; these drugs are more dose-dependent Example: cyclophosphamide (alkylating agent) © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer Types of Chemotherapy Primary Chemotherapy Initial cancer treatment with curative intent; used for Hodgkin’s disease, lymphoma, leukemias, testicular cancer Adjuvant Chemotherapy Treatment of residual cells after surgical removal or tumor reduction (e.g., after mastectomy for breast cancer). Neoadjuvant chemotherapy shrinks large tumor for surgical removal. Both curative if tumor is removed. Palliative Chemotherapy For incurable cancer: prolongs and improves quality of life; reduces tumor size, symptoms © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer Traditional Chemotherapy and Cytotoxic Drugs Cytotoxic drugs interfere with some normal process of cell function or proliferation Four categories: alkylating agents (oldest), antimetabolites, topoisomerase inhibitors, antimicrotubule agents See Table 21.1 for a list of cytotoxic drugs in each category and their major side effects Cytotoxic drugs do not target tumor cells specifically; can cause many side effects to normal cell function See Table 21.2 for toxicities of specific chemotherapy drugs and preventive measures to avoid these toxicities © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer Common Side Effects of Chemotherapy Drugs Bone marrow suppression (decreased production of blood cells, increased risks of infections and bleeding) Hair loss (alopecia) Nausea and vomiting Mucosal damage to the lining of the mouth and intestinal tract (mucositis) © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Your Turn Question 1: What is the purpose of giving chemotherapy in combination regimens? Answer: Combination chemotherapy maximizes effectiveness of the regimen while minimizing toxicity and resistance. Question 2: What is the reason traditional chemotherapy drugs cause a lot of side effects related to normal cell function? Answer: These cytotoxic drugs exert the majority of their effects on cancer cells, but they do not target tumor cells specifically. © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer Alkylating Agents Mechanism of Action: bind to and damage DNA during the cell division process, preventing cell replication Indication: treat a wide variety of cancer types Side Effects (common): bone marrow suppression, infertility, nausea, vomiting, hair loss Side Effects (rare, severe): secondary cancers (mutagenic) Cautions (cisplatin): renal damage, depletion of potassium and magnesium, peripheral neuropathy, ototoxicity Cautions (ifosfamide): hemorrhagic cystitis; can be prevented if co-administered with mesna © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer Antimetabolites Mechanism of Action: work in the synthesis phase of the cell cycle by a variety of different mechanisms Some inhibit enzyme activity needed for DNA/RNA synthesis; others interfere with enzymes needed for tumor proliferation; still others act as false nucleotides Indication: variety of tumors (see Tables 21.3 and 21.4) Side Effects (common): bone marrow suppression, immune system suppression, mucositis Side Effects (capecitabine): hand-foot syndrome Side Effects (cytarabine): conjunctivitis © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer Antimetabolites (continued) Methotrexate Indication: leukemias, bone cancer, breast cancer, lymphomas Complicated to administer; very wide range of doses Can cause serious toxicities such as kidney damage IV fluids are given to alkalinize (increase pH of) urine to avoid formation of damaging crystals in kidneys Can cause severe bone marrow suppression, mucosal injury in the intestinal tract Prevent by administering leucovorin (folinic acid) © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer Topoisomerase Inhibitors Mechanism of Action: interfere with DNA repair function of topoisomerases and disrupt the cell replication process Indications: very important in the treatment of many different types of cancer (see Tables 21.3 and 21.4) Side Effects (common): bone marrow suppression, mucositis, nausea and vomiting, alopecia Topoisomerase I inhibitors include topotecan (ovarian and lung cancers) and irinotecan (lung and colon cancers) Side Effect (irinotecan): severe diarrhea; managed with injectable atropine (an anticholinergic) © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer Topoisomerase Inhibitors: Anthracyclines Mechanism of Action: inhibit topoisomerase activity by inserting themselves (or intercalating) into DNA strands Indication (doxorubicin): breast cancer and lymphomas Indication (epirubicin): breast, stomach, esophageal cancer Indication (daunorubicin and idarubicin): leukemia Side Effect (most serious, all): cardiac toxicity; typically occurs many years after patients have received drug Caution (all): extravasation (drugs are called vesicants) Some anthracyclines are in liposomal products to decrease toxicity © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer Chemotherapy Vesicant Drugs Daunorubicin Mitomycin Doxorubicin Vinblastine Epirubicin Vincristine Idarubicin Vinorelbine Mechlorethamine © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer Antimicrotubule Agents Mechanism of Action: interfere with the formation and function of microtubules; prevent cell growth and division Most antimicrotubules are derived from plant sources The vinca alkaloids are derived from periwinkle plants The taxanes are derived from yew trees Indications: lung, breast, ovarian, prostate, and testicular cancers; leukemia; lymphoma Side Effects (paclitaxel, docetaxel): allergic reactions during administration (can premedicate to avoid) Side Effects (all): peripheral neuropathy © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer Miscellaneous Cytotoxic Drugs: Bleomycin Mechanism of Action: causes cuts or breaks in DNA strands, preventing the process of cell proliferation Indications: testicular cancer, Hodgkin’s disease Side Effect: pulmonary fibrosis (deadly lung toxicity); however, does not cause bone marrow suppression Miscellaneous Cytotoxic Drugs: Asparaginase Indication: acute lymphocytic leukemia in children Mechanism of Action: breaks down asparagine, depriving leukemia cells of this essential amino acid Side Effect: possible allergic reaction; can switch types © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer Hormonal Drug Therapies Some types of cancer depend on naturally occurring hormones for growth Estrogen and progesterone often stimulate breast tumors Prostate cancer often depends on testosterone for growth Antiestrogens are often used to treat breast cancer Tamoxifen, anastrazole, letrozole, exemestane Antiandrogens, such as bicalutamide and flutamide, are used to treat prostate cancer © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer Hormonal Drug Therapies (continued) LHRH stimulates the production of both male and female reproductive hormones Over time, continuous exposure to LHRH shuts down production of sex hormones Leuprolide (Lupron) and goserelin (Zoladex) are analogs of naturally occurring LHRH Indication: hormone-sensitive tumors, such as breast and prostate cancers Mechanism of Action: eliminates source of endogenous estrogen, progesterone, and testosterone production luteinizing hormone releasing hormone (LHRH) © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer Targeted Drug Therapies Therapies are directed at specific molecular entities required for tumor cell development, proliferation, growth They exert fewer effects on normal cells; usually much better tolerated than traditional cytotoxic drugs Many signal transduction inhibitors affect the molecular abnormalities associated with specific tumor types Indication (imatinib and dasatinib): CML Monoclonal antibodies target markers on tumor cells Indication (trastuzumab): breast cancer Indication (rituximab): non-Hodgkin’s lymphoma chronic myelogenous leukemia (CML) © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer Targeted Anticancer Therapy Category Anticancer Effect Examples Signal transduction inhibitors Prevent transmission of intracellular signals that stimulate cell proliferation Dasatinib (Sprycel) Erlotinib (Tarceva) Imatinib (Gleevec) Sunitinib (Sutent) Angiogenesis inhibitors Prevent formation of blood vessels that allow tumor growth and invasion of tissue Bevacizumab (Avastin) Thalidomide (Thalomid) © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer Targeted Anticancer Therapy (continued) Category Anticancer Effect Examples Monoclonal antibodies Directed at a specific marker or receptor on the surface of tumor cells, leading to destruction of those cells Cetuximab (Erbitux) Panitumumab (Vectibix) Rituximab (Rituxan) Trastuzumab (Herceptin) © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer Targeted Drug Therapies (continued) Some targeted therapies have narrow therapeutic application; many agents target a wider variety of cancers Bevacizumab, an angiogenesis inhibitor, treats breast, lung, colon, and brain cancers Also enhances the effects of cytotoxic drugs when co- administered Cetuximab, a monoclonal antibody, treats head, neck, colon, lung, and pancreatic cancers © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer Targeted Drug Therapies: Side Effects Targeted therapies are usually much better tolerated than are traditional cytotoxic drugs They can cause acne-like skin reactions Sometimes, the rash is a sign that treatment is working Rash managed with topical creams and antibiotic gels Monoclonal antibodies can cause allergic reactions Premedicating with acetaminophen, diphenhydramine, corticosteroids can prevent infusion reactions Severe: bevacizumab can interfere with blood vessel formation, preventing wound healing © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Drugs for Cancer Targeted Drug Therapies: Side Effects (continued) Severe: bevacizumab can cause bleeding, high blood pressure, and kidney damage Targeted Drug Therapies: The Future Typically provide much more direct treatment for cancer Fewer side effects than traditional cytotoxic drugs © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Your Turn Question 1: What has caused drug companies to manufacture some anthracycline drugs in lipid formulations? Answer: Anthracyclines can cause severe tissue damage if extravasation occurs (the infusion leaks under the skin during administration). Liposomal products help decrease toxicity. Question 2: Targeted drug therapies offer newer and smarter approaches for chemotherapy treatment. How is this done? Answer: These agents target specific molecular entities required for tumor cell development, proliferation, and growth. By targeting specific features of tumor cells, these therapies exert fewer effects on normal cells and are usually much better tolerated than traditional cytotoxic drugs. © Paradigm Publishing, Inc.
Preparing and Handling Cytotoxic DrugsRequired Precautions Long-term exposure to cytotoxic drugs require precautions in handling, preparation, and administration Compounding of oral or injectable hazardous drugs must be done in either a Class II BSC or a CACI It is crucial to adhere to strict aseptic and negative pressure techniques as well as wearing PPE The CSTD vial-transfer system allows no venting or exposure of hazardous substances to the environment It is used inside a BSC or a CACI Biological Safety Cabinet (BSC) Compounding Aseptic Containment Isolator (CACI or glove box) personal protective equipment (PPE) Closed System Transfer Device (CSTD) © Paradigm Publishing, Inc.
Preparing and Handling Cytotoxic DrugsRequired Precautions (continued) Dispose of all unused hazardous drugs as bulk chemotherapy waste; requires special handling See the ASHP Web site for Guidelines on Handling Hazardous Drugs Personal Protective Equipment (PPE) Always use PPE when handling oral and injectable hazardous drugs Includes: gloves, gowns, shoe and hair covers, respirator, safety goggles or glasses American Society of Health-System Pharmacists (ASHP) © Paradigm Publishing, Inc.
Preparing and Handling Cytotoxic DrugsPersonal Protective Equipment (PPE) (continued) Use PPE when Performing inventory control measures, such as unpacking a drug order Assembling hazardous drugs for compounding Compounding or cleaning up hazardous drugs Cleaning up spills inside or outside a BSC or a CACI Discard all PPE as chemotherapy waste © Paradigm Publishing, Inc.
Preparing and Handling Cytotoxic DrugsAseptic and Negative Pressure Techniques Use proper aseptic technique when compounding any IV preparation Use a BSC or a CACI with a vertical airflow hood when compounding hazardous preparations Use a slight negative pressure (vacuum inside the vial) to prevent spraying or leaking © Paradigm Publishing, Inc.
Preparing and Handling Cytotoxic DrugsHandling Spills/Exposures Clean up small accidental spills to reduce exposure to hazardous drugs Accidental exposure to hazardous drugs inhalation, ingestion, injection, topical absorption (skin, eyes) Spill kits should be available in all areas where hazardous drugs are prepared, administered, or transported MSDS best source for information about hazardous drugs Available from manufacturers; keep in pharmacies Material Safety Data Sheet (MSDS) © Paradigm Publishing, Inc.
Preparing and Handling Cytotoxic DrugsSpecial Preparations Many hazardous drugs require special handling during preparation or administration Have sensitivity to light (cisplatin, doxorubicin) Need refrigeration to maintain stability (busulfan, dacarbazine) Require special equipment due to issues with plastic (etoposide, paclitaxel, carmustine) Require filters in the infusion tubing (paclitaxel) Follow procedures for compatibility and precipitation of drugs (etoposide, fluorouracil) © Paradigm Publishing, Inc.
Preparing and Handling Cytotoxic DrugsSpecial Preparations (continued) Use correct diluent for reconstitution and final dilution Follow the same rules for PPE that apply to IV product compounding that apply to oral product compounding Follow special precautions for preparations of IT hazardous drugs via lumbar puncture into Ommaya reservoir Delivers chemotherapy directly into CSF Includes: methotrexate, cytarabine, hydrocortisone Do not use preservatives in drug or diluent Use special precautions so drugs for IV administration are not confused with drugs for IT administration intrathecally (IT) cerebrospinal fluid (CSF) © Paradigm Publishing, Inc.
Preventing Chemotherapy-Related Medication ErrorsRole of Pharmacy Technicians Are responsible for drug inventory and medication storage Should implement measures to prevent drug and product mix-ups, especially in SALAD Do not store SALADs next to each other Apply sound-alike/look-alike stickers (e.g., for doxorubicin and liposomal doxorubicin [Doxil]) Use colored and/or lidded storage bins Notice tall-man lettering on labels (CISplatin vs. CARBOplatin, vinCRIStine vs. vinBLAStine) Differing parts of two similar words in capital letters sound-alike, look-alike drugs (SALAD) © Paradigm Publishing, Inc.
Preventing Chemotherapy-Related Medication ErrorsRole of Pharmacy Technicians (continued) Prevent errors in calculations: double-check every calculation and verify the correct drug concentration Prevent errors in pharmacist order entry: compare final product label to the original physician order Verify drug, dose, administration schedule, route, and duration of therapy Prevent errors in dosing: ensure adherence to specific manufacturer-provided drug warnings © Paradigm Publishing, Inc.
Preventing Chemotherapy-Related Medication ErrorsRole of Pharmacy Technicians (continued) Prevent errors in administration route Use syringe overwrap from manufacturer for vincristine and vinblastine to indicate that giving these drugs by the IT route is lethal Maintain a clean and organized work environment to avoid chemotherapy medication errors and contamination Ensure that there is no confusion about what is being mixed and which drug and concentration are being used Complete compounding so products meet acceptable standards and are safe © Paradigm Publishing, Inc.
© Paradigm Publishing, Inc.Summary Treating cancer involves multiple modalities, such as surgery, radiation, and drug therapy Traditional cytotoxic agents are potent cancer-fighting drugs, but cause a lot of toxicities to normal tissue Targeted therapies are generally safer and better tolerated, but still pose risks for serious side effects Oral cancer treatment expanding into community settings Technicians must follow special precautions in handling, preparation, and administration of cytotoxic drugs © Paradigm Publishing, Inc.
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