Chapter 21
Cancer and Chemotherapy
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Chapter 21
Topics
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Pathophysiology of Cancer Malignancy
Drugs for Cancer
Preparing and Handling Cytotoxic Drugs
Preventing Chemotherapy-Related Medication Errors
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Pathophysiology of Cancer and Malignancy
About Cancer and Chemotherapy Agents
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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
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Pathophysiology of Cancer and Malignancy
About 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 protooncogenes (code for growth factors or their receptors)
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Pathophysiology of Cancer and Malignancy
About 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
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Pathophysiology of Cancer and Malignancy
Cell 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
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Pathophysiology of Cancer and Malignancy
Cell 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
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Pathophysiology of Cancer and Malignancy
Tumor 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
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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
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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
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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)
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Drugs for Cancer
Types of Chemotherapy
Primary
Initial cancer treatment with curative intent;
Chemotherapy used for Hodgkin’s disease, lymphoma,
leukemias, testicular cancer
Adjuvant
Treatment of residual cells after surgical
Chemotherapy 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
For incurable cancer: prolongs and improves
Chemotherapy quality of life; reduces tumor size, symptoms
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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
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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)
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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.
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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
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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
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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)
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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)
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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
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Drugs for Cancer
Chemotherapy Vesicant Drugs
• Daunorubicin
• Mitomycin
• Doxorubicin
• Vinblastine
• Epirubicin
• Vincristine
• Idarubicin
• Vinorelbine
• Mechlorethamine
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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
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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
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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
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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
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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
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Drugs for Cancer
Targeted Anticancer Therapy
Category
Anticancer Effect
Signal
Prevent transmission of
transduction intracellular signals
inhibitors
that stimulate cell
proliferation
Angiogenesis Prevent formation of
inhibitors
blood vessels that
allow tumor growth
and invasion of tissue
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Examples
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Dasatinib (Sprycel)
Erlotinib (Tarceva)
Imatinib (Gleevec)
Sunitinib (Sutent)
Bevacizumab
(Avastin)
• Thalidomide
(Thalomid)
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Drugs for Cancer
Targeted Anticancer Therapy (continued)
Category
Anticancer Effect
Monoclonal
antibodies
Directed at a specific
marker or receptor on
the surface of tumor
cells, leading to
destruction of those
cells
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Examples
• Cetuximab
(Erbitux)
• Panitumumab
(Vectibix)
• Rituximab (Rituxan)
• Trastuzumab
(Herceptin)
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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 coadministered
• Cetuximab, a monoclonal antibody, treats head, neck,
colon, lung, and pancreatic cancers
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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
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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
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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.
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Preparing and Handling Cytotoxic Drugs
Required 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
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Preparing and Handling Cytotoxic Drugs
Required 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
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Preparing and Handling Cytotoxic Drugs
Personal 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
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Preparing and Handling Cytotoxic Drugs
Aseptic 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
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Preparing and Handling Cytotoxic Drugs
Handling 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
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Preparing and Handling Cytotoxic Drugs
Special 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)
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Preparing and Handling Cytotoxic Drugs
Special 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
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Preventing Chemotherapy-Related Medication Errors
Role 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
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Preventing Chemotherapy-Related Medication Errors
Role 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
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Preventing Chemotherapy-Related Medication Errors
Role 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
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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
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