CHAPTER
38
Targeted Therapies to Treat Cancer
Katherine L. Byar and M. Linda Workman
http://evolve.elsevier.com/KeeHayes/pharmacology/
• Case Studies
• Content Updates
• Frequently Asked Questions
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• WebLinks
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Pharmacology Animations
IV Therapy Checklists
Medication Error Checklists
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Electronic Calculators
Top 200 Drugs with Pronunciations
References from the Textbook
OBJECTIVES
• Compare the mechanisms of action of targeted therapies
for cancer with those of standard chemotherapy drugs.
• Distinguish among the different types of targeted therapies for cancer treatment with regard to indications,
possible side effects and adverse effects, route of administration, and nursing responsibilities.
• Apply the nursing process related to the needs of clients
receiving targeted therapies for cancer.
• Develop a teaching plan for clients and their families
about the use and side effects of targeted therapy for
cancer.
OUTLINE
Objectives
Key Terms
Pathophysiology
Normal Cell Growth Regulation
Cancer Cell Loss of Growth Regulation
Targeted Therapy Drugs
Tyrosine kinases inhibitors
Multikinase inhibitors
Nursing Process: Tyrosine Kinases Inhibitors and Multikinase Inhibitors
Epidermal growth factor receptor inhibitors
Vascular endothelial growth factor/receptor inhibitors
Nursing Process: Epidermal Growth Factor Receptor
Inhibitors and Vascular Endothelial Growth Factor/
Receptor Inhibitors
Proteasome inhibitors
Angiogenesis inhibitors
Monoclonal antibodies
Nursing Process: Proteasome Inhibitors, Angiogenesis
Inhibitors, and Monoclonal Antibodies
Key Websites
Critical Thinking Case Study
NCLEX Study Questions
KEY TERMS
apoptosis, p. 000
cyclin-dependent kinase inhibitors, p. 000
cyclins, p. 000
cytotoxic, p. 000
gene expression, p. 000
gene overexpression, p. 000
mitosis, p. 000
monoclonal antibody, p. 000
proteasome, p. 000
signal transduction, p. 000
suppressor gene, p. 000
targeted therapy
telomeric DNA, p. 000
transcription factors, p. 000
tyrosine kinase inhibitor, p. 000
tyrosine kinase, p. 000
38-1
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CHAPTER 38 Targeted Therapies to Treat Cancer
As described in Chapter 37 and in the Unit 12 opener, cancers
develop from normal cells that have sustained gene damage.
Cancer cells differ from normal cells in many ways, especially
in their unrelenting growth and invasive spread (metastasis).
This excessive growth serves no useful function, and causes
death when normal tissues are invaded by cancer cells to the
extent that vital organs can no longer perform their life-sustaining functions.
Traditional chemotherapy is generalized, systemic, chemical, cytotoxic treatment that directly kills or severely damages
cells. Mechanisms of action for different categories of chemotherapy drugs vary, but the overall outcome is the inhibition of cell division (mitosis) and cell death. Often, these
drugs damage the cell DNA to prevent DNA replication and
formation of new cancer cells (see Chapter 37). This form of
treatment has improved cancer control and increased longterm survival. Although these drugs have some selectivity for
exerting cytotoxic effects on cancer cells, the drugs also have
a toxic impact on many normal cells. As a result, acute side
effects of traditional combination chemotherapy are uncomfortable and can be life-threatening. Thus the cancer cell–
killing effects of traditional chemotherapy is limited by the
dosages and scheduling regimens needed to reduce toxic side
effects on normal cells.
Targeted therapy for cancer treatment differs from traditional cancer chemotherapy by taking advantage of biologic
features, such as cellular receptors, enzymes, pathways, or
other molecular proteins of cancer cells that either are not
present or are present in much smaller quantities in normal cells. Thus, targeted therapies are more specific in their
mechanisms and effects than traditional cancer chemotherapy agents. The National Cancer Institute’s (NCI) definition
of targeted therapies is drugs or other substances that block
the growth and spread of cancer by interfering with specific
molecules involved in tumor growth and progression. It is
important to remember that, unlike traditional cytotoxic
chemotherapy (which exerts its effects by damaging the DNA
of nearly any cell), targeted therapies require a specific molecular target as the recipient of their effects. The increased
specificity of targeted therapies also means that more tests are
required on cancer cells to determine whether or not a target
is present in sufficient amounts to make the targeted therapy
effective. For example, not all breast cancer cells have the
molecular target for trastuzumab (Herceptin), nor do all leukemia cells have the molecular target for imatinib (Gleevec).
Cancers that do not have sufficient quantities of the specific
molecular target will not respond to targeted therapy.
PATHOPHYSIOLOGY
Normal Cell Growth Regulation
A critical aspect of human health is the tight regulation of cell
division, cell function, and cell death. For tissues composed
of cells that can undergo mitosis, such as the bone marrow,
cells perform their physiologic functions, age, and eventually
die. (Mitosis is cell division in which one cell [the parent cell]
divides and forms two new daughter cells that are identical
to each other and to the original parent cell.) For example,
optimum hematopoietic function requires that the majority
of blood-producing cells in the marrow at any one time be at
their peak functional level. This requires a balance between
cell growth (cell division) and cell death within any tissue
or organ. Too few functional cells within an organ lead to
decreased organ efficiency. Too many functional cells within
an organ reduce organ efficiency by using excessive energy
and resources. Similarly, too many poorly functional cells
within an organ drain resources and reduce overall organ
function. Thus, ensuring optimal organ function requires
that just the right amount of healthy cells is present in the
organ workforce. The main force of this regulation is genetic
control over cell division and cell death.
Genetic Control over Cell Division
As discussed in Chapter 37, the process of cell division (cellular reproduction, mitosis) involves entering the cell cycle.
Normal cells capable of cell division enter the cell cycle only
when needed to replace dead or poorly functional cells. As
shown in Figure XII-1 at the beginning of Unit 12, which
depicts the cell cycle, to enter the cell cycle and continue
to progress through each phase of the cycle to mitosis, cell
cycle checkpoints must be overcome. Initially, general factors
determine whether or not the cell enters the cell cycle, including the following:
• Whether or not the cell has retained the ability to undergo
mitosis
• Recognition of the need for more cells in the specific tissue
where the cell resides
• Adequate nutrition (especially protein, glucose, and oxygen) to support the cells that already exist as well as new
cells
• Adequate energy supplies or production
• Adequate sources of substances needed in the synthesis of
more membranes, more DNA, intracellular proteins, and
organelles
Signal transduction is a method of communication that
allows events, conditions, and substances outside of the cell
to influence the cell’s decision to divide, not to divide, or to
perform its designated function. Some of the known external and internal signaling substances that promote cell division are enzymes, growth factors; adhesion proteins; steroid
hormones; and cell-to-cell physical, chemical, and electrical
interactions. Figure 38-1 shows a segment of a cell with one
interconnecting signal transduction pathway that, when activated, leads to gene activation for those proteins that promote cell division. This pathway can be activated by growth
factors binding to their receptors, the interaction of certain
drugs with the cell plasma membrane, the presence of adhesion proteins, changes in ion movement (especially sodium
and calcium), ligand binding, and other cell-to-cell interactions. When any of these conditions activate the signal transduction pathway, the amount of tyrosine kinases inside the
cell is increased.
Tyrosine kinases (TKs) are a family of enzymes that activate other substances by adding a phosphate group (PO4) to
38-3
CHAPTER 38 Targeted Therapies to Treat Cancer
Growth
factor
Drug entry
site
Growth factor
receptor
Membrane
“sticky zone”
Tyrosine
kinases
Activation of
transcription
factors
Ligand-associated
receptor
Cell adhesion and
contact factors
Cell plasma
membrane
Tyrosine
kinase
Activation of
transcription
factors
Nucleus
Increased production of cyclins;
Decreased production of
suppressor gene products
More cell
division
DNA and
genes
FIGURE 38-1 Simplified sample signal transduction pathway promoting cell division.
them, a process known as phosphorylation. There are many
different TKs. Some are unique to the cell type; others may be
present only in cancer cells that express a specific gene mutation. Regardless of how a pro-cell division signal transduction pathway is activated, the result is an increase in TK levels
that propagate the signal by activating a variety of transcription factors within the pathway.
Transcription factors for cell division are substances that
enter the nucleus and signal the cell that mitosis is needed.
Many different types of substances serve as transcription factors. The overall response is greater expression of oncogene
products (cyclins) that promote cell division, and the reduced
expression of suppressor gene products that inhibit cell division. When the cell responds to these mitotic signals indicating that cell division is needed and resources are adequate,
the cell leaves G0 and enters the G1 phase of the cell cycle.
Once the cell has entered G1, whether or not it can progress
to the next phase is determined by the presence of specific
cyclins (Figure 38-2).
Cyclins are part of a family of proteins that, when active,
stimulate the cell to move through the cell cycle. They are
the products of oncogenes, and most are activated when a
phosphorous group is added to the cyclin chemical structure.
(Removal of a phosphorous molecule from a cyclin [dephosphorylation] inhibits its activity). Kinases that activate cyclins
are cyclin-dependent kinases (CDKs). CDKs combine with
cyclins to form complexes that initiate cell mechanisms to
complete cell division. In normal cells, the oncogenes that
produce cyclins are carefully regulated by suppressor gene
products so that cell division only occurs when it is needed
and to the degree that it is needed.
Cyclin-A/CDK
Cyclin-E/CDK
Cyclin-B
S
G1
G2
Cyclin-B/Cdc2
M
Cyclin-D/CDK
Cyclin-A/Cdc2
Aurora kinase
G0
FIGURE 38-2 Cyclin activity promoting progression through
the cell cycle.
The amount of cyclin and the type of cyclins, as well as
which specific CDK is present in the cell during cell division,
vary by the phase of the cycle. It is these differences in types
of cyclins and CDKs that determines when or if a particular cell moves from one phase of the cycle to the next. Many
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CHAPTER 38 Targeted Therapies to Treat Cancer
Growth
factor
inhibitor
Drug entry
site
Membrane
“sticky zone”
Ligand-associated
receptor
Cell adhesion and
contact factors
Cell membrane
contacted on all
sides with other cells
Growth factor
receptor
Tyrosine
kinases
Activation of
transcription
factors
Cell plasma
membrane
Tyrosine
kinases
Activation of
transcription
factors
Nucleus
Decreased production of cyclins;
Increased production of
suppressor gene products
Less cell
division
DNA and
genes
FIGURE 38-3 External signals that inhibit the sample signal transduction pathway, resulting in
greatly reduced cell division.
different groups of cyclins have been identified, with the D
group being most well understood.
A common signal for entering and starting the cell cycle at
G1 is the combining of a cyclin-D with the appropriate cyclindependent kinase (CDK), forming a cyclin-D/CDK complex
(see Figure 38-2). Movement of the cell from G1 into the S,
G2, and M phases of the cell cycle is regulated by the continued presence of pro-cell division transcription factors that
promote DNA transcription and increased synthesis of specific pro-cell division cyclins and CDKs.
Even when cell division is needed, the process is well controlled in normal cells. Proteins synthesized by suppressor
genes determine how much oncogene expression is needed to
allow cell division to occur but not lead to excessive cell division. Such control is exemplified by normal wound repair.
For example, when a person falls and scrapes skin from the
knee, the skin cells at the edge of the wound are signaled to
divide and fill in the gap. When the wound area is closed, cell
division normally stops. The person does not have uncontrolled cell division in this area to the extent that a large skin
flap develops over and past the wound site.
When cell division is not needed, external signals, such as
growth factor inhibitors and the surrounding of a cell plasma
membrane with other cells, send signals that are inhibitory
to the pro–cell division signal transduction pathway (Figure
38-3). The result of this inhibition leads to low levels of TKs
and reduced levels of pro-cell division transcription factors.
Instead, suppressor gene activity is increased, resulting in
production of more suppressor gene products that inhibit the
synthesis of cyclins and CDKs by oncogenes. There are many
suppressor genes, and, although all are present in every cell
type, specific suppressor genes may be more active in selected
types of tissues. For example, the BRCA1 suppressor gene
appears most active in suppressing excessive cell division in
breast, ovary, and genitourinary tract tissues. One of the most
well-characterized suppressor genes is the Tp53 suppressor
gene. Its gene product restricts the entry of cells into the cell
cycle and restricts progression through the cell cycle for many
cell types. Without suppressor gene products, oncogenes
would be overexpressed continually, leading to uncontrolled
and unneeded cell division.
Internal cell conditions, such as poor cell nutrition and
reduced energy stores, can trigger the activation of suppressor genes to disrupt the pro–cell division signal transduction
pathway even when external conditions indicate a need for
cell division (Figure 38-4). Thus, healthy and active suppressor genes guard against cell division when it is not in the
body’s best interest.
Genetic Control over Cell Death
As some cells age, they begin to function less optimally. When
a cell is damaged, reduced function occurs at an earlier cell age.
In normal tissues that are capable of cell division, damaged
cells and older cells respond to signals for apoptosis, which
is programmed cell death, intended to ensure that tissues and
organs contain only healthy and optimally functional cells.
Apoptosis is under strict genetic control in normal tissues so
that healthy functional cells do not self-destruct faster than
they can be replaced, and that older or damaged cells unable
to perform vital functions do not overpopulate a tissue and
CHAPTER 38 Targeted Therapies to Treat Cancer
Growth
factor
Drug entry
site
Growth factor
receptor
Membrane
“sticky zone”
Tyrosine
kinases
Activation of
transcription
factors
Ligand-associated
receptor
38-5
Cell adhesion and
contact factors
Cell plasma
membrane
Tyrosine
kinases
Activation of
transcription
factors
Activation of suppressor
gene products
Nucleus
Decreased production of cyclins;
Increased production of
suppressor gene products
Less cell
division
DNA and
genes
FIGURE 38-4 Suppressor gene activity inhibiting the sample signal transduction pathway,
resulting in greatly reduced cell division.
reduce organ efficiency. Maintenance of optimally functional
organs depends on a balance of cell division with apoptosis.
The signals for apoptosis may come from the aging cell with
the loss of telomeric DNA. Telomeric DNA is special DNA
that caps the ends of each chromosome much like plastic tips
cap the ends of a shoelace to prevent raveling (Figure 38-5).
The function of telomeric DNA is to maintain the integrity of
the double DNA strands within each chromosome. With each
round of cell division, the telomeric DNA shortens. When the
cell has undergone its lifespan’s worth of cell divisions, the
telomeric DNA that capped the chromosomes is gone, allowing the DNA to unravel and fragment. These processes then
trigger genetic and other intracellular signals for self-destruction through the action of autoenzymes, especially caspase
9. Activated caspase 9 leads to a cascade reaction for rapid
activation of many more types of caspase enzymes. These
enzymes degrade the cell’s internal structures and cause the
plasma membrane to lyse and break the cell into small fragments that are removed from the body by white blood cells.
Apoptosis is regulated by different gene products, including those of the Tp53 suppressor gene (Tp53 stands for
tumor protein 53). When cells reach a certain age or experience DNA damage, the Tp53 gene is expressed and older
or damaged cells either undergo apoptosis or are prohibited
from progression through the cell cycle.
Growth Regulation and Cancer
Loss of Genetic Control of Cell Growth. As stated earlier,
cancers develop from cells that were once normal. Normal
cells become cancer cells when external or internal conditions
Chromosome
Telomeres
Chromosome
end segment
3,000–20,000 bases
FIGURE 38-5 Chromosome with telomeric DNA and chromosome end segment with telomeric DNA.
lead to gene damage. Although cancer can develop from a
normal cell that has sustained damage to its oncogenes, most
commonly, one or more suppressor genes are damaged and
are no longer able to control oncogene expression. As a result
of excessive oncogene expression, cyclins and CDKs are overproduced and cell division occurs when it is not needed.
Excessive cell division from gene damage/mutations
appears to be self-perpetuating, leading to further gene mutations that do the following:
• Allow one or more specific pro-cell division signal transduction pathways to become more active
• Allow greater expression of cancer cell membrane receptors
that trigger pro-cell division signal transduction pathways
• Increase or amplify the production of specific TKs and
transcription factors
Loss of Apoptosis. Mutations that occur in suppressor genes
as a result of DNA damage inactivate the suppressor genes,
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CHAPTER 38 Targeted Therapies to Treat Cancer
preventing them from controlling oncogene activity. Some
suppressor genes, such as the Tp53 gene, also regulate apoptosis. Inactivation of suppressor genes regulating apoptosis makes
cancer cells unresponsive to apoptotic signals. These cancer
cells are now resistant to natural cell death, a feature known as
cellular immortality. The combined effects of lack of regulation
for cell division and the loss of apoptosis result in cancer cells
having no balance between cell division and apoptosis. This
unbalanced condition favors continuous cancer cell division.
TARGETED THERAPY DRUGS
Targeted cancer therapies are a relatively new approach
in cancer treatment. They work by interfering with cancer
cell growth and division in different ways. These drugs are
broadly known as signal transduction inhibitors. Targeted
therapies generally inhibit cancer cell division by blocking a
cancer membrane receptor, blocking tyrosine kinase activity,
interfering with signal transduction, stimulating an immune
system attack on cancer cells, or inducing the cell to undergo
apoptosis. These agents may be used as monotherapy (as a
single agent), in combination with traditional chemotherapy,
and with radiotherapy. Some targeted therapies are oral and
are self-administered at home where it is convenient for clients; others are administered parenterally.
TABLE 38-1
The rapid identification of specific cancer cell targets in
recent years has lead to increased development of targeted
therapies, and the number of drugs approved for cancer targeted therapy has more than tripled in the last 5 years. Some
are in relatively common use, and others are used less frequently or for rarer cancer types. Management of client issues
related to targeted therapies is an evolving area of study. With
many targeted therapies being new to the market, costs can
be high and may not be covered by insurance. New targeted
therapies are approved frequently. Older targeted therapy
drugs may be newly approved for use in a different way or
with a different cancer type. Expect to see indications for use
of different targeted therapies in additional cancer types in
the future. Because newly approved therapies have been less
widely used and their adverse effects are not yet fully characterized, this chapter focuses on those therapies that have been
in use for a year or more.
There are several major classes of targeted cancer therapies, based on their most common mechanism of action
(Table 38-1). Some targeted therapies have more than one
action. Those discussed in this chapter include the following:
tyrosine kinases inhibitors, multikinase inhibitors, epidermal growth factor receptor inhibitors, vascular endothelial
growth factor/receptor inhibitors, proteasome inhibitors,
angiogenesis inhibitors, and monoclonal antibodies.
TARGETED THERAPIES FOR CANCER TREATMENT
DRUG TYPE AND NAME
ROUTE AND DOSAGE
USES AND CONSIDERATIONS
TYROSINE KINASE INHIBITORS (TKIs)
dasatinib (Sprycel)
For leukemia:
A: PO
140 mg once daily with or without a meal.
imatinib mesylate
(Gleevec)
For (leukemia; myelodysplastic syndrome):
A: PO: recommended starting dose is 400 mg/d
for chronic phase and 600 mg/d for accelerated
phase or blast crisis. Dose increases to max of
800 mg (given as 400 mg twice daily); may be
considered if tolerated for accelerated phase or
blast crisis
For GIST:
A: PO: recommended starting dose is 400 mg/d
C: PO: >3 years: 260 mg/m2/day PO given as a
single daily dose, or the dose may be divided
given once in the morning and once in the
evening.
Approved for chronic myelogenous leukemia
(CML) and acute lymphocytic leukemia (ALL).
Do not crush or cut tablets; if tablets are crushed
or broken, handle with gloves.
Administer antacids 2 hours before and 2 hours
after each dose; Avoid H2 blockers and proton
pump inhibitors (PPIs)
Pregnancy category: D; PB: 95%; t½: 3 to 5 h
Approved for Philadelphia chromosome–positive
CML, metastatic malignant gastrointestinal stromal tumors (GIST), ALL, chronic eosinophilic
leukemia (CEL), and myelodysplastic
syndrome (MDS).
Avoid pregnancy and breastfeeding. Take with
a meal and a large glass of water to minimize
gastric irritation.
Pregnancy category: D; PB: 95%; t½: 18 to 40 h
MULTIKINASE INHIBITORS (MKIs)
sorafenib (Nexavar)
For hepatocellular cancer and renal cell
carcinoma:
A: oral
400 mg twice daily
Approved for hepatocellular cancer and advanced
renal cell carcinoma.
Administer orally without food (at least 1 hour
before or 2 hours after a meal).
Pregnancy Category: D; PB: 99.5%: t½: 25 to 48 h
CHAPTER 38 Targeted Therapies to Treat Cancer
TABLE 38-1
38-7
TARGETED THERAPIES FOR CANCER TREATMENT—cont’d
DRUG TYPE AND NAME
ROUTE AND DOSAGE
MULTIKINASE INHIBITORS (MKIS)—cont’d
sunitinib (Stutent)
For gastrointestinal stromal tumors:
A: PO
50 mg PO once daily on a schedule of 4 weeks
on treatment then 2 weeks off.
For renal cell carcinoma:
A: PO
50 mg once daily on a schedule of 4 weeks on
treatment then 2 weeks off.
USES AND CONSIDERATIONS
Approved for GIST and advanced renal cell carcinoma (RCC).
Sunitinib can only be obtained directly from
McKesson Specialty.
Administer orally with or without food.
Pregnancy Category: D; PB: 90%; t½ of sunitinib
is 40 to 60 h, and that of its major metabolite is
80 to 110 h.
EPIDERMAL GROWTH FACTOR/RECEPTOR (EGRF) INHIBITORS
cetuximab (Erbitux)
For colorectal and head and neck cancer:
A: IV: initial infusion dose is 400 mg/m2
IV over 2 hours (with a maximum rate of
5 mL/min). Then continue weekly infusions
of 250 mg/m2 IV over 60 minutes (with a
maximum rate of 5 mL/min).
erlotinib (Tarceva)
For non–small cell lung cancer:
A: PO:
150 mg once daily
For pancreatic cancer:
A: PO:
100 mg once daily in combination with gemcitabine
(1000 mg/m2 IV: Cycle 1—Days 1, 8, 15, 22, 29,
36, and 43 of an 8-week cycle; Cycle 2 and subsequent cycles—Days 1, 8, and 15 of a 4-week
cycle)
For NSCLC:
A: PO:
250 mg once daily
Gefitinib (Iressa)
panitumumab (Vectibix)
For colorectal cancer
A: IV
6 mg/kg administered over 60 minutes
(administer doses >1000 mg over 90 minutes)
given once every 2 weeks.
trastuzumab (Herceptin)
For breast cancer:
A: IV
4 mg/kg infused over 90 minutes on week 1.
If the initial infusion is tolerated, starting at
week 2 administer 2 mg/kg IV over at least
30 minutes once weekly
Approved for EGFR-expressing colorectal and
head and neck cancers.
Administer only as an IV infusion with an infusion
controller, never as a bolus or as an IV push.
Administer with low-protein– binding 0.22-micron
filter.
Do not shake or further dilute vial.
Do not mix with other drugs. Premedicate the
client with an H1 antagonist (e.g., diphenhydramine 50 mg IV) 30 to 60 minutes before the
first dose of cetuximab.
Pregnancy Category: C; t½: 41 to 214 h
Approved for non–small cell lung cancer (NSCLC)
and pancreatic cancer.
Give the drug on an empty stomach, 1 hour
before or 2 hours after ingestion of food (administering with food increases the risk for side
effects). Administer at the same time each day
between meals. Pregnancy Category: D; PB:
93%; t½: 36 h
Approved for NSCLC.
Administer tablet with water without regard for
meals.
Pregnancy Category: D; PB: 90%; t½: 48 h
Approved for EGFR-expressing metastatic
colorectal cancer.
Administer only as an IV infusion with an IV controller and never as a bolus or an IV push injection.
Administer with low-protein– binding 0.2-micron
or 0.22-micron in-line filter.
Flush line with 0.9% sodium chloride injection
before and after administration. Do not mix
drug with other drugs or other infusions.
Infuse over 60 minutes through a peripheral line
or indwelling catheter (doses over 1,000 mg
should be infused over 90 minutes.
Pregnancy Category: C; t½: 7.5 d
Approved for breast cancer that overexpresses
EGFR2 (HER2/neu receptor).
Do not administer IV push or as a bolus.
Monitor clients for infusion-related reactions such
as fever or chills, respiratory distress, or severe
hypersensitivity reactions. Interrupt the infusion
for clients who experience dyspnea or significant hypotension.
Pregnancy Category: D; t½: 25 d
Continued
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CHAPTER 38 Targeted Therapies to Treat Cancer
TABLE 38-1
TARGETED THERAPIES FOR CANCER TREATMENT—cont’d
DRUG TYPE AND NAME
ROUTE AND DOSAGE
USES AND CONSIDERATIONS
VASCULAR ENDOTHELIAL GROWTH FACTOR/RECEPTOR (VEGRF) INHIBITORS
For metastatic breast cancer:
A: IV
10 mg/kg on days 1 and 15 in combination
with paclitaxel (90 mg/m2 IV on days 1, 8,
and 15) every 28 days; or 7.5 mg/kg to
15 mg/kg on day 1 in combination with
docetaxel (100 mg/m2 IV), repeated every
3 weeks.
For colorectal cancer:
A: IV
5 or 10 mg/kg over 60 or 90 minutes every
14 days in combination with 5-fluorouracil–
based chemotherapy.
For non–small cell lung cancer:
A: IV
15 mg/kg over 60 or 90 minutes every
3 weeks in combination with carboplatin
and paclitaxel.
For metastatic renal cell carcinoma:
A: IV
10 mg/kg IV every 2 weeks in combination with
interferon alfa (9 million units subcutaneously
3 times/week up to 52 weeks)
PROTEASOME INHIBITORS
Approved for metastatic breast cancer, colorectal
cancer, NSCLC, and RCC.
Administer as an IV infusion and never as an IV
push or bolus.
Mix infusions with only 0.9% sodium chloride
and never with dextrose solutions.
Discard any unused portion left in the vial, as the
product contains no preservatives.
Pregnancy Category: C; t½: 11 to 50 d
bortezomib (Velcade)
Approved for mantle cell lymphoma (MCL) and
multiple myeloma.
At least 72 hours should elapse between consecutive doses of bortezomib.
Administered as an intravenous injection bolus
over 3 to 5 seconds.
Reconstitute for injection each vial with 3.5 mL
of 0.9% sodium chloride for a final concentration of 1 mg/mL. The final product should be a
clear, colorless, solution.
Pregnancy Category: D; PB: 83%: t½: 9 to 15 h
bevacizumab (Avastin)
For mantle cell lymphoma:
1.3 mg/m2 IV bolus on days 1, 4, 8, and 11
followed by a 10-day rest period (days 12 to 21).
For extended therapy of more than 8 cycles,
administer bortezomib on the standard
3-week cycle or on days 1, 8, 15, and 22
followed by a 13-day rest period (days 23
to 35).
For multiple myeloma:
A: IV
Treatment is administered for nine 6-week
cycles. In cycles 1 to 4, 1.3 mg/m2/dose IV
bolus is given on days 1, 4, 8, and 11 followed by a 10-day rest period (days 12 to 21)
and again on days 22, 25, 29, and 32 followed
by a 10-day rest period (days 33 to 42) in
combination with melphalan (9 mg/m2/day on
days 1 to 4) and prednisone (60 mg/m2/day on
days 1 to 4); this 6-week cycle is considered
one course. In cycles 5 to 9, bortezomib 1.3
mg/m2/dose IV bolus is given on days 1, 8,
22, and 29 in combination with melphalan (9
mg/m2/day, days 1 to 4) and prednisone (60
mg/m2/day, days 1 to 4); this 6-week cycle is
considered one course.
CHAPTER 38 Targeted Therapies to Treat Cancer
TABLE 38-1
38-9
TARGETED THERAPIES FOR CANCER TREATMENT—cont’d
DRUG TYPE AND NAME
ROUTE AND DOSAGE
USES AND CONSIDERATIONS
ANGIOGENESIS INHIBITORS
temsirolimus (Torisel)
For renal cell carcinoma:
A: IV
25 mg IV given over 30 to 60 minutes once a
week
Approved for advanced RCC.
Premedicate client with diphenhydramine 25 to
50 mg IV, or a similar antihistamine, approximately 30 minutes before the start of each
temsirolimus dose.
Two dilutions are required before IV infusion.
Use only the supplied diluent for the initial
dilution.
Use an in-line polyethersulfone filter with a pore
size of not greater than 5 microns and an infusion pump.
Administer only through polyethylene-lined
administration sets.
Administer dose over 30 to 60 minutes.
Pregnancy Category: D; t½: 17 to 20 d
MONOCLONAL ANTIBODIES
alemtuzumab (Campath)
gemtuzumab ozogamicin
(Mylotarg)
For chronic lymphocytic leukemia:
A: IV
Start the drug at 3 mg IV over 2 hours once
daily. When the 3-mg dose is tolerated (infusion reactions are grade 2 or less), escalate
the daily dose to 10 mg IV once daily and
continue until infusion reactions are grade 2 or
less, then start the maintenance dose of
30 mg IV given 3 times weekly on alternate
days (e.g., Monday, Wednesday, Friday); the
total therapy duration including dose escalation is 12 weeks.
For acute myelogenous leukemia:
A: IV
9 mg/m2 as a 2-hour infusion on days 1 and 15.
C: IV
4 to 9 mg/m2/course for up to 3 courses.
Approved for chronic lymphocytic leukemia (CLL).
Administer as an IV infusion over 2 hours and
never as an IV push or bolus dose.
Monitor client closely for serious, sometimes
fatal, infusion-related reactions. Premedicate
the client 30 minutes before the first dose,
with any dose escalation, and as needed with
diphenhydramine (50 mg) and acetaminophen
(500 to 1,000 mg).
Withhold alemtuzumab administration if a grade
3 or 4 infusion reaction occurs
Pregnancy Category: C; t½: 12 d
Approved for CD33-positive acute myelogenous
leukemia (AML).
Do not administer to clients with known murine
(mouse) hypersensitivity.
Premedicate the client 30 minutes before
administration with oral diphenhydramine
(50 mg) and acetaminophen 650 to 1,000 mg
(adults).
Do not mix gemtuzumab ozogamicin with
other drugs, electrolyte solutions, or 5% dextrose.
Protect the drug against direct and indirect
sunlight and unshielded fluorescent light during
preparation and administration of the
infusion.
Administer as an IV infusion over 2 hours and
never as an IV push or bolus dose.
Monitor vital signs at least every half hour during
the infusion and 4 hours following the
infusion.
Pregnancy Category: D; t½: 60 h
Continued
38-10
CHAPTER 38 Targeted Therapies to Treat Cancer
TABLE 38-1
TARGETED THERAPIES FOR CANCER TREATMENT—cont’d
DRUG TYPE AND NAME
ROUTE AND DOSAGE
USES AND CONSIDERATIONS
MONOCLONAL ANTIBODIES—cont’d
ibritumomab tiuxetin
(Zevalin)
rituximab (Rituxan)
I131 tositumomab
(Bexxar)
For non-Hodgkin’s lymphoma:
A: IV
Step 1
Rituximab 250 mg/m2 IV is administered first
(see Rituximab monograph). Within 4 hours of
completing the rituximab infusion, give 5 mCi
(1.6 mg total antibody dose) of In-111 ibritumomab tiuxetan IV over 10 minutes.
Step 2
Seven to nine days following step 1, give a second dose of Rituximab 250 mg/m2 IV. Within
4 hours of completing the rituximab infusion,
give Y-90 ibritumomab tiuxetan 0.4 mCi/kg
(14.8 Mbq/kg) or 0.3 mCi/kg (11.1 MBq/kg)
IV over 10 minutes.
For non-Hodgkin’s lymphoma (NHL):
A: IV
375 mg/m2 once weekly for 4 doses; may be
retreated for an additional 4 doses.
In combination with CHOP (cyclophosphamide,
doxorubicin, vincristine, prednisone), 375 mg/m2
IV on day 1 of each cycle of chemotherapy for
up to 8 cycles.
For non-Hodgkin’s lymphoma:
A: IV
Step 1: dosimetric step
On day 0, 450 mg unlabeled tositumomab IV
over 1 hour followed by iodine I-131 tositumomab 5 mCi (35 mg tositumomab) IV over
20 minutes. Total body gamma counts using a
gamma camera are obtained on day 0; day 2,
3, or 4; and on day 6 or 7. Using these counts,
perform calculations based on standard internal
radiation dosimetry methods to determine
the patient-specific activity (in millicuries) of
radiolabeled tositumomab required to deliver a
maximum tolerated dose of 75 cGy total-body
dose.
Step 2: therapeutic step
450 mg unlabeled tositumomab IV over 1 hour
followed by the patient-specific activity (in
millicuries) iodine I-131 labeled to 35 mg of
tositumomab IV between day 7 and day 14.
Approved for B-cell NHL.
Use appropriate precautions for handling, preparing, and administering radiopharmaceuticals.
Do not administer In-111 ibritumomab tiuxetan
and Y-90 ibritumomab tiuxetan unless the rituximab predose has been administered.
Do not give Y-90 ibritumomab tiuxetan to clients
with a platelet count <100,000/mm3).
Pregnancy Category: D; t½: 30 h
Approved for CD20-positive B-cell NHL.
Premedicate the client 30 minutes before
administration with diphenhydramine (50 mg),
acetaminophen 650 to 1,000 mg (adults), and
possibly corticosteroids.
Do not administer as an IV push or bolus.
Administer first IV infusion at an initial rate of 50
mg/h. If no hypersensitivity or infusion-related
events occur, increase infusion rate in 50 mg/h
increments every 30 minutes, to a maximum of
400 mg/h.
Monitor clients closely during infusion for profound hypotension, dyspnea, and any cardiovascular infusion–related reactions.
Do not mix rituximab solution with other drugs.
Pregnancy Category: C; t½: 31.5 to 52.6 h
Approved for relapsed or refractory CD20positive, follicular NHL.
Administer thyroid protection agents at least 24
hours before step 1 and step 2.
Do not administer to clients with known murine
(mouse) hypersensitivity.
Premedicate the client 30 minutes before administration with oral diphenhydramine (50 mg) and
acetaminophen 650 to 1,000 mg (adults).
Use appropriate precautions for handling, preparing, and administering radiopharmaceuticals.
Administer through an IV tubing set with a
0.22-micron in-line filter. The same IV tubing set
and filter must be used throughout the entire
dosimetric or therapeutic step.
Administer iodine I-131 tositumomab infusion
over 60 minutes.
After infusion of the iodine I-131 tositumomab
is complete, close the stopcock to the syringe.
Flush the extension set and the secondary IV
infusion set with 0.9% sodium chloride for
injection.
Pregnancy Category: ×; t½: 8.5 d
CHAPTER 38 Targeted Therapies to Treat Cancer
Tyrosine Kinase Inhibitors
Several types of targeted therapies have as an outcome the
inhibition of tyrosine kinases using a variety of mechanisms.
Specific drugs that cause this action as their main mechanisms are referred to as tyrosine kinase inhibitors (TKIs).
The most common TKIs currently prescribed are imatinib
mesylate (Gleevec) and dasatinib (Sprycel). Table 38-1 lists
the TKIs and their dosages, routes, uses, and considerations.
Prototype Drug Chart 38-1 lists specific drug information
about the TKI imatinib (Gleevec). Newly approved TKIs
include pazopanib (Votrient), which is used in advanced renal
cell carcinoma, and lapatinib (Tykerb), which is used with
other drugs in the treatment of HER2 positive breast cancer.
TKIs are chemicals that exert their effects by directly
inhibiting only specific types of tyrosine kinases. The types
they inhibit are the SRC kinases, which are present in many
cells (normal and cancerous) and a very specific type, the
BCR-ABL tyrosine kinase. As shown in Figure 38-1, receptors
on the cell membrane can activate tyrosine kinases, which
then turn on signal transduction pathways promoting cell
division. The TKIs are nonreceptor kinase inhibitors because
they do not bind to the receptors on the plasma membrane.
Instead they work directly on the tyrosine kinase molecule.
The SRC kinases are involved in the activation of signal
transduction pathways promoting cell division in many cell
types. The BCR-ABL tyrosine kinase is present only in cancer cells that have a specific gene mutation resulting from a
chromosome structural rearrangement that forms a “Philadelphia chromosome.” This mutation is highly present in
chronic myelogenous leukemia (CML) cells and has recently
been found in some other cancer cell types. When activated
and expressed, BCR-ABL tyrosine kinase turns on a strong
pro-cell division signal transduction pathway that leads to
proliferation of cancer cells. The TKIs prevent activation of
tyrosine kinases, which then inhibits further activation of the
signal transduction pathway and stops the proliferation of
cancer cells. This action can control the disease but cannot
alone eradicate it.
Dasatinib
Dasatinib (Sprycel) is approved for Philadelphia chromosome–
positive chronic myeloid leukemia (CML) and acute lymphocytic leukemia (ALL).
Pharmacokinetics. Dasatinib is an oral drug that is readily
absorbed from the GI tract and can be taken with or without
food. Antacids slow the absorption. The drug is extensively
metabolized in the liver by the cytochrome P450 (CYP) 3A4
isoenzyme.
Pharmacodynamics. Dasatinib most specifically targets
BCR-ABL tyrosine kinase, found in CML cells. The drug
blocks the ATP (adenosine triphosphase) binding site on the
tyrosine kinase so that it does not become activated. This lack
of BCR-ABL tyrosine kinase activation inhibits further activation of the signal transduction pathway and stops the proliferation of cancer cells. The drug has the greatest effects on
cancer cells expressing the Philadelphia chromosome genetic
mutation.
38-11
Side Effects and Adverse Reactions. Dasatinib often
causes electrolyte imbalances, especially low serum levels
of phosphorus and calcium. These imbalances may require
phosphorus and calcium replacement. ECG abnormalities,
especially prolonged QT interval, have been seen in clients
taking dasatinib. This drug should be used cautiously in anyone at risk for long QT, such as those who have hypokalemia
or hypomagnesemia and those with a family history of long
QT syndrome. Fluid retention has also been seen in up to
50% of clients. Hematologic side effects of myelosuppression
with anemia, thrombocytopenia, and neutropenia are relatively common.
Drug Interactions. Dasatinib activity is affected by CYP3A4
enzyme inhibitors, which decrease dasatinib metabolism,
resulting in an increased serum concentration and increased
risk for toxicity. Other drugs that strongly increase the serum
concentration of dasatinib include atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone,
nelfinavir, ritonavir, saquinavir, telithromycin, triazolobenzodiazepines, and voriconazole.
HERBAL ALERT 38-1
Grapefruit juice increases the serum concentration and
toxicity of TKIs, EGFRIs, MKIs, proteasome inhibitors, and
angiogenesis inhibitors. St. John’s wort reduces the serum
concentration and the effectiveness of drugs from these
classes.
Drugs that enhance the activity of the CYP3A4 enzyme
decrease dasatinib serum levels and reduce its effectiveness.
Such drugs include aminoglutethimide, barbiturates, carbamazepine, dexamethasone, grisefulvin, modafinil, nafcillin,
phenytoin, primidone, rifabutin, and rifampin. Other drugs
that appear to reduce the effectiveness of dasatinib include
antacids, H2 histamine blockers, and proton pump inhibitors.
Dasatinib may interfere with the metabolism of other
drugs that use the CYP3A4 enzyme system, such as alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, and ergot
alkaloids.
Multikinase Inhibitors
The multikinase inhibitors (MKIs) are chemicals that
directly inhibit the activity of specific kinases in cancer
cells and in cancer cell vasculature. (Recall that kinases are
enzymes that activate other proteins, including those that
activate signal transduction pathways promoting cancer cell
division.) Table 38-1 lists the MKIs and their dosages, routes,
uses, and considerations.
Sorafenib
Sorafenib (Nexavar) is a multikinase inhibitor that specifically targets serine/threonine and receptor tyrosine kinases,
which are activated as a result of gene mutations and are most
commonly found in pancreatic cancer, colon cancer, and
non–small cell lung cancer. In addition, the drug may be used
[AQ2]
38-12
CHAPTER 38 Targeted Therapies to Treat Cancer
PROTOTYPE DRUG CHART 38-1
Imatinib Mesylate
Drug Class
Tyrosine kinase inhibitor (TKI)
Trade name: Gleevec
Pregnancy Category: D
Dosage
Leukemias; myelodysplastic syndrome: A: PO: Recommended starting dose is 400 mg/d for
chronic phase and 600 mg/d for accelerated phase or blast crisis. Dose increases to max of
800 mg (given as 400 mg twice daily); may be considered if tolerated for accelerated phase
or blast crisis.
C: PO: Children >3 years: 260 mg/m2/day PO given as a single daily dose, or the dose may
be divided given once in the morning and once in the evening.
For GIST:
A: PO: Recommended starting dose is 400 mg/d.
Contraindications
Clients who may become pregnant, are pregnant, or are breastfeeding; have severe heart failure
or severe kidney disease; have
moderate to severe liver disease
and are also taking another hepatotoxic chemotherapy drug(s);
or have severe neutropenia,
anemia, or thrombocytopenia
Drug-Lab-Food Interactions
Drug:
Any agent that inhibits cytochrome P450 (CYP) 3A4 may decrease the metabolism of imatinib and increase imatinib concentrations leading to an increased incidence of adverse
reactions (examples include ketoconazole, amiodarone, antiretroviral protease inhibitors,
dalfopristin quinupristin, mifepristone).
Any drug that induces cytochrome P450 (CYP) 3A4 may increase the metabolism of imatinib
and decrease imatinib concentrations and clinical effects (examples include barbiturates,
bosentan, carbamazepine, dexamethasone, phenobarbital, rifabutin, and rifapentine).
Any drug that is metabolized by cytochrome P450 (CYP) 2D6 may have higher than normal
blood levels of the drug (examples include amoxapine, atomoxetine, carvedilol, metoprolol,
propranolol, timolol, clozapine, codeine, cyclobenzaprine, darifenacin, fenfluramine, dexfenfluramine, dextromethorphan, flecainide, haloperidol, hydrocodone, maprotiline, methadone,
methamphetamine, mexiletine, morphine, oxycodone, paroxetine, perphenazine, propafenone, risperidone, thioridazine, tramadol, trazodone, tricyclic antidepressants, and venlafaxine).
St. John’s wort decreases imatinib blood levels and may decrease its effectiveness.
Taking imatinib with acetaminophen increases the risk for acetaminophen poisoning.
Taking imatinib with NSAIDs increases hypertension and disruption of platelet aggregation.
Taking imatinib with warfarin increases the risk for severe bleeding.
Lab: May alter liver enzyme levels and bilirubin levels
Food: Grapefruit juice increases imatinib plasma concentrations
Pharmacokinetics
Absorption: Bioavailability is 98%.
Steady-state levels achieved in 1
to 2 days.
Distribution: 95% PB with extensive distribution
Metabolism: Metabolized mainly in
the liver by the cytochrome P450
(CYP) 3A4 and CYP2D6 isoenzymes; t½ of drug is 18 hours, of
its major metabolite 40 hours.
Excretion: Mainly in the feces
Pharmacodynamics
Oral absorption is fast and not affected by meal timing.
Therapeutic Effects/Uses
Approved for chronic myelogenous leukemia (CML), metastatic malignant gastrointestinal stromal tumors (GIST), acute lymphocytic
leukemia (ALL), chronic eosinophilic leukemia (CEL), gastrointestinal stromal tumors (GIST), and myelodysplastic syndrome (MDS)
Mode of Action: Imatinib competitively inhibits the ATP binding site on tyrosine kinases specific for Abl, PDGF, SCF, and c-Kit,
preventing the activation of those specific tyrosine kinases. This action inhibits platelet-derived growth factor (PDGF) and stem
cell factor (SCF) mediated cellular events. This leads to reduced cancer cell division and induction of apoptosis. This action results
in blockage of downstream EGFR-TK mediated signal transduction pathways, cell cycle arrest, and inhibition of angiogenesis.
Side Effects
Decreased appetite, diarrhea, difficulty sleeping, headache, heartburn, joint pain, muscle cramps or
pain, nausea, and upset stomach.
Adverse Reactions
Allergic reactions, severe neutropenia increasing the risk for infection, severe thrombocytopenia increasing the risk for excessive bleeding/hemorrhage, liver impairment, kidney
impairment.
A, adult; PO, by mouth; PB, protein-binding; >, greater than; t½, half-life
CHAPTER 38 Targeted Therapies to Treat Cancer
in those hepatocellular carcinomas and renal cell carcinomas
that overexpress the target.
Pharmacokinetics. Sorafenib (Nexavar) is an oral drug
whose absorption and bioavailability are inhibited when
taken with a high-fat meal. The drug is metabolized in liver,
mainly by the CYP3A4 enzyme system. It is 99.5% proteinbound and reaches peak plasma level in about 3 hours. The
drug is eliminated in the feces and urine, with a half-life of 25
to 48 hours.
Pharmacodynamics. Sofafenib inhibits Raf kinase, vascular endothelial growth factor (VEGF) receptors VEGFR-2
and VEGFR-3, platelet-derived growth factor receptor
(PDGFR), Kit receptor tyrosine kinase (KIT), fms-like
tyrosine kinase 3 (FLT-3), and RET. When these tyrosine
kinase receptors are activated by cytokines or growth factors, a protein-kinase–mediated cascade starts, leading to
uncontrolled cellular proliferation. The inhibition of these
signaling pathways by sorafenib results in decreased cancer cellular proliferation. In addition, sorafenib specifically
inhibits two VEGF receptors (VEGFR-2 and VEGFR-3),
which are key receptor tyrosine kinases involved in angiogenesis. This action results in reduced blood vessel formation in cancer cells. This anticancer activity is present only
when the drug is present, and cancer growth returns when
therapy is stopped.
Side Effects and Adverse Reactions. Sorafenib has many
common side effects. Hypertension is very common and can
occur within the first 6 weeks of therapy. Skin side effects
include alopecia, pruritus, dry skin, exfoliative dermatitis,
acne, flushing, and palmar-plantar erythrodysesthesia (handfoot syndrome), which also manifest within the first 6 weeks.
Other side effects include weight loss, nausea/vomiting, diarrhea, anorexia, constipation, abdominal pain, mucositis,
dyspepsia, dysphagia, and mild neutropenia and thrombocytopenia. More severe effects are possible, including pancreatitis, erectile dysfunction, and myocardial ischemia.
Drug Interactions. Sorafenib levels are not increased by the
presence of other drugs, even those that inhibit the enzyme
that metabolizes sorefenib. However, drugs that induce
metabolizing enzyme activity can reduce the blood levels and
effectiveness of sorafenib. These include rifampin, phenytoin,
phenobarbital, carbamazepine, dexamethasone, rifabutin,
and rifapentint.
Sorafenib can increase the blood levels of rapaglinide,
amiodarone, ibuprofen, loperamide, irinotecan, propfol, and
warfarin.
Sunitinib
Sunitinib (Sutent) inhibits more than 80 tyrosine kinases.
This inhibition results in regression of tumor growth, especially in clear cell renal cell carcinoma (RCC) and gastrointestinal stromal tumors.
Pharmacokinetics. Sunitinib is an oral drug that is well
absorbed with or without meals. It is 90% protein-bound
and reaches peak plasma levels in 6 to 12 hours. The drug is
metabolized in liver, mainly by the CYP3A4 enzyme system,
and is eliminated in the feces. The half-life of sunitinib is 40
38-13
to 60 hours, and its major active metabolite has a half-life of
80 to 110 hours.
Pharmacodynamics. The action of sunitinib is the inhibition of many receptor tyrosine kinases (RTKs), including
those of platelet-derived growth factor receptors (PDGFR),
vascular endothelial growth factor receptors (VEGFR1,
VEGFR2, VEGFR3), and a variety of others. This inhibition results in decreased cancer cell proliferation and in
reduced blood vessel formation in cancer cells. This drug
also increases adverse effects on normal tissues, especially
hair and skin.
Side Effects and Adverse Reactions. Sunitinib side effects
and adverse reactions are more widespread as a result of the
number of different types of kinases this drug inhibits. Cardiovascular effects include hypertension, peripheral edema,
left ventricular dysfunction, prolonged QT interval, and
venous thromboembolism. GI effects include nausea/vomiting, diarrhea, stomatitis, dyspepsia, anorexia, constipation,
abdominal pain, glossodynia, and flatulence. Neuromuscular effects include fatigue, asthenia, headache, dizziness,
peripheral neuropathy, mild arthralgia, limb pain, myalgia,
and back pain. Liver impairment may occur with elevated
liver enzyme levels and jaundice of the skin and sclerae.
Common integumentary changes include lightening of the
hair, rash, dry skin, and palmar-plantar erythrodysesthesia (hand-foot syndrome). Endocrine changes may include
hypothyroidism and adrenal insufficiency. Hematologic
changes may include mild neutropenia and thrombocytopenia. Respiratory-associated effects may include mild dyspnea
and cough.
Drug Interactions. Sunitinib blood levels and activity are
increased by drugs that inhibit the CYP3A4 enzyme levels,
including atazanavir, clarithromycin, ketoconazole, itraconazole, indinavir, nefazondone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, diltiazem, and verapamil.
When these drugs are used during sunitinib therapy, side
effects of sunitinib are more common and more severe. Drugs
that increase sunitinib elimination and reduce its effectiveness include rifampin, phenytoin, phenobarbital, carbamazepine, dexamethasone, rifabutin, and rifapentin.
Epidermal Growth Factor/Receptor Inhibitors
The epidermal growth factor/receptor inhibitors (EGFRIs)
include erlotinib, gefitinib, panitumumab, cetuximab, and
trastuzumab. Most EGFRIs ultimately also inhibit tyrosine kinase, but they do it more indirectly than the TKIs. As
shown in Figure 38-1, the growth factor receptors on the cell
membrane can activate tyrosine kinases, which then turn on
signal transduction pathways promoting cell division. The
EGFRIs bind to different areas of the epidermal growth factor
receptor, blocking its activity so that it cannot activate tyrosine kinase. As a result, the downstream signal transduction
pathway for promotion of cell division is inhibited and cell
proliferation is severely limited. Table 38-1 lists the EGFRIs
and their dosages, routes, uses, and considerations. Prototype
Drug Chart 38-2 lists the specific drug information for erlotinib (Tarceva).
38-14
CHAPTER 38 Targeted Therapies to Treat Cancer
NURSING PROCESS
Tyrosine Kinase Inhibitors and Multikinase
Inhibitors for Cancer Treatment
Assessment
baseline physical condition of the client before
initiating targeted therapy regimen and during the treatment period.
Assess laboratory studies, including CBC with differential, hepatic and renal studies, electrolytes, and urinalysis
at the beginning of therapy and at specified time intervals
(ranging from weekly to monthly) during therapy.
Conduct a detailed medication history, including a list
of all concurrent medications, including prescriptions,
over-the-counter medicines, antacids, dietary supplements, vitamins, and herbal supplements to avoid drugdrug interactions.
Assess client and family knowledge related to therapeutic
regimen.
Assess
Nursing Diagnoses
Knowledge, deficient, related to targeted therapy regimen
Skin integrity, impaired, risk for, related to dermatologic
effects and toxicities of therapy
Infection, risk for, related to bone marrow suppression
Fluid volume, deficient, risk for, related to GI effects of
therapy
Electrolyte imbalance, risk for, related to actions of targeted therapy
Planning
Client and family will verbalize understanding of targeted
therapy as part of an anticancer treatment regimen.
and family will demonstrate understanding of the
importance of reporting targeted therapy–related side
effects and adverse reactions.
Client and family will verbalize strategies to minimize
risks related to targeted therapy–related side effects.
Client’s side effects will be managed to a level that the client can tolerate and are not life-threatening.
Client will remain infection-free.
Client will have fluid balance and electrolytes within
expected normal ranges.
Client
Nursing Interventions
Follow institution guidelines for safe handling, preparing,
administering, and dispensing of targeted therapy agents.
prescribed premedications according to
established protocols for specific targeted therapies.
Monitor complete blood cell count with differential and
platelet count at baseline, once weekly for the first month,
every other week for the second month, and at least every
2 to 3 months thereafter.
Monitor electrolytes regularly during treatment and for 8
weeks after treatment has stopped, especially phosphorus
Administer
and calcium levels, because low levels may require
replacement.
Monitor liver function and renal function tests at baseline and at least once monthly during therapy.
Monitor blood pressure at baseline and at least weekly
during therapy.
Monitor ejection fraction at baseline and periodically
during therapy.
Monitor thyroid function if client experiences symptoms
of hypothyroidism (cold intolerance, hair loss, decreased
memory or mental alertness, constipation, bradycardia).
Discontinue therapy prior to elective surgery.
For clients receiving sunitinib, monitor adrenal function
in clients exposed to stress (e.g., surgery, shock, trauma,
or infections).
Monitor hands and feet for signs of palmar-plantar erythrodysesthesia (redness, pain, swelling or blisters).
Sorafenib potentiates the activity of warfarin. Check the
client’s INR weekly.
Client Teaching
alcohol and nonessential drugs that are cleared by
the liver or have liver-toxic effects (e.g., acetaminophen).
Report symptoms of adverse effects or severe side effects
promptly, especially fever, chills, persistent sore throat,
swelling, weight gain, or increasing shortness of breath).
Report symptoms of bleeding immediately, including
black stools, vomit that looks like coffee grounds, or easy
bleeding/bruising.
Report symptoms of liver impairment immediately,
including stomach/abdominal pain, yellowing eyes or
skin, dark urine, or unusual fatigue.
Remind women with childbearing potential to avoid
pregnancy throughout treatment and for up to 12 months
after treatment is completed.
Advise breastfeeding women to stop breastfeeding during
and for 60 days after therapy.
Teach clients that drinking grapefruit juice can increase
the blood levels of most targeted therapies and make side
effects or adverse effects worse. Instruct them to avoid this
food while receiving treatment with targeted therapies.
Teach clients to avoid using the herbal St. John Wort
while receiving treatment with targeted therapies because
this agent decreases the effectiveness of most of these
drugs.
Teach clients to take imatinib with food or with at least
240 mL of water to reduce gastric irritation.
Teach clients to weigh themselves daily and report a
weight gain of more than 2 pounds in 1 day or 4 pounds
in 1 week to the health care provider.
Teach clients to check hands and feet daily for signs of
palmar-plantar erythrodysesthesia (redness, pain, swelling, or blisters) and to report these symptoms when they
appear.
Remind clients receiving sorafenib who also take warfarin to keep all appointments for INR testing.
[AQ1]
Avoid
CHAPTER 38 Targeted Therapies to Treat Cancer
38-15
PROTOTYPE DRUG CHART 38-2
Erlotinib
Drug Class
Dosage
Epidermal growth factor/receptor inhibitor (EGFRI) For non–small cell lung cancer:
Trade name: Tarceva
A: PO: 150 mg once daily
Pregnancy Category: D
For pancreatic cancer:
A: PO: 100 mg once daily in combination with gemcitabine (1,000 mg/m2 IV
Cycle 1—Days 1, 8, 15, 22, 29, 36, and 43 of an 8-week cycle; Cycle 2 and
subsequent cycles—Days 1, 8, and 15 of a 4-week cycle)
Contraindications
Clients who may become pregnant, are pregnant,
or are breastfeeding; have preexisting respiratory problems (because pulmonary fibrosis may
occur); or those who are dehydrated or have
liver impairment (because risk for renal failure is
high).
Use cautiously in clients who have a history of
peptic ulcer disease or diverticulitis (increases
the risk for GI perforation).
Drug-Lab-Food Interactions
Drug:
Drugs that increase the blood levels of erlotinib and may lead to increased
adverse reactions or toxicities include ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir,
telithromycin, troleandomycin (TAO), voriconazole.
Drugs that reduce the effectiveness of erlotinib include rifampicin, rifabutin,
rifapentine, phenytoin, carbamazepine, phenobarbital, H2 histamine blockers,
proton pump inhibitors.
Lab:
Erlotinib may increase INR and lead to increased risk for bleeding.
Food:
Grapefruit juice increases erlotinib drug levels and increases the risk for
adverse effects.
St. John’s wort decreases erlotinib blood levels and reduces its effectiveness
Cigarette smoking also decreases erlotinib blood levels.
Pharmacokinetics
Pharmacodynamics
Oral absorption is moderately fast and is enhanced with food intake. High
Absorption: Bioavailability is 60%.
gastric pH levels inhibit oral absorption.
Distribution: 93% PB. Steady-state levels are
achieved in 7 to 8 days.
Metabolism: Liver (CYP3A4 and CYP1A2 enzymes)
Excretion: Mainly in the feces
Therapeutic Effects/Uses
Approved for treatment of non–small cell lung cancer (NSCLC) and pancreatic cancer.
Mode of Action: Erlotinib selectively inhibits the activation of the epidermal growth factor receptor-tyrosine kinase (EGFR-TK).
Side Effects
Diarrhea and skin reactions
Adverse Reactions
Ocular changes (inflammation, corneal perforation), GI perforation, skin desquamation, renal failure, hepatic failure.
A, adult; d, day; PB, protein-binding; PO, by mouth.
Some of the epidermal growth factor/receptor inhibitors
carry a Black Box Warning for adverse effects. A Black Box
Warning indicates that the FDA has provided notice that a
drug may produce serious or even life-threatening effects in
some people in addition to its beneficial effects. This warning is printed on the package insert sheet and is bordered
in black. Drugs with this warning can still be used, but prescribers are instructed to make certain that such drugs are
prescribed only for clients who meet strict criteria and who
understand the serious nature of the possible adverse effects.
Gefitinib
Gefitinib (Iressa) is a synthetic anilinoquinazoline that selectively inhibits the epidermal growth factor receptor-tyrosine
kinase (EGFR-TK). It is most commonly used in the management of advanced non–small cell lung cancer.
Pharmacokinetics. Gefitinib is absorbed slowly in the
gastrointestinal tract, with 60% reaching systemic circulation. It is metabolized mainly in the liver by the CP3A4
enzyme and is primarily excreted in the feces. The half-life
is 48 hours.
Pharmacodynamics. Gefitinib selectively inhibits EGFRTK. This action results in blockage of downstream EGFRTK–mediated signal transduction pathways, cell cycle arrest,
and inhibition of angiogenesis.
Side Effects and Adverse Reactions. Gefitinib can cause
conjunctivitis and abnormal eyelash growth. Rash occurs in
about 43% of patients. Some patients experience a moderate
to low potential for nausea/vomiting, diarrhea, and mouth
ulcers. Hypersensitivity with a vesiculobullous rash, toxic
epidermal necrolysis, erythema multiforme, angioedema,
and urticaria is rare.
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CHAPTER 38 Targeted Therapies to Treat Cancer
Drug Interactions. Gefitinib activity is affected by CYP3A4
enzyme inhibitors, which decrease dasatinib metabolism,
resulting in an increased serum concentration and increased
risk for toxicity. These drugs include atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone,
nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole. Drugs that lower gefitinib serum levels and reduce its
activity include carbamazepine, phenytoin, phenobarbital,
rifabutin, and rifampin. Because gefitinib works best in an
acid environment, its activity is reduced with the use of H2
histamine blockers and proton pump inhibitors. When this
drug is received by clients on warfarin therapy, the effectiveness of warfarin (Coumadin) is greatly increased and bleeding risks are increased. The dosage of warfarin should be
adjusted based on INR results.
liation, rash, skin fissures, acne, dry skin, and paronychia
and other nail disorders. Electrolyte imbalances (specifically
hypomagnesemia and hypocalcemia) may occur and require
replacement. Severe diarrhea can occur when panitumumab is
given along with irinotecan. Severe infusion reactions, including angioedema and anaphylaxis, have occurred with hypotension and bronchospasm. Although this reaction is rare,
clients should be monitored closely throughout the infusion.
Drug Interactions. This drug has not been shown to be
associated with general drug interactions. However, when
administered with other EGRFIs, the side effects and toxicities are additive and more severe. Panitumumab is not recommended for use in combination with other antineoplastic
drug regimens.
Panitumumab
Cetuximab (Erbitux) is a partially humanized monoclonal
antibody (see Table 38-2). (See the Monoclonal Antibodies
section for a more complete description of antibody types.)
It is most commonly used for the management of colorectal
and head and neck cancers.
Pharmacokinetics. Cetuximab is administered as an
intravenous infusion. Steady-state concentration occurs by
the third weekly infusion. The half-life is long, ranging from
41 to 213 hours, with a mean of 97 hours.
Pharmacodynamics. Cetuximab still contains about 30%
mouse proteins. It binds specifically to EGFR on both normal and tumor cells and prevents formation of a ligand that
usually attaches epidermal growth factor to the receptor.
This action prevents the receptor from binding to agonists
that activate it. As a result, EGFR-TKs are not activated and
the signals are not conducted downstream. Other effects of
this drug also include inhibition of cell growth, induction of
apoptosis, decreased proinflammatory cytokine and vascular
growth factor production, and internalization of the EGFR.
Cetuximab may make cancer cells more vulnerable to other
cancer chemotherapy agents and radiation therapy. The drug
is most effective in causing regression in tumors that have the
wild-type K-RAS oncogene and overexpress EGFR.
Side Effects and Adverse Reactions. Cetuximab carries
a Black Box Warning for infusion reactions, usually with
the initial dosing, although severe reactions also have been
reported during later infusions. Manifestations include rapid
onset of airway obstruction, including bronchospasm, stridor, hoarseness, urticaria, and hypotension. Be aware that
patients who live in certain geographic areas, such as North
Carolina and Tennessee, have an increase risk of hypersensitivity to cetuximab than patients who live in other geographic locations. Cetuximab is associated with dermatologic
changes that typically involve the face, upper chest, and back.
An acneform rash occurs in 90% of clients, usually within the
first 2 weeks of therapy. Most clients continue to have the
rash for at least 28 days after therapy is stopped.
Drug Interactions. This drug has not been shown to be
associated with general drug interactions. However, when
administered with other EGRFIs, the side effects and toxicities are additive and more severe.
Panitumumab (Vectibex) is a fully humanized monoclonal
antibody (Table 38-2). (See the Monoclonal Antibodies section for a more complete description of antibody types.) It is
most commonly used in the management of advanced metastatic colorectal carcinomas that express or overexpress EGFR.
Pharmacokinetics. Panitumumab is administered as
an intravenous infusion. It is a small immunoglobulin that
appears to be eliminated in the feces. The half-life is 7.5 days.
Pharmacodynamics. Panitumumab binds strongly to the
EGFR when it is overexpressed on malignant cells. It binds
specifically to EGFR on both normal and tumor cells, and
prevents formation of a ligand (arm) that usually attaches
epidermal growth factor to the receptor. As a result, EGFRTKs are not activated and the signals are not conducted
downstream. Other effects of this drug also include inhibition
of cell growth, induction of apoptosis, and decreased proinflammatory cytokine and vascular growth factor production.
In addition, binding of panitumumab to the EGFR causes the
receptor to be taken into the cell, preventing it from binding
to agonists that activate the receptor. Tumors must express
EGFR for clients to be candidates for panitumumab.
Side Effects and Adverse Reactions. Panitumumab carries
a Black Box Warning for dermatologic problems and toxicity. Manifestations usually occur within the first 2 weeks of
therapy and include erythema, acneform rash, pruritus, exfoTABLE 38-2
SUFFIXES OF TARGETED
CANCER THERAPIES
SUFFIX
MEANING
mab
momab
imab
A monoclonal antibody
Composed of only murine (mouse) proteins
Composed of more human proteins (>60%)
than murine proteins (~30%)
Composed of mostly human proteins (95% or
more) and only a few murine proteins (<5%)
Composed of only human proteins and no
murine proteins
A tyrosine kinase inhibitor
A proteasome inhibitor
zumab
umab
inib
zomib
Cetuximab
CHAPTER 38 Targeted Therapies to Treat Cancer
Trastuzumab
Trastuzumab (Herceptin) is a monoclonal antibody that
binds to the HER2 protein on the surface of cancer cells that
overexpress this receptor. The HER2 receptor is structurally
related to the EGFR. The HER2 receptor is overexpressed in
some breast, ovarian, and colon cancers. When this receptor
is overexpressed, there is increased cancer cell proliferation
and increased angiogenesis. Trastuzumab is most commonly
used in combination with chemotherapy agents to manage
breast, ovarian, and colorectal cancers that have demonstrated overexpression of the HER2 receptor.
Pharmacokinetics. Trastuzumab is administered as a
weekly intravenous infusion. Its half-life averages 25 days, but
it may be present in the blood for as long as 18 weeks after
therapy is stopped. Just like most monoclonal antibodies,
trastuzumab appears to be eliminated slowly through the feces.
Pharmacodynamics. Trastuzumab is a mostly humanized
monoclonal antibody that binds to the HER2 protein on the
surface of breast cancer, ovarian cancer, and colon cells that
overexpress this receptor. This drug specifically inhibits the
proliferation of cancer cells that overexpress HER2 receptors.
In addition, binding of trastuzumab to the cancer cell receptor increases killing of these cells through attack by immune
system cells, especially natural killer cells and monocytes.
Side Effects and Adverse Reactions. Trastuzumab carries
a Black Box Warning for cardiomyopathy manifesting as congestive heart failure when the drug is used as monotherapy.
This risk is increased when the drug is given in combination with other drugs that cause cardiotoxicities, such as the
anthracyclines and cyclophosphamide. Hypersensitivity reactions, including anaphylaxis, may occur but are not common.
Trastuzumab is associated with pain, asthenia, fever, chills, and
nausea during the initial infusion. After the initial infusion,
these symptoms usually do not reoccur. Other common side
effects include loss of appetite, headache, and muscle aches.
Drug Interactions. Trastuzumab can increase the incidence and severity of cardiac dysfunction in clients who
receive trastuzumab in combination with anthracyclines and
cyclophosphamide. This drug may increase myelosuppressive effects of other antineoplastic agents.
Vascular Endothelial Growth Factor/Receptor
Inhibitors
Bevacizumab
The currently approved drug in this class is bevacizumab
(Avastin), a humanized monoclonal antibody. Table 38-1
lists the dosages, routes, uses, and considerations for bevacizumab. It binds to vascular endothelial growth factor
(VEGF) and prevents the binding of VEGF with its receptors, VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1/KDR), which are
found on the surface of endothelial cells. The role of VEGF is
critical in angiogenesis, the formation of new blood vessels.
In human cancers, the increased expression of VEGF is associated with increased microvascular density, tumor growth,
metastasis, and a poor prognosis. The result of bevacizumab therapy is the reduction of microvascular growth and
inhibition of metastatic disease progression. Bevacizumab is
38-17
approved for many types of malignancies, all in combination
with chemotherapy.
Pharmacokinetics. Bevacizumab is administered as an
intravenous infusion, usually every 2 to 3 weeks. Half-life is
about 20 days (range of 11 to 50 days) and steady-state levels
are achieved in about 100 days. Clearance varies with weight,
gender, and tumor burden, with men clearing the drug faster
than women.
Pharmacodynamics. Bevacizumab binds to the vascular
endothelial growth factor receptor (VEGFR) on tumors that
overexpress this receptor. The result of this binding is the
competitive inhibition of vascular endothelial growth factor
with the VEGFR. This action leads to reduced tumor vascularity, the development of tumor necrosis, and reduced metastatic potential.
Side Effects and Adverse Reactions. Bevacizumab carries
a Black Box Warning for GI perforations, wound dehiscence,
impaired wound healing, hemorrhage, and fistula formation after surgery. Thus, the drug should not be given within
28 days of after major surgery. Hypertension is a common
side effects of bevacizumab. Other side effects are associated
with hematopoietic suppression, including neutropenia and
thrombocytopenia. Proteinuria can be seen in about 36% of
clients, and, in rare situations, nephrotic syndrome has developed. The risk for thromboembolism and deep vein thrombosis is increased among clients taking the drug for colon
cancer and non–small cell lung cancer.
Drug Interactions. No specific drug interactions have been
reported with bevacizumab; however, coadministration of
drugs with similar pharmacologic effects, especially traditional chemotherapy agents, may cause additive pharmacologic effects, including toxicity.
Proteasome Inhibitors
Bortezomib
Bortezomib (Velcade) is the major drug in this class. Table
38-1 lists the dosages, routes, uses, and considerations for
bortezomib. It works by inhibiting the 26S proteasome, which
is part of the most common proteasome pathway. A proteasome is a large complex of proteins in cell fluid (cytoplasm)
and cell nucleus that regulates protein expression and the degradation of damaged or old proteins within the cell. Its activity is critical to activation or suppression of cellular functions.
This system regulates the expression of substances that mediate cell cycle progression (especially oncogene products and
cyclins), suppressor genes (especially the Tp53 gene), and proteins that signal apoptosis. When proteasomes are inhibited,
cells are much more likely to undergo apoptosis. Although
proteasomes are present in normal and cancer cells, the cancer cells are much more sensitive to the effects of proteasome
inhibition than normal cells. Thus, proteasome inhibition
results in suppression of cancer cell division and enhancement
of cancer cell apoptosis. Bortezomib is most commonly used
to manage mantle-cell lymphoma and multiple myeloma.
Pharmacokinetics. Bortezomib is administered as an
intravenous injection bolus. More than 80% of the drug
is protein-bound and distributed to most body tissues,
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CHAPTER 38 Targeted Therapies to Treat Cancer
NURSING PROCESS
Epidermal Growth Factor Receptor Inhibitors
and Vascular Endothelial Growth Factor
Receptor Inhibitors for Cancer Treatment
Assessment
baseline physical condition of the client before
initiating targeted therapy regimen and during the treatment period.
Assess laboratory studies, including CBC with differential, hepatic and renal studies, electrolytes, and urinalysis
at the beginning of therapy and at specified time intervals
(ranging from weekly to monthly) during therapy.
Conduct a detailed medication history, including a list
of all concurrent medications, including prescriptions,
over-the-counter medicines, antacids, dietary supplements, vitamins, and herbal supplements to avoid drugdrug interactions.
Assess client and family knowledge related to therapeutic
regimen.
Assess
Nursing Diagnoses
Knowledge, deficient, related to targeted therapy regimen
Skin
integrity, impaired, risk for, related to dermatologic
effects and toxicities of therapy
Infection, risk for, related to bone marrow suppression
Fluid volume, decicient, risk for, related to GI effects of
therapy
Electrolyte imbalance, risk for, related to actions of targeted therapy
Planning
Client and family will verbalize understanding of targeted
therapy as part of an anticancer treatment regimen.
and family will demonstrate understanding of the
importance of reporting targeted therapy–related side
effects and adverse reactions.
Client and family will verbalize strategies to minimize
risks related to targeted therapy–related side effects.
Client’s side effects will be managed to a level that the client can tolerate and are not life-threatening.
Client will remain infection-free.
Client will have fluid balance and electrolytes within
expected normal ranges.
Client
Nursing Interventions
prescribed premedications according to
established protocols for specific targeted therapies.
Monitor complete blood cell count with differential and
platelet count at baseline, and as often as recommended
for specific agents.
Monitor renal function tests at baseline and at least once
monthly during therapy.
Follow institution guidelines for safe handling, preparing,
administering, and dispensing targeted therapy agents.
Administer
Examine
client’s skin closely at each visit for the presence
of erythema, rash, peeling, or blister formation, and rate
the severity of dermatologic reactions. Also determine
whether infection is present in any nonintact skin.
When administering monoclonal antibodies intravenously, have resuscitation equipment nearby, and stay
with the client during the first 15 minutes of the infusion.
Thereafter, monitor vital signs every 15 to 30 minutes during the infusion and for 1 hour after infusion is complete.
Monitor electrolytes regularly during treatment and for
8 weeks after treatment has stopped, especially phosphorus and calcium levels, because low levels may require
replacement.
Gefitinib potentiates the activity of warfarin. Check the
client’s INR weekly.
Before administering trastuzumab, ask whether the client
has a known allergy to hamsters or hamster products.
With trastuzumab therapy, monitor electrocardiogram
and ejection fraction at baseline and periodically during
treatment.
Use with caution in older adults (older than 65 years of
age) because the incidence of serious adverse events is
higher among older clients.
Monitor blood pressure at least every 2 to 3 weeks during
therapy. Monitor more frequently if hypertension develops.
Monitor for proteinuria with a urine dipstick before each
dose. Clients with a 2+ or greater reading should undergo
further assessment, such as 24-hour urine collection.
Initiate bevacizumab therapy at least 28 days after major
surgery or when the surgical incision is completely
healed, whichever occurs latest. Consider discontinuing
bevacizumab before elective surgery or delaying the surgery until 2 months after therapy has stopped.
Assess lower extremities for deep vein thrombosis at
every visit.
Client Teaching
symptoms of adverse effects or severe side effects
promptly, especially fever, chills, persistent sore throat,
swelling, weight gain, or increasing shortness of breath).
Report symptoms of bleeding immediately, including
black stools, vomit that looks like coffee grounds, easy
bleeding/bruising.
Remind women with childbearing potential to avoid
pregnancy throughout treatment and for up to 12 months
after treatment is completed.
Advise breastfeeding women to stop breastfeeding during
and for 60 days after therapy.
Teach clients to avoid direct sunlight and tanning beds to
prevent worsening of skin side effects.
Teach clients to avoid cigarette smoking with erlotinib.
Instruct clients taking erlotinib to immediately report
worsening of skin rash; severe or persistent diarrhea, nausea, anorexia, or vomiting; onset or worsening of unexplained shortness of breath or cough; or eye irritation.
Report
CHAPTER 38 Targeted Therapies to Treat Cancer
NURSING PROCESS—cont’d
Teach
clients to avoid taking NSAIDs, such as aspirin
(except for low-dose aspirin), celecoxib, ibuprofen, and
naproxen, to prevent excessive bleeding.
Remind clients receiving gefitinib who also take warfarin
to keep all appointments for INR testing.
Teach clients to weigh themselves daily and report a
weight gain of more than 2 pounds in 1 day or 4 pounds
in 1 week to the health care provider.
Instruct clients to notify the health care provider if foaming of urine occurs (an indication of protein in the urine).
including myocardium. The half-life ranges from 9 to 15
hours. Bortezomib is metabolized by the CYP3A4, CYP2C19,
and CYP1A2 enzymes in the liver. At present, elimination
pathways are not known.
Pharmacodynamics. Bortezomib inhibits the activity of
the 26S proteasome. This inhibition causes an increase in
cell cycle checkpoint activity, a decrease in cell proliferation,
and a greater responsiveness to cellular signals for apoptosis.
The overall results are inhibition of cancer cell growth and an
increase in cancer cell apoptosis.
Side Effects and Adverse Reactions. The most common
side effects of bortezomib are nausea, vomiting, anorexia,
abdominal pain, bowel changes (constipation or diarrhea),
and decreased taste sensation. Most clients also experience either new-onset peripheral neuropathy or worsening
of existing peripheral neuropathy, including both loss of
sensation and orthostatic hypotension. Other general side
effects include headache, insomnia, rash, pruritus, back pain,
arthralgia, bone pain, and muscle cramps. Respiratory effects
include dyspnea, cough, and pneumonia. Weakness (asthenia) and low-grade fever are relatively common. Moderate
to severe thrombocytopenia, anemia, and neutropenia can
occur during bortezomib therapy.
Rare but serious cardiopulmonary side effects have been
reported. These include new onset congestive heart failure or
worsening of pre-existing heart failure, decreased left ventricular function, and pulmonary pneumonitis.
Additional neurologic side effects may include anxiety,
fatigue, headaches, lethargy, dizziness, insomnia, and blurred
or double vision. An uncommon adverse event is the development of reversible posterior leukoencephalopathy syndrome
(RPLS) in clients receiving bortezomib. RPLS is a reversible
neurologic condition that can present as seizures, hypertension, headache, lethargy, confusion, visual impairment
(including blindness), or other neurologic disturbances.
Because bortezomib causes rapid killing of cancer cells,
the development of tumor lysis syndrome (TLS), including
hyperkalemia and hyperphosphatemia, is possible. This complication is more likely in clients with a high tumor burden at
the start of bortezomib therapy.
Drug Interactions. Drugs that inhibit the CYP3A4
enzyme can lead to increased serum levels of bortezomib,
which increases the risk for severe side effects. These drugs
include ketoconazole, atazanavir, clarithromycin, indinavir,
38-19
Instruct
clients to seek medical help immediately if chest
pain, symptoms of stroke (e.g., change in mental awareness; inability to talk or move one side of the body; sudden numbness or weakness of the face, arm, or leg; or
seizures), severe abdominal pain, or swelling associated
with redness or pain in one leg occurs.
Teach clients receiving bevacizumab ways to promote
venous return and avoid deep vein thrombosis (DVT),
such as avoiding becoming dehydrated, not wearing
clothing that restricts circulation, and avoiding smoking
cigarettes.
itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir,
telithromycin, voriconazole, amprenavir, aprepitant, diltiazem, fluconazole, verapamil, and cimetidine.
Drugs that induce CYP3A4 enzyme activity may lower
bortezomib blood serum levels and reduce its effectiveness.
These drugs include rifampin, carbamazepine, and phenytoin.
Angiogenesis Inhibitors
Temsirolimus/Sirolimus
Temsirolimus (Torisel) and its active metabolite, sirolimus, is
the major drug in this class. The target of this drug is a protein
kinase known as the mammalian target of rapamycin (mTOR).
When temsirolimus or sirolimus bind to an intracellular protein called FKBP-12, a protein-drug complex forms that directly
inhibits the activity of mTOR. With inhibition of mTOR, the
concentration of vascular endothelial growth factor (VEGF) is
greatly reduced. In addition, by its inhibition of mTOR, a variety
of downstream pro-cell–division signal transduction pathways
are disrupted, especially in renal cell carcinoma cells. This drug is
most commonly used to manage advanced renal cell carcinoma.
Pharmacokinetics. Temsirolimus is administered by
intravenous infusion. It is extensively metabolized in the liver
by CYP3A4 into five active metabolites, including sirolimus.
The half-life or temsirolimus is 17 hours, and the half-life of
sirolimus is 54 hours. The drug and its metabolites are primarily excreted in the feces.
Pharmacodynamics. Temsirolimus and its metabolites
bind to an intracellular protein forming a drug-protein complex that inhibits the protein kinase, mTOR, in the tumor
cells of renal cell carcinoma (RCC). As a result of this inhibition RCC tumors lose vascularity. Inhibition of mTOR also
reduces production of cyclin D so that progression through
the cell cycle does not occur. RCC cell proliferation is inhibited, even under hypoxic kidney conditions.
Side Effects and Adverse Reactions. Hypersensitivity
reactions to temsirolimus are common, and pretreatment
is recommended (see the Nursing Process section). Hyperglycemia is very common (in about 89%) in clients receiving
temsirolimus, and it may require treatment with oral antidiabetic agents or with insulin. Hematologic side effects of
anemia, neutropenia, and thrombocytopenia may be moderate to severe. Other common side effects include headache, insomnia, nausea and vomiting, back pain, arthralgia,
myalgia, mucositis, and diarrhea. Integumentary problems
38-20
CHAPTER 38 Targeted Therapies to Treat Cancer
such as rash, pruritus, nail disorder, dry skin, acne, and
abnormal wound healing may occur.
Respiratory adverse effects of interstitial pneumonitis or
other interstitial lung disease are possible. Liver impairment
and renal impairment have been reported. Cardiovascular
effects of edema formation, chest pain, hypertension, venous
thromboembolism, and thrombophlebitis are possible.
Drug Interactions. Drugs that inhibit the CYP3A4 enzyme
can lead to increased serum levels of temsirolimus, which
increases the risk for severe side effects. These drugs include
ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, amprenavir, aprepitant, diltiazem,
fluconazole, verapamil, and cimetidine.
Drugs that induce the CYP3A4 enzyme activity may lower
temsirolimus blood serum levels and reduce its effectiveness.
These drugs include rifampin, carbamazepine, and phenytoin.
Clients taking antihypertensive drugs such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin II
receptor antagonists during temsirolimus therapy are at
increased risk for angioedema of the face and upper airways.
The combination of temsirolimus and sunitinib may result
in dose-limiting integumentary toxicities of erythematous
maculopapular rash and gout/cellulitis that require hospitalization. The use of live vaccines such as intranasal influenza,
measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and typhoid vaccines should be avoided during treatment with temsirolimus.
Monoclonal Antibodies
Monoclonal antibodies largely exert their effects on specific
cell membrane surface proteins. All of the FDA-approved
monoclonal antibodies currently used in cancer treatment
are given intravenously because their protein structure would
be altered and inactivated in the GI tract.
Antigens are normal cell surface proteins or ligands that
serve as targets for binding engineered monoclonal antibodies for the treatment of cancer. Ideal target antigens for cancer
treatment should be specific to tumor cells; be located on the
surface of the tumor cell and not shed into the bloodstream;
occur in high numbers; and play a role in tumor cell survival.
Monoclonal antibody therapy is aimed specifically at tumor
cells expressing the target antigen. The side effects of monoclonal antibodies are related to activation of the immune system, location of the target antigen, and type of monoclonal
antibody. Some monoclonal antibodies sensitize tumor cells
to chemotherapy and overcome chemotherapy resistance.
The function of an antibody or immunoglobulin is to recognize an antigen and then interact with other serum proteins to eliminate the antigen or the cell associated with that
antigen. The Y shape of the antibody has two active sites (Fab
and Fc) and the following two activities:
1. The Fab portion of the antibody contains the antigenbinding sites that recognize and bind to a specific antigen.
2. The Fc or constant region is the end of the antibody that
signals the immune system to destroy the cell the antibody
has bound.
The binding of antibody to antigen is highly selective,
rather like a lock-and-key fit. When an antibody selectively
binds to a specific antigen, the antibody/antigen complex acts
as a flag or target, drawing other immune cells to the bound
cell to destroy it.
A monoclonal antibody recognizes only a single unique
antigen and is produced by cloning a single cell. Hybridoma
technology, developed in 1975, allowed for mass production of monoclonal antibodies. In this technique, a mouse
is inoculated with a purified antigen and antibody-producing cells are isolated from the mouse spleen. Then antibody
producing cells are mixed with myeloma cells (which are
immortal cells unable to produce antibodies). When antibody-producing cells fuse with myeloma cells, the resulting
cells can make large quantities of the specific monoclonal
antibody.
Binding of a monoclonal antibody to its specific target
antigen on the cancer cell inactivates or destroys the cancer
cell by one or more of the following mechanisms:
• Causing neutralization of tumor cell growth by direct
interference with normal biologic activities of the antigen,
such as signal transduction of cell growth messages. This
cytostatic process can slow growth of the tumor cells.
• Promoting antibody-dependent cell-mediated cytotoxicity (ADCC) in which the Fc portion of the bound monoclonal antibody recruits effector cells such as phagocytes,
T-cells, and natural killer cells of the immune system to
release cytokines that destroy the target cell.
• Initiating complement-dependent cytotoxicity (CDC),
which activates the complement system (a cascade of naturally circulating blood proteins), thus enhancing immune
system destruction of antibody-bound cells.
• Directly inducing apoptosis, or programmed cell death.
• In fully human antibodies, the entire antibody has been
engineered to contain only human antibody protein
sequences. Human antibodies are usually named with the
suffix “umab” (see Table 38-2).
Murine monoclonal antibodies are derived from mice.
Mouse antibodies have a very short half-life in the human
body, are not as effective as human antibodies in eliciting a
response from the CDC and ADCC systems, and can cause
the development of human anti-mouse antibodies (HAMA)
that neutralize and render the mouse antibodies ineffective
against the tumor. Mouse antibodies are usually named
with the suffix “momab.” Chimeric monoclonal antibodies
end with the suffix “ximab” and contain both human and
mouse protein sequences (typically 70% human and 30%
mouse).
Humanized monoclonal antibodies ending in zumab contain human and gene mouse sequences; however they are
not considered chimeric because they contain more human
sequences than do chimeric monoclonal antibodies, usually
90% to 95% human and 5% to 10% mouse.
When monoclonal antibodies are named, not only is the
suffix a clue to the make-up, but also you can tell what they
target by their names. If a generic monoclonal antibody has a
u in the name, then the target is on a tumor cell. Monoclonal
CHAPTER 38 Targeted Therapies to Treat Cancer
antibodies can be naked, or unconjugated, with nothing
attached to them. They also may be conjugated, in which
other anticancer agents such as chemotherapy agents, toxins,
or radioisotopes are attached with the antibody. Although
agents attached to conjugated antibodies are targeted specifically against tumor cells, nearby healthy cells can still be
negatively affected, especially if radioisotopes are used. If the
specific target antigen is found on normal cells, these antibodies also cause damage to these cells.
The five major monoclonal antibodies currently in use
for cancer therapy are alemtuzumab, gemtuzumab ozogamicin, ibritumomab tiuxetin, rituximab, and tositumomab.
Table 38-1 lists the monoclonal antibodies and their dosages,
routes, uses, and considerations. Prototype Drug Chart 38-3
lists specific drug information for rituximab. Ofatumumab
(Arzerra) is a newly approved monoclonal antibody for management of chronic lymphocytic leukemia (CLL).
38-21
Alemtuzumab
Alemtuzumab (Campath) is an unconjugated, humanized
monoclonal antibody against the cell surface antigen CD52.
CD52 is found on most B- and T-lymphocytes, the majority of monocytes, macrophages and natural killer or NK cells,
some granulocytes, stem cells, and mature spermatozoa.
Although normal cells may express this antigen, malignant
cells are much more sensitive to the destructive activity of this
antibody. This drug is most commonly used for management
of chronic lymphocytic leukemia.
Pharmacokinetics. Alemtuzumab is administered as an
intravenous infusion. Its average half-life is 12 days, and
steady-state levels are reached by about 6 weeks. Because
all monoclonal antibodies bind to target cell surfaces and
are destroyed along with the target cell, they are cleared as
debris from the blood by the liver and eliminated in the
feces.
PROTOTYPE DRUG CHART 38-3
Rituximab
Drug Class
Dosage
Monoclonal antibody
Trade name: Rituxan
Pregnancy Category: C
A: IV: 375 mg/m2 IV once weekly for 4 doses; may be re-treated for an additional
4 doses. In combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), 375 mg/m2 IV on Day 1 of each cycle of chemotherapy for up
to 8 cycles.
Contraindications
Clients who may become pregnant, are pregnant, or are breastfeeding; have previously
had hepatitis B; have active bacterial or viral
infection; have moderate to severe renal, liver,
and/or cardiac disease; or have preexisting
pulmonary fibrosis
Drug-Lab-Food Interactions
Drug:
Potentiation of hypotension when co-administered with antihypertensive drugs
Potentiation of bone marrow suppression when co-administered with other
drugs that also cause bone marrow suppression, increasing the risk for infection and bleeding
Reduces effectiveness of vaccinations
Lab: None known
Food: None known
Pharmacokinetics
Pharmacodynamics
Antibody binding specifically to the CD20 cell surface antigen on B-lymphocytes
Absorption: 100% bioavailability after intravenous infusion
Distribution: Throughout extracellular fluid, bone
marrow, and secondary lymphoid tissues
(primarily the spleen)
Metabolism: Degraded by circulating and liverbased phagocytic cells
Excretion: As cellular debris in feces
Therapeutic Effects/Uses
CD20-positive non-Hodgkin’s lymphoma (NHL)
Rheumatoid arthritis (lower dosages)
Mode of Action: Binds to CD20-positive B-lymphocytes and lymphoma cells, leading to complement-dependent cytotoxicity,
antibody-dependent cellular cytotoxicity, and apoptosis.
Side Effects
Bone marrow suppression with pancytopenia,
Tumor lysis syndrome, hypotension, night
sweats, joint and muscle aches, headaches,
soreness at injection site
A, adult; IV, intravenous.
Adverse Reactions
Infusion reactions
Reactivation of dormant viruses, pulmonary fibrosis, cardiac dysrhythmias, heart
failure
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CHAPTER 38 Targeted Therapies to Treat Cancer
Pharmacodynamics. Alemtuzumab binds to leukemic
cells expressing the CD52 cell surface antigen and induces
antibody-dependent lysis. T-cell prolymphocytic leukemia cells are most sensitive to this drug, but monocytes and
monocytic leukemias are resistant to it, despite expressing
similar amounts of antigen. As an unconjugated monoclonal
antibody, this drug relies on inducing apoptotic signals and
the activation of mechanisms such as complement or T-cells
to attack and kill the targeted cells. Alemtuzumab is also associated with the release of tumor necrosis factor (TNF), interleukin-6, and interferon gamma.
Side Effects and Adverse Reactions. Alemtuzumab therapy induces fatigue as the most common side effect that is not
related to infusion reactions or pancytopenia. This drug carries a Black Box Warning because of profound bone marrow
suppression that may require dose interruptions or reduction, based on severity. This suppression is more profound
in clients who are also receiving standard cytotoxic chemotherapy. In addition, infusion reactions with fever, nausea,
chills, blood pressure changes, hyperglycemia, and hypoxia
are common and often require premedication with antihistamines and acetaminophen. Some clients have reduced reactions with subsequent infusions.
Drug Interactions. Specific drug interactions have not
been reported with this drug; however, concomitant administration of drugs with similar pharmacologic effects may
cause additive side effects, including toxicity.
Gemtuzumab
Gemtuzumab ozogamicin (Mylotarg) is a conjugated humanized monoclonal antibody directed against the CD33 surface
antigen that is expressed by leukemic cells and immature
myelomonocytic cells. It is conjugated with an antitumor
antibiotic called calicheamicin. This drug is most commonly
used to manage acute myeloid leukemia (AML) that is positive for the CD33 cell surface protein.
Pharmacokinetics. Gemtuzumab ozogamicin is administered as an intravenous infusion. Its half-life is 45 hours for
the first dose and 60 hours for the second dose. Because all
monoclonal antibodies bind to target cell surfaces and are
destroyed along with the target cell, they are cleared as debris
from the blood by the liver and eliminated in the feces.
Pharmacodynamics. Gemtuzumab ozogamicin is conjugated with calicheamicin, an antitumor antibiotic. The binding of the of the antibody portion of this combination to
CD33 antigen on leukemia cells results in the formation of a
complex that is internalized by the cell. Upon internalization,
calicheamicin is released from the antibody and binds to the
minor groove of the cell’s DNA. This action breaks the DNA
double strands and causes cell death.
Side Effects and Adverse Reactions. Gemtuzumab ozagamicin carries a Black Box Warning for severe hypersensitivity reactions, pulmonary edema, and acute respiratory
distress syndrome. This drug can induce hepatotoxicity,
most commonly in clients who have received a hematopoietic stem cell transplant and have experienced any degree of
hepatic veno-occlusive disease. Just as with all monoclonal
antibodies, this drug causes profound bone marrow suppression that may require dose interruptions or reduction, based
on severity. The suppression is more profound in clients who
are also receiving standard cytotoxic chemotherapy. Infusion
reactions with fever, nausea, chills, blood pressure changes,
hyperglycemia, and hypoxia are common and often require
premedication with antihistamines and acetaminophen.
Some clients have reduced reactions with the second and
subsequent infusions.
Drug Interactions. Specific drug interactions have not
been reported with this drug; however, concomitant administration of drugs with similar pharmacologic effects may
cause additive side effects, including toxicity.
Ibritumomab Tiuxetan
Ibritumomab tiuxetan (Zevalin) is a conjugated murine
monoclonal antibody. Ibritumomab is the antibody, and
tiuxetan is a linker-chelater to which either Indium-111 or
Yttrium-90 can be bound. Like rituximab, this drug combination binds specifically to the human B-lymphocytes that
express the CD20 cell surface antigens. This drug is most commonly used for management of B-cell types of non-Hodgkin’s
lymphoma that express the CD20 cell surface protein.
Pharmacokinetics. Ibritumomab tiuxetin is administered
as an intravenous infusion. Its physical half-life is 64 hours,
and its biologic half-life (determined by radioactivity detection) is 30 hours. The drug is excreted to a slight degree by the
kidneys but is mostly eliminated in the feces.
Pharmacodynamics. Ibritumomab tiutuxetin binds to the
CD20 antigen on B-lymphocytes and lymphoma cells. Following binding with the CD20 antigen, beta wave radioactive
emissions from the attached radionuclide, Y-90, induce cellular damage by the formation of free radicals in the target and
neighboring cells. This cellular damage prevents cells from
dividing and also causes cell death.
Side Effects and Adverse Reactions. Ibritumomab tiuxetan carries a Black Box Warning for infusion reactions with
fever, nausea, chills, and blood pressure changes. Severe infusion reactions warrant discontinuing the drug. Less severe
infusion reactions may be managed using premedication with
antihistamines and acetaminophen. Some clients experience
reduced reactions with the second and subsequent infusions.
Additional Black Box Warnings for this drug include severe
cytopenia and severe cutaneous and mucocutaneous reactions, fetal damage if given during pregnancy, and possible
second malignancies. Just as with all monoclonal antibodies,
this drug causes profound bone marrow suppression that
may require dose interruptions or reduction (based on severity) and are more profound in clients who are also receiving standard cytotoxic chemotherapy. Ibritumomab tiuxetan
side effects and adverse effects not associated with bone marrow suppression or infusion reaction include nausea, vomiting, diarrhea, abdominal pain, cough, rash, pruritus, and
urticaria.
Drug Interactions. Ibritumomab tiuxetin increases the risk
for bleeding or hemorrhage when used along with anticoagulant or antiplatelet therapy. Other specific drug interactions
CHAPTER 38 Targeted Therapies to Treat Cancer
are not associated with this drug; however, concomitant
administration of drugs with similar pharmacologic effects
may cause additive side effects, including toxicity.
Tositumomab
Tositumomab (Bexxar) is a murine monoclonal antibody
conjugated with the radioactive isotope iodine-131 (131I).
Like rituximab and ibritumomab tiuxetin, the antibody portion of this drug binds specifically to the human B-lymphocytes that express the CD20 cell surface antigens. This drug is
most commonly used to manage B-cell non-Hodgkin’s lymphoma that does not respond to rituximab.
Pharmacokinetics. Tositumumab is administered as an
intravenous infusion. It has a median blood clearance of 68.2
mg/hour (with 485-mg dosage). The mean total-body effective half-life is 67 hours. The radioisotope (131I) decays over
time (half-life is 8 days) and is eliminated in the urine.
Pharmacodynamics. Tositumomab induces cytotoxicity
by combining the immunologic effects of antibody binding
with the preferential targeting of radiation therapy against
CD20-positive lymphocytes and lymphoma cells. Actions of
the antibody include the induction of complement-mediated
cytolysis, antibody-dependent cellular cytotoxicity, and
apoptosis. Radiation activity is cytotoxic not only to the cells
bound by the radiolabeled antibody, but also to adjacent
cells that may not have been bound by the antibody or do
not express the target antigen (a process called the cross fire
effect). Together, these actions result in sustained depletion
of circulating CD20-positive lymphocytes and lymphoma
cells.
NURSING PROCESS
Proteosome Inhibitors, Angiogenesis Inhibitors,
and Monoclonal Antibodies for Cancer Treatment
Assessment
baseline physical condition of the client before
initiating targeted therapy regimen and during the treatment period.
Assess laboratory studies, including CBC with differential, hepatic and renal studies, electrolytes, and urinalysis
at the beginning of therapy and at specified time intervals
(ranging from weekly to monthly) during therapy.
Conduct a detailed medication history, including a list of all
concurrent medications, including prescriptions, over-the
counter medicines, antacids, dietary supplements, vitamins,
and herbal supplements to avoid drug-drug interactions.
Assess client and family knowledge related to therapeutic
regimen.
Assess
Nursing Diagnoses
Knowledge, deficient, related to targeted therapy regimen
Skin integrity, impaired, risk for, related to dermatologic
effects and toxicities of therapy
Infection, risk for, related to bone marrow suppression
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Side Effects and Adverse Reactions. Tositumomab carries
a Black Box Warning for severe hypersensitivity reactions,
severe bone marrow suppression, and fetal damage (when
used during pregnancy). Specific tositumomab side effects
and adverse effects include asthenia, headache, hypotension,
nausea, vomiting, abdominal pain, diarrhea, hypothyroidism,
cough, dyspnea, pleural effusion, and pneumonia. Toxicities
associated with radioimmunotherapy can be acute, delayed,
or long-term. The most common acute toxicities are fever,
rigors, fatigue, headache, and nausea, whereas hypotension
and allergic reactions are less common. Delayed toxicities
include shortness of breath, fever, signs of infection, inflammation, pain with urination, rash, sore joints, and bone marrow suppression. Long-term toxicities are myelodysplasia or
acute leukemia, secondary malignancies, and hypothyroidism. Just as with other monoclonal antibodies, this drug
causes profound bone marrow suppression that may require
dose interruptions or reduction, based on severity, and are
more profound in clients who are also receiving standard
cytotoxic chemotherapy. In addition, infusion reactions with
fever, nausea, chills, blood pressure changes, hyperglycemia,
and hypoxia are common and often require premedication
with antihistamines and acetaminophen. Some clients have
reduced reactions with subsequent infusions.
Drug Interactions. Tositumomab increases the risk for
bleeding or hemorrhage when used along with anticoagulant or antiplatelet therapy. Other specific drug interactions
have not been reported with this drug; however, concomitant
administration of drugs with similar pharmacologic effects
may cause additive side effects, including toxicity.
Fluid
volume, deficient, risk for, related to GI effects of
therapy
Electrolyte imbalance, risk for, related to actions of targeted therapy
Planning
Client and family will verbalize understanding of targeted
therapy as part of an anticancer treatment regimen.
and family will demonstrate understanding of the
importance of reporting targeted therapy–related side
effects and adverse reactions.
Client and family will verbalize strategies to minimize
risks related to targeted therapy–related side effects.
Client’s side effects will be managed to a level that the client can tolerate and are not life-threatening.
Client will remain infection-free.
Client will have fluid balance and electrolytes within
expected normal ranges.
Client
Nursing Interventions
prescribed premedications according to
established protocols for specific targeted therapies.
Monitor complete blood cell count with differential and
platelet count at baseline, and as often as recommended
for specific agents.
Administer
Continued
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CHAPTER 38 Targeted Therapies to Treat Cancer
NURSING PROCESS—cont’d
Monitor
liver function tests and renal function tests at
baseline and at least once monthly during therapy.
Follow institution guidelines for safe handling, preparing, administering, and dispensing of targeted therapy
agents.
Bortezomib
Check
the client’s peripheral sensation and blood pressure at each visit throughout the duration of treatment.
Ensure that client is adequately hydrated before, during,
and after therapy to reduce the risk for tumor lysis syndrome.
Discuss with the health care provider the possible need
for prophylactic allopurinol therapy.
Monitor output and serum potassium levels closely.
Check for manifestations of tumor lysis syndrome
(decreased urine output, hyperkalemia, and hypertension).
Temsirolimus/Sirolimus
Ask
the client about any known hypersensitivity to temsirolimus or sirolimus.
If prescribed, premedicate the client with diphenhydramine 25 to 50 mg IV, or a similar antihistamine, approximately 30 minutes before the start of each dose.
Ensure that resuscitation equipment is nearby, and stay
with the client during the first 15 minutes of the infusion. Thereafter, monitor vital signs every 15 to 30 minutes during the infusion and for 1 hour after infusion is
complete.
Check the client’s blood glucose level before, during, and
after drug administration.
Monitor fasting blood glucose and serum electrolytes at
baseline and at least every 2 weeks during therapy.
Monitor chest radiograph at baseline and periodically
during therapy for onset of pulmonary toxicity.
Monitor renal and hepatic function at baseline and then
periodically during therapy.
Monoclonal Antibodies
Infusion
reactions are common with intravenous infusion of monoclonal antibodies. Ensure that resuscitation
equipment is nearby, and stay with the client during the
first 15 minutes of the infusion. Thereafter, monitor vital
signs every 15 to 30 minutes during the infusion and for
1 hour after infusion is complete.
Monoclonal antibodies against leukocytes can profoundly suppress bone marrow activity and increase the
risk for infection.
Monitor for signs and symptoms of infection.
Clients receiving alemtuzumab are usually prescribed to
start antimicrobial prophylaxis beginning on the first day
of therapy to reduce the risk for serious infection. Prophylaxis is continued for 2 months after the last dose.
Gemtuzumab ozogamicin can cause liver toxicity. Closely
monitor liver function tests.
clients for hepatitis B infection before the initiation of rituximab therapy.
Ensure that clients are adequately hydrated before, during, and after rituximab therapy to reduce the risk for
tumor lysis syndrome.
Monitor output and serum potassium levels closely.
Check for manifestations of tumor lysis syndrome
(decreased urine output, hyperkalemia).
Screen
Client Teaching
alcohol and nonessential drugs that are cleared by
the liver or have liver-toxic effects (e.g., acetaminophen).
Report symptoms of adverse effects or severe side effects
promptly, especially fever, chills, persistent sore throat,
swelling, weight gain, or increasing shortness of breath).
Report symptoms of bleeding immediately, including
black stools, vomit that looks like coffee grounds, easy
bleeding/bruising.
Report symptoms of liver impairment immediately,
including stomach/abdominal pain, yellowing eyes or
skin, dark urine, or unusual fatigue.
Remind women with childbearing potential to avoid
pregnancy throughout treatment and for up to 12 months
after treatment is completed.
Advise breastfeeding women to stop breastfeeding during
and for 60 days after therapy.
Avoid
Bortezomib
Teach
clients to avoid driving or operating dangerous
machinery during periods of blurred or double vision or
when fatigue is extreme.
Instruct clients (or family members) to immediately
report the development of convulsions, persistent headache, reduced eyesight, blood pressure increases, or
blurred vision.
Teach clients to drink at least 4 liters of fluid daily on the
day before therapy, on the days of therapy, and for 2 days
following therapy. Stress the importance of keeping fluid
intake consistent throughout the 24-hour day, and help
clients draw up a schedule of fluid intake.
Instruct clients to contact the health care provider or cancer
clinic immediately if nausea and vomiting prevent adequate
fluid intake so they can be started on parenteral fluids.
Temsirolimus/Sirolimus
Instruct nondiabetic clients to report symptoms of hyper-
glycemia (excessive thirst or any increase in the volume
or frequency of urination).
Instruct diabetic clients to test blood glucose levels more
frequently. If prescribed dosages of oral antidiabetic
drugs are not sufficient to maintain target blood glucose
levels, instruct the client to go to his or her primary care
health care provider for diabetic therapy adjustments.
CHAPTER 38 Targeted Therapies to Treat Cancer
Instruct
clients who develop swelling of the face, lips,
or tongue to immediately go to the nearest emergency
department.
Instruct the client and live-in family members not to
receive any vaccinations without consulting the oncologist.
Monoclonal Antibodies
Teach
clients the signs and symptoms of bone marrow
depression and infection.
Instruct the client receiving alemtuzumab therapy and livein family members not to receive any live-virus vaccinations
during therapy or for 2 months after therapy is completed.
Teach clients that the monoclonal antibodies conjugated to radioisotopes (ibritumomab tiuxetin and tositumomab) make the client somewhat radioactive for a time
after the infusion and pose a radiation hazard to others
38-25
for 4 to 7 days. Teach these clients to use the following
precautions for one week after each drug administration:
Sleep in a separate bed.
Maintain a distance of six feet or more from children and
pregnant women.
Limit time spent in public places.
Use a separate bathroom and sit while urinating.
Wash hands frequently, especially after using the toilet or
handling genitals.
Drink plenty of liquids (at least 3 L daily)
Keep eating utensils separate from others.
Wash laundry separately from those of others.
Avoid using disposable products.
Avoid sexual contact and avoid becoming pregnant.
Clean spilled urine and dispose of body fluid–contaminated
material so that others will not inadvertently handle it.
KEY WEBSITES
American Cancer Society (ACS):
www.cancer.org/docroot/ETO/content/ETO_1_2x_Targeted_
Therapy.asp
National Cancer Institute (NCI): www.cancer.gov/cancertopics/
understandingcancer/targetedtherapies/htmlcourse
National Comprehensive Cancer Network (NCCN):
www.nccn.org/professionals/meetings
www.nccn.com/breast_cancer_IV.aspx
www.nccn.com/metastatic_colorectal_cancer.aspx
CRITICAL THINKING CASE STUDY
The client is a 64-year-old man diagnosed with stage III B-cell
non-Hodgkin’s lymphoma (NHL). He is scheduled to receive
rituximab (Rituxan) and a traditional chemotherapy regimen
of cyclophosphamide (Cytoxan), doxorubicin (Adriamycin),
vincristine (Oncovin), and prednisolone, a combination
known as “CHOP.” The dosage and schedule of rituximab
for this client is 600 mg IV on day 1 and 6 before the first cycle
of CHOP chemotherapy (which will be administered on day
8). The next 2 doses will be administered 2 days before the
third and fifth cycles, and the remaining 2 cycles of rituximab
will be administered after the sixth cycle of CHOP on days
134 and 141. He has a friend who is taking imatinib (Gleevec)
daily as an oral drug for chronic myelogenous leukemia.
The client asks why rituximab must be taken intravenously.
He also asks that because he has an implanted port, if his
spouse, who is an LPN, could administer the rituximab at
home so that he will not have to travel to the cancer center in
addition to his standard chemotherapy appointments.
1. What is your best response about why rituximab must be
administered intravenously?
2. How are rituximab and imatinib different?
3. Why can his spouse not administer rituximab at home?
4. What side effects are specific for rituximab?
5. What are the most common adverse effects of rituximab?
6. What should you teach this client specifically related to the
rituximab therapy?
NCLEX STUDY QUESTIONS
1. The nurse works in the oncology clinic and knows that
targeted therapies for cancer differ from traditional chemotherapy due to which factor?
a. They are more likely to kill cancer cells rather than just
slow their growth.
b. They are so specific for cancer cells that they do not
have effects on normal cells.
c. They attack and inactivate specific cellular chemicals
or structures that are more commonly found in cancer
cells than in normal cells.
d. They make the plasma membranes of malignant cells
more permeable so that intracellular proteins leak out
to the extent that cancer cells are unable to perform
their specific functions.
2. The client on chemotherapy for breast cancer asks why she
is not receiving trastuzumab
(Herceptin) like her sister with breast cancer did. What is
the nurse’s best response?
a. “Your breast cancer cells are estrogen receptor–positive,
and targeted therapy is not needed.”
b. “ You are much older than your sister and would not
tolerate that treatment well.”
c. “The drug is expensive, and your insurance does not
cover it.”
d. “Your cancer cells do not have the target for trastuzumab.”
CHAPTER 38 Targeted Therapies to Treat Cancer
3. Which instruction is important for the nurse to include
when teaching the client about imatinib (Gleevec) therapy?
a. Do not drink grapefruit juice while taking this drug.
b. Go immediately to the emergency department if you
develop a headache while taking this drug.
c. This drug will only work for about 2 months before
your cancer develops resistance to it.
d. Be sure to take this drug on an empty stomach, either
1 hour before eating or at least 3 hours after eating.
4. Which of the following is the priority nursing diagnosis for clients receiving epidermal growth factor receptor
inhibitors (EGFRIs)?
a. Risk for infection related to bone marrow suppression
and neutropenia
b. Risk for impaired skin integrity related to skin side
effects
c. Risk for injury related to reduced platelet activity
d. Disturbed body image related to alopecia
5. When administering which class of targeted therapies
should the nurse be most alert to a possible infusion
reaction?
a. Tyrosine kinase inhibitors
b. Multikinase inhibitors
c. Monoclonal antibodies
d. Proteasome inhibitors
6. The client taking sunitinib (Sutent) reports that the skin
on her hands and feet is red, painful, and has some blisters. What is the nurse’s best action?
a. Document the report as the only action because this is
a mild side effect of the drug.
b. Instruct the client to wear gloves and mittens when
going outdoors in cold weather.
c. Instruct the client to avoid getting her hands wet and
to avoid touching food.
d. Notify the oncologist to determine whether or not a
dosage reduction is needed.
7. Which action is most important for the nurse to teach a
client taking Tositumumab (Bexxar)?
a. Avoid drinking alcohol for 1 week after receiving this
drug.
b. Avoid smoking cigarettes for the entire period you are
being treated with this drug.
c. Use a separate bathroom and sit while urinating for 1
week after receiving this drug.
d. Be sure to take this drug on an empty stomach, either
1 hour before or 2 hours after eating.
8. Which activity should the nurse instruct the client taking
erlotinib (Tarceva) to avoid?
a. Drinking alcoholic beverages
b. Taking aspirin or aspirin-containing drugs
c. Exposing himself or herself to crowds or persons who
are ill
d. Exposing himself or herself to direct sunlight or tanning beds
9. Why should clients taking or receiving targeted therapies
for cancer avoid using St. John’s wort?
a. This herbal drug increases the blood levels of most
targeted therapies and increases the risk for severe side
effects or adverse reactions.
b. This herbal drug decreases the blood levels of most
targeted therapies and reduces their effectiveness.
c. Targeted therapies increase the blood levels of St.
John’s wort, increasing the risk of an overdose of this
herbal agent.
d. Targeted therapies bind with St. John’s wort in the
intestinal tract, preventing the absorption of both the
drug and the herbal agent.
10. The client taking imatinib (Gleevec) has gained 5 pounds
in the past week. Is this cause for concern?
a. No, weight gain is an expected side effect of this drug
because it increases the appetite.
b. Yes, weight gain is an indication of slow metabolism
and possible hypothyroidism.
c. Yes, weight gain is an indication of water retention
and possible renal impairment.
d. Yes, weight gain is an indication of a drug interaction
between imatinib and loop diuretics.
Answers: 1, c; 2, d; 3, a; 4, b; 5, c; 6, d; 7, c; 8, d; 9, b; 10, c.
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