SECTION 16
ONCOLOGIC DISORDERS
88
Cancer Principles and
Therapeutics
Lisa M. Holle
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Describe the etiology of cancer.
2. Define the tumor, nodes, metastases (TNM) system of cancer staging.
3. Classify each drug used in the treatment of cancer and compare and contrast the mechanisms of action,
uses, and adverse effects.
4. Outline actions for all healthcare professionals to prevent medication errors with cancer treatments.
5. Describe what cancer survivorship means and how this impacts future healthcare needs of an individual.
INTRODUCTION
T
he word cancer covers a diverse array of tumor
types that affect a significant number of Americans
and individuals worldwide and are a major
cause of mortality. The term cancer actually refers to more than
100 different diseases. What is common to all cancers is that the
cancerous cell is uncontrollably growing and has the potential for
invading local tissue and spreading to other parts of the body, a
process called metastases. Cancer is the second leading cause of
death behind heart disease.1 In 2021, it was projected that nearly
1.9 million Americans will be diagnosed with cancer, and that an
estimated 608,570 Americans will die from cancer.1 Figure 88–1
describes cancers by gender, new cases, and deaths.
Once diagnosed, a cancer patient may encounter many different healthcare professionals. All healthcare professionals must
collaborate to ensure safe and appropriate prescribing, preparation, administration, and monitoring of anticancer agents; management of toxicities; resolution of reimbursement issues; and
participation in clinical trials. The pharmacist is a pivotal member of the care team because of their medication expertise.2,3
As a result of advances in research and technology, available
cancer treatments have increased dramatically in the last couple of
decades. The fields of radiation therapy, surgery, and drug development have made enormous progress over the years. Therefore,
patients are often receiving treatments that are less toxic and with
better treatment outcomes than in the past. Supportive care therapies have also improved, and patients now may be at less risk
for toxicity and have a better quality of life than patients in the
past. Twenty years ago, most patients received chemotherapy in
the hospital because of side effects. Today, many more patients
are able to receive chemotherapy in outpatient clinics and/or take
oral anticancer agents at home.
Cancer Prevention
Because most cancers are not curable in advanced stages, cancer
prevention is an important and active area of research. Both
lifestyle modifications and chemoprevention agents may significantly reduce the risk of developing some cancers. An active
area of investigation, The Food and Drug Administration (FDA)
has approved vaccines that can help prevent cancer. Available
vaccines include those that prevent infection with human papillomavirus (HPV), responsible for many cancers of the cervix,
vulva, vagina, and anus and a vaccine that prevents hepatitis
B viral infections, which can cause liver cancer. Additionally,
orally administered medications, such as the selective estrogen
receptor (ER) modulator (SERM) tamoxifen, reduces the risk
of breast cancer in premenopausal women. Another SERM,
raloxifene and the aromatase inhibitor (AI) exemestane both
have shown a reduction in breast cancer in high-risk postmenopausal women. Because these agents will have adverse effects
and possible long-term complications (eg, an increased risk of
endometrial cancer with the use of tamoxifen), benefits versus
risks needs to be weighed when initiating these breast cancer
prevention strategies.
Tobacco
Tobacco smoking increases the risk of developing not only lung
cancer but also many other types of cancer, including cancer of
the bladder, mouth, pharynx, larynx, and esophagus as well as
kidney cancer. Smoking cessation is associated with a gradual
decrease in the risk of cancer, but more than 5 years is needed
before a major decline in risk is detected. In addition, most studies have found that passive smoking (ie, secondhand smoke) also
increases a person’s risk of developing lung cancer.4
Ultraviolet Radiation
Ultraviolet light (sunlight or tanning booths and lamps) exposure may increase the risk of developing melanoma and other
skin cancers, especially in individuals who have a positive family
history, fair skin, light-colored eyes, high degrees of freckling,
and a tendency to burn instead of tan. Practitioners can counsel patients on proper sun protection, including minimizing sun
exposure, using sunscreens with a sun protection factor (SPF) of
15 or greater on exposed areas (along with proper reapplication),
wearing protective clothing and sunglasses, avoiding tanning
beds and sun lamps, and the importance of early detection.
1389
Chisholm_Ch088_p1389-1420.indd 1389
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1390 SECTION 16 | ONCOLOGIC DISORDERS
Estimated New Cases
Prostate
Lung & bronchus
Colon & rectum
Urinary bladder
Melanoma of the skin
Kidney & renal pelvis
Non-Hodgkin lymphoma
Oral cavity & pharynx
Leukemia
Pancreas
All sites
Estimated Deaths
Male
Lung & bronchus
Prostate
Colon & rectum
Pancreas
Liver & intrahepatic bile duct
Leukemia
Esophagus
Urinary bladder
Non-Hodgkin lymphoma
Brain & other nervous system
All sites
Female
191,930
116,300
78,300
62,100
60,190
45,520
42,380
38,380
35,470
30,400
893,660
21%
13%
9%
7%
7%
5%
5%
4%
4%
3%
Breast
Lung & bronchus
Colon & rectum
Uterine corpus
Thyroid
Melanoma of the skin
Non-Hodgkin lymphoma
Kidney & renal pelvis
Pancreas
Leukemia
All sites
72,500
33,330
28,630
24,640
20,020
13,420
13,100
13,050
11,460
10,190
321,160
23%
10%
9%
8%
6%
4%
4%
4%
4%
3%
Lung & bronchus
Breast
Colon & rectum
Pancreas
Ovary
Uterine corpus
Liver & intrahepatic bile duct
Leukemia
Non-Hodgkin lymphoma
Brain & other nervous system
All sites
276,480
112,520
69,650
65,620
40,170
40,160
34,860
28,230
27,200
25,060
912,930
30%
12%
8%
7%
4%
4%
4%
3%
3%
3%
63,220
42,170
24,570
22,410
13,940
12,590
10,140
9,680
8,480
7,830
285,360
22%
15%
9%
8%
5%
4%
4%
3%
3%
3%
Female
Male
Estimates are rounded to the nearest 10, and cases exclude basal cell and squamous cell skin cancers and in situ carcinoma except urinary bladder. Estimates
do not include Puerto Rico or other US territories. Ranking is based on modeled projections and may differ from the most recent observed data.
©2020, American Cancer Society, Inc., Surveillance Research
FIGURE 88–1. Cancer incidences (top) and deaths (bottom) in the United States for males and females—2020 estimates. (Reproduced,
with permission, from American Cancer Society. Cancer Facts and Figures 2020. Atlanta, GA: American Cancer Society, Inc.)
CARCINOGENESIS
The exact cause of cancer remains unknown and is probably
very diverse given the vast array of diseases called cancer. It
is thought that cancer develops from a single cell in which the
normal mechanisms for control of growth and proliferation are
altered. Current evidence indicates that there are four stages
in the cancer development process. The first step, initiation,
occurs when a carcinogenic substance encounters a normal
cell to produce genetic damage and results in a mutated cell.
The environment is altered by carcinogens or other factors to
favor the growth of the mutated cell over the normal cell during promotion, the second step. The main difference between
initiation and promotion is that promotion is a reversible process. Third, transformation (or conversion) occurs when the
mutated cell becomes malignant. Depending on the type of
cancer, many years may elapse between the carcinogenic phases
and the development of a clinically detectable tumor. Finally,
progression occurs when cell proliferation takes over and the
tumor spreads or develops metastases.
There are substances known to have carcinogenic risks, including chemicals, environmental factors, and viruses. Chemicals in
the environment, such as aniline and benzene, are associated
with the development of bladder cancer and leukemia, respectively. Environmental factors, such as excessive sun exposure,
can result in skin cancer, and smoking is widely known as a cause
of lung cancer. Viruses, including HPV, Epstein-Barr virus, and
hepatitis B virus, have been linked to cervical cancers, lymphomas, and liver cancers, respectively. Anticancer agents such as the
Chisholm_Ch088_p1389-1420.indd 1390
alkylating agents (eg, melphalan), anthracyclines (eg, doxorubicin), epipodophyllotoxins (eg, etoposide), and poly ADP ribose
polymerase (PARP) inhibitors (eg, olaparib) can cause secondary
malignancies (eg, leukemias) years after therapy has been completed. Additionally, factors such as the patient’s age, gender, family history, diet, and chronic irritation or inflammation may be
considered to be promoters of carcinogenesis.
Cancer Genetics
Because the human genome has been sequenced and with the
great improvements in genetic technology, growing knowledge regarding the genetic changes of cancer exist. Two major
classes of genes are involved in carcinogenesis: oncogenes and
tumor suppressor genes. Proto-oncogenes are normal genes
that, through some genetic alteration caused by carcinogens,
change into oncogenes. Proto-oncogenes are present in all normal cells and regulate cell function and replication. Genetic
damage of the proto-oncogene may occur through point
mutation, chromosomal rearrangement, or an increase in gene
function, resulting in the oncogene. The genetic damage may
either be inherited from an individual’s parents (germline
mutations) or by way of carcinogenic agents (eg, smoking).
The oncogene produces abnormal or excessive gene product
that disrupts normal cell growth and proliferation.5 As a result,
this may cause the cell to have a distinct growth advantage,
increasing its likelihood of becoming cancerous. Table 88–1
provides examples of oncogenes by their cellular function and
associated cancer.6
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CHAPTER 88 | CANCER PRINCIPLES AND THERAPEUTICS 1391
Table 88–1
Examples of Oncogenes and Tumor Suppressor Genes
Gene
Function
Associated Human Cancer
Oncogenes
Genes for growth factors or their receptors
EGFR? ERBB1
Codes for epidermal growth factor (EGFR) receptor
HER2/ERBB2
Codes for a growth factor receptor
RET
Codes for a growth factor receptor
Genes for cytoplasmic relays in stimulatory signaling pathways
KRAS and NRAS
Code for guanine nucleotide-proteins with
GTPase activity
Genes for transcription factors that activate growth-promoting genes
cMYC
Codes for transcription factor
NMYC
Codes for transcription factor
Genes for cytoplasmic kinases
BCR-ABL
Codes for a nonreceptor tyrosine kinase
ALK
Receptor tyrosine kinase
BRAF
Serine-threonine protein kinase
KIT (CD117)
Receptor tyrosine kinase
PIK2CA
Lipid kinases
RET
Codes a receptor tyrosine kinase
Genes for other molecules
BCL2
Codes for a protein that blocks apoptosis
BCL1/PRAD1
Codes for cyclin D1, a cell-cycle clock stimulator
MDM2
Protein antagonist of p53 tumor suppressor protein
Tumor-Suppressor Genes
Genes for proteins in the cytoplasm
APC
Step in a signaling pathway
NF1
Codes for a protein that inhibits the stimulatory
Ras protein
NF2
Codes for a protein that inhibits the stimulatory
Ras protein
Genes for proteins in the nucleus
MTS1
Codes for p16 protein, a cyclin-dependent kinase
inhibitor
RB1
Codes for the pRB protein, a master brake of the
cell cycle
TP53
Codes for the p53 protein, which can halt cell
division and induce apoptosis
PTEN
Phosphatase and tensin homolog deleted on
chromosome ten
Genes for protein whose cellular location is unclear
BRCA1
DNA repair, transcriptional regulation
BRCA2
DNA repair
VHL
Regulator of protein stability
MSH2, MLH1, PMS1,
DNA mismatch repair enzymes
PMS2, MSH6
Glioblastoma, breast, head and neck, and colon cancers
Breast, salivary gland, prostate, bladder, and ovarian
cancers
Thyroid cancer
Lung, ovarian, colon, pancreatic cancers
Neuroblastoma, acute leukemia
Leukemia and breast, colon, gastric, and lung cancers
Neuroblastoma, small cell lung cancer, and glioblastoma
Chronic myelogenous leukemia
Lung cancer, lymphomas, neuroblastoma, and ovarian
cancer
Colon cancer, lung cancer, melanoma, ovarian, thyroid
cancer
Acute Leukemia, gastrointestinal, stromal tumor, and
gastrointestinal stromal tumor
Lung cancer, ovarian cancer
Lung cancer, thyroid cancer
Indolent B-cell lymphomas
Breast, head, and neck cancers
Sarcomas
Colon and gastric cancer
Neurofibroma, leukemia, and pheochromocytoma
Meningioma, ependymoma, and schwannoma
Involved in a wide range of cancers
Retinoblastoma, osteosarcoma, and bladder, small cell lung,
prostate, and breast cancers
Involved in a wide range of cancers
Lung cancer, ovarian cancer
Breast and ovarian cancers
Breast cancer
Kidney cancer
Hereditary nonpolyposis colorectal cancer
From Cordes LM, Shord SS. Cancer treatment and chemotherapy. In: DiPiro JT, Yee GC, Posey LM, et al. eds. Pharmacotherapy: A Pathophysiologic
Approach, 11th ed. New York, NY: McGraw-Hill; 2020: Table 144–2.
Tumor suppressor genes inhibit inappropriate cellular growth
and proliferation. When gene loss or mutation occurs, this results
in a loss of control over normal cell growth. The TP53 gene is one
of the most common tumor suppressor genes, and mutations of
TP53 may occur in up to 50% of all malignancies. This gene stops
the cell cycle to enable “repair” of the cell. If TP53 is inactivated,
then the cell allows the mutations to occur. Although mutations
Chisholm_Ch088_p1389-1420.indd 1391
of the TP53 gene are found in many tumors, such as breast, colon,
and lung cancer, it is also associated with drug resistance of
cancer cells. Deoxyribonucleic acid (DNA) repair genes fix errors
in DNA that occur because of environmental factors or errors
in replication and can be classified as tumor suppressor genes.
Mutations in DNA repair genes have been reported in hereditary
nonpolyposis colon cancer and in some breast cancer syndromes.
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1392 SECTION 16 | ONCOLOGIC DISORDERS
Death
1-kg tumor mass
Disease symptoms
become
incapacitating
Clinically
undetectable
tumor
Chemotherapy
treatment A
1010
Log/number of cancer cells
Diagnosis
possible
(first symptoms)
Plateau growth phase
(lower growth fraction, longer tumor-doubling times)
1012
108
Bulk tumor reduction necessary:
1. Surgery
2. Irradiation
3. Multiple-course intensive
chemotherapy regimens
3
1-cm mass
106
105
104
10
2
10
0
Log-linear
growth phase
(high-growth fraction,
short-doubling time)
Immunotherapy
of greatest
benefit
Micrometastatic
disease area
Chemotherapy
treatment B
Time
FIGURE 88–2. The Gompertzian growth curve demonstrating symptoms and treatments versus tumor volume.
Numerous cellular changes occur in the genetic
material of the cancer cell so that programmed cell death (PD), or
apoptosis, does not occur. Proliferation of cancer cells goes unregulated. If mutations persist and cells are not repaired or suppressed,
cancer may develop. Apoptosis, or PD, may prevent the mutated
cell from becoming cancerous. Loss of TP53 and overexpression of
B-cell lymphoma 2 (BCL2) are two examples of changes within the
cell that occur to result in enhanced cell survival.
Identification of genes involved in cancer may be conducted
for various reasons, including cancer screening to determine if an
individual is at an increased risk of cancer, to develop new anticancer agents, to aid in diagnosis, and to predict response and/or
the toxicity of the agents used in individual patients.
Principles of Tumor Growth
It takes about 109 cancer cells to be clinically detectable by palpation or radiography. Figure 88–2 demonstrates the classic Gompertzian kinetics tumor growth cycle. From the diagram, one can
see that malignant cell growth occurs many times before a mass
may be detected. The number of malignant cells may decrease
drastically because of surgery or in decreasing steps by each
administration of chemotherapy. One dosing round, or cycle, of
chemotherapy does not eliminate all malignant cells; therefore,
repeated cycles of chemotherapy are administered to eliminate
tumor cell burden. The cell kill hypothesis states that a fixed percentage of tumor cells will be killed with each cycle of chemotherapy. According to this hypothesis, the number of tumor cells will
never reach zero. This theory assumes that all cancers are equally
responsive and that anticancer drug resistance and metastases do
not occur, which is not the case.7
Metastases
A metastasis is a growth of the same cancer cell found at some distance from the primary tumor site.8 The metastasis may be large,
or it may be just a few cells that may be detected through polymerase chain reaction (PCR); however, the presence of metastasis
at diagnosis usually is associated with a poorer prognosis than a
Chisholm_Ch088_p1389-1420.indd 1392
patient with no known metastatic disease. As the technology to
detect malignant cells evolves, the dilemma exists on how to treat
patients based on current guidelines that were not based on cellular detection technology.
Cancers spread usually by two pathways: hematogenous
(through the bloodstream) or through the lymphatics (drainage
through adjacent lymph nodes). The malignant cells that split
from the primary tumor find a suitable environment for growth.
It is believed that malignant cells secrete mediators that stimulate
the formation of blood vessels for growth and oxygen, the process of angiogenesis. Common metastatic sites for solid tumors
include the brain, bone, lung, and liver.
PATHOPHYSIOLOGY
Tumor Origin
Tumors may arise from any of four basic tissue types: epithelial, connective (ie, muscle, bone, and cartilage), lymphoid, or nerve tissue.
The suffix -oma is added to the name of the cell type if the tumor cells
are benign. A lipoma is a benign growth that resembles fat tissue.
Precancerous cells have cellular changes that are abnormal
but not yet malignant and may be described as hyperplastic or
dysplastic. Hyperplasia occurs when a stimulus is introduced and
reverses when the stimulus is removed. Dysplasia is an abnormal
change in the size, shape, or organization of cells or tissues.
Malignant cells are divided into categories based on the cells of
origin. Carcinomas arise from epithelial cells, whereas sarcomas
arise from muscle or connective tissue. Adenocarcinomas arise
from glandular tissue. Carcinoma in situ refers to cells limited to
epithelial origin that have not yet invaded the basement membrane. Malignancies of the bone marrow or lymphoid tissue, such
as leukemias or lymphomas, are named differently.
Tumor Characteristics
Tumors are either benign or malignant. Benign tumors often
are encapsulated, localized, and indolent; they seldom metastasize; and they rarely recur once removed. Histologically, the cells
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CHAPTER 88 | CANCER PRINCIPLES AND THERAPEUTICS 1393
Patient Encounter 1, Part 1
The patient is a 71-year-old previously healthy man who has
had symptoms of fatigue, bright red blood when urinating
for 2 weeks and back pain. He has self-treated with over-thecounter (OTC) pain products without relief. Today, he presents
to his primary care provider for evaluation. His complete
blood count (CBC) reveals a hemoglobin level of 12.6 g/dL
and his PSA level is 22.4 ng/dL. He is referred to an urologist
for further evaluation.
After a prostate gland biopsy and subsequent computed
tomography (CT) and bone scans, a diagnosis of metastatic
prostate cancer is made and treatment is planned to start as
soon as possible.
What signs and symptoms does this patient have that are
consistent with a cancer presentation?
What is your desired outcome when treating this patient?
resemble the cells from which they developed. Malignant tumors
are invasive and spread to other locations even if the primary
tumor is removed. The cells no longer perform their usual functions, and their cellular architecture changes. This loss of structure
and function is called anaplasia. Despite improvements in screening procedures, many patients have metastatic disease at the time
of diagnosis. Usually, once distant metastases have occurred, the
cancer is considered incurable.9
DIAGNOSIS OF CANCER
Cancer can present as a number of different signs and symptoms. Unfortunately, many people fear a diagnosis of cancer
and may not seek medical attention at the first warning signs
when the disease is at its most treatable stage. After the initial visit with the clinician, a variety of tests will be performed,
which are somewhat dependent on the initial differential diagnoses. Appropriate laboratory tests, radiologic scans, and tissue
samples are necessary. The sample of tissue may be obtained
by a biopsy, fine-needle aspiration, or exfoliative cytology. No
treatment of cancer should be initiated without a pathologic
diagnosis of cancer. During the pathologic workup, genetic
analysis may be done. Depending on the type of cancer, the
genetic analysis can provide the additional information on
prognosis of the malignancy and whether certain therapies may
be appropriate.
Once the pathology of cancer is established, staging of the disease is done before treatment is initiated.
The basis of
cancer staging is tumor size, extent of lymph node involvement,
and the presence or absence of metastases, also referred to as the
tumor, nodes, metastases (TNM) system (Table 88–2),10 and is
usually referred to as stages I, II, III, or IV. Not all cancers can be
staged according to this system, but many of the solid tumors are.
Staging cancer is an important for determing prognosis and guiding treatment decisions.
Some cancers produce substances (eg, proteins) that are
detected by a blood test and may be useful in following response
to therapy or detecting a recurrence; these are referred to as
tumor markers. An example of a clinically used tumor marker
is the prostate-specific antigen (PSA). The PSA serum level is
used to monitor response to treatment. Unfortunately, some
tumor markers are nonspecific and may be elevated from nonmalignant causes. In the case of PSA, nonmalignant causes such
as prostatitis, trauma, surgery, ejaculation, some medications,
benign prostatic hypertrophy, or riding on an exercise bicycle
can all cause increased PSA levels, which needs to be considered when using tumor markers to assess cancer presence of
response.9
Clinical Presentation and Diagnosis: Cancer Chemotherapy and Treatment
Signs and Symptoms
The seven warning signs of cancer are:
•• Change in bowel or bladder habits
•• A sore that does not heal
•• Unusual bleeding or discharge
•• Thickening or lump in breast or elsewhere
•• Indigestion or difficulty in swallowing
•• Obvious change in a wart or mole
•• Nagging cough or hoarseness
The eight warning signs of cancer in children are:
•• Continued, unexplained weight loss
•• Headaches with vomiting in the morning
•• Increased swelling or persistent pain in bones or joints
•• Lump or mass in abdomen, neck, or elsewhere
•• Development of a whitish appearance in the pupil of the eye
•• Recurrent fevers not caused by infections
•• Excessive bruising or bleeding
•• Noticeable paleness or prolonged tiredness
Chisholm_Ch088_p1389-1420.indd 1393
Diagnostic Procedures
•• Laboratory tests: CBC, lactate dehydrogenase (LDH), renal
function, and liver function tests
•• Radiologic scans: X-rays, CT scans, magnetic resonance
imaging (MRI), positron emission tomography (PET)
•• Biopsy of tissue or bone marrow with pathologic
evaluation
•• Cytogenetics
•• Tumor markers
Staging determination of the primary tumor size, extent of
lymph node involvement, and the presence or absence of
metastases, referred to as the TNM system (see Table 88–2).
Most solid tumors are staged according to the TNM
classification system. The size of the primary tumor, extent
of nodal involvement, and the presence of metastases are
used to determine the stage. Metastases are cancer cells that
have spread to sites distant from the primary tumor site and
have started to grow. The most frequently occurring sites
of metastases of solid tumors are the brain, bone, liver, and
lungs.
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Table 88–2
Tumor (T), Node (N), Metastasis (M) Staging for Non–Small Cell Lung Cancer
Primary Tumor
Description
Tx
Primary tumor cannot be assessed or tumor proven by presence of malignant cells in sputum or
bronchial washings but not visualized by imaging or bronchoscopy
No evidence of primary tumor
Carcinoma in situ
Tumor under 3 cm in greatest dimension, surrounded by lung or visceral pleura, without invasion
more proximal than lobar bronchus
Minimally invasive adenocarcinoma
Superficial spreading tumor in central airways (spreading tumor of any size but confined to the
tracheal or bronchial wall) and tumor ≤ 1 cm in greatest dimension
Tumor > 1 cm but ≤ 2 cm in greatest dimension
Tumor > 2 cm but ≤ 3 cm in greatest dimension
Tumor > 3 cm but ≤ 5 cm, or tumor with any of the following features:
•• Involves main bronchus regardless of distance from the carina but without involvement of the carina
•• Invades visceral pleura
•• Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but
does not involve the entire lung
Tumor > 3 cm but ≤ 4 cm in greatest dimension
Tumor > 4 cm but ≤ 5 cm in greatest dimension
Tumor > 5 cm but ≤ 7 cm in greatest dimension of associated with separate tumor nodule(s) in
the same lobe as the primary tumor or directly invades any of the following structures:
•• chest wall (including the parietal pleura and superior sulcus)
•• phrenic nerve
•• parietal pericardium
Tumor > 7 cm in greatest dimension or associated with separate tumor nodules(s) in a different
ipsilateral lobe than that of the primary tumor or invades any of the following structures
•• diaphragm
•• mediastinum
•• heart
•• great vessels
•• trachea
•• recurrent laryngeal nerve
•• esophagus
•• vertebral body
•• carina
T0
Tis
T1
T1a (mi)
T1a
T2
T3
T1b
T1c
T2a
T2b
T4
Regional lymph nodes (N)
Nx
N0
N1
Regional lymph nodes cannot be assessed.
No regional lymph node metastases
Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary
nodes, including involvement by direct extension
Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or
supraclavicular lymph node(s)
N2
N3
Distant metastasis (M)
M0
M1
M1a
No distant metastasis
Distant metastasis
Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural
or pericardial effusion
Single extrathoracic metastasis
Multiple extrathoracic metastasis in one or more organs
M1b
M1c
Stage
Stage 0
Stage Ia
Stage Ib
Stage IIa
Stage IIb
Stage IIIa
Stage IIIb
Stage IIIc
Stage IVa
Stage IVb
T
Tis
T1a
T2a
T2b
T1, T2
T3
T1, T2
T3, T4
T4
T1, T2
T3, T4
T3, T4
Any T
Any T
N
N0
N0
N0
N0
N1
N0
N2
N1
N0
N3
N2
N3
Any N
Any N
M
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M1a or M1b
M1c
5-Year Survival (%)
92
68
60
53
36
26
13
10
0
From Detterbeck FC, Boffa DJ, Kim AW, Tanoue LT. The eighth edition lung cancer stage classification. Chest. 2017;151(1):193–203.
1394
Chisholm_Ch088_p1389-1420.indd 1394
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CHAPTER 88 | CANCER PRINCIPLES AND THERAPEUTICS 1395
TREATMENT
Desired Outcome
Surgery may be able to remove all macroscopic disease; however, microscopic cells may still be present near the surgical site
or may have traveled to other parts of the body. When malignant cells have traveled to other parts of the body and become
established there and are able to grow in this new environment,
they are called metastatic cancer cells. Thus, for chemotherapysensitive diseases, systemic therapies may be administered after
surgery to destroy these microscopic malignant cells; this is
called adjuvant chemotherapy. The goals of adjuvant chemotherapy are to decrease cancer recurrence by eliminating microscopic malignant cells and to prolong survival. Chemotherapy
may also be given before surgical resection of the tumor; this is
referred to as neoadjuvant chemotherapy. Chemotherapy given
before surgery should decrease the tumor burden to be removed
(which may result in a shorter surgical procedure or less physical disfigurement to the patient) and make the surgery easier to
perform because the tumor has shrunk away from vital organs
or vessels. Neoadjuvant chemotherapy also gives the clinician
an idea of the responsiveness of the tumor to that particular
chemotherapy.
Chemotherapy may be given to cure cancers, or it may be
given to help control the symptoms of an incurable cancer
(also known as palliation). Palliative care, however, is used
throughout therapy to prevent or treat, as early as possible, the
symptoms and side effects of the disease and treatment psychological, social, and spiritual problems. It consists of pharmacologic and nonpharmacologic treatments to improve quality
of life and is most effective when initiated at the time of other
treatments.11
Response
The responses to chemotherapy for solid tumors are described
as complete response (CR), partial response (PR), stable disease (SD), or disease progression. A cure in oncology implies
that the cancer is completely gone, and the patient will have the
same life expectancy as a patient without cancer. The response
evaluation criteria in solid tumors (RECIST) was developed in
2000 and revised in 2009 and is considered to be the standard
criteria to evaluate a response to therapy (Table 88–3).12 The
term overall objective response rate refers to all patients with
a PR or a CR.
Cancer cells may be sensitive to certain chemotherapy agents,
but with repeated exposure, the cells may become resistant to
treatment. The resistant cells then may grow and multiply. In
some cancers, a number of genetic mutations, including epidermal growth factor receptor (EGFR), reticular activating system
(RAS), and BRAF, may be used to predict which patients will be
sensitive to certain chemotherapy that targets these mutations.
These mutations will be discussed in depth in the following cancerspecific chapters.
Nonpharmacologic Therapy
The three primary treatment modalities of cancer are surgery,
radiation, and pharmacologic therapy. Surgery is useful to gain
tissue for diagnosis of cancer and for treatment, especially
those cancers with limited disease. Radiation plays a key role
not only in the treatment and possible cure of cancer but also
in palliative therapy. Together, surgery and radiation therapy
may provide local control of symptoms of the disease. However,
when cancer is widespread, surgery may play little or no role,
Chisholm_Ch088_p1389-1420.indd 1395
Table 88–3
RECIST 1.1 Criteria: Target Lesion Evaluation
Term
Description
Complete response
(CR)
Disappearance of all targeted lesions. All
pathological lymph nodes must have
decreased to < 10 mm in short axis
At least a 30% decrease in the sum of the
longest diameter (SLD) of target lesions
from baseline
SLD increased by at least 20% from the
smallest value on study (including
baseline, if that is the smallest)
The SLD must also demonstrate an
absolute increase of at least 5 mm. (Two
lesions increasing from 2 to 3 mm, for
example, do not qualify)
Neither sufficient shrinkage to qualify for
PR nor sufficient increase to qualify for
progressive disease
Partial response (PR)
Progressive disease
Stable disease (SD)
Adapted from Eisenhauer E, Therasse P, Bogaerts J, et al. New
response evaluation criteria in solid tumours: revised RECIST
guideline (version 1.1). Eur J Cancer. 2009;45:228–247.
but radiation therapy localized to specific areas may palliate
symptoms.
Pharmacologic Therapy
Chemotherapy of cancer started in the early 1940s when nitrogen
mustard was first administered to patients with lymphoma. Since
then, numerous agents have been developed for the treatment of
different cancers.
Dosing of Chemotherapy
Chemotherapeutic agents typically have a very narrow therapeutic index. If too much is administered, the patient may suffer from severe or even fatal toxicities. If too little is given, the
desired effect on cancer cells may not be achieved. Many chemotherapy agents have significant organ toxicities that preclude
using steadily increasing doses to treat the cancer. The doses
of chemotherapy must be given at a frequency that allows the
patient to recover from the toxicity of the chemotherapy; each
period of chemotherapy dosing is referred to as a cycle. Each
cycle of chemotherapy may have the same dosages; the dosages
may be modified based on toxicity; or a chemotherapy regimen
may alternate from one set of drugs given during the first, third,
and fifth cycles to another set of different drugs given during the
second, fourth, and sixth cycles. Dose density of chemotherapy
refers to shortening of the period between cycles of chemotherapy. This can accomplish two things: first, the tumor has less time
between cycles of chemotherapy to grow, and second, patients
receive the total number of required cycles in a shorter time
period. Administration of dose-dense chemotherapy regimens
often requires the use of colony-stimulating factors (eg, filgrastim
or granulocyte–colony stimulating factor [G-CSF], pegfilgrastim)
to be administered. These agents shorten the duration and severity of neutropenia. The chemotherapy regimens that are dose
dense tend to be adjuvant regimens, and the goal of therapy is
cure. When a chemotherapy regimen is used as palliation (to control symptoms), the dosages of chemotherapy may be decreased
11/10/21 4:42 PM
1396 SECTION 16 | ONCOLOGIC DISORDERS
Table 88–4
Performance Status Scales
Karnofsky
Scale (%)
Zubrod Scale
(ECOG)
Description: ECOG Scale
No complaints; no evidence of disease
Able to carry on normal activity; minor signs or
symptoms of disease
Normal activity with effort; some signs or symptoms
of disease
100
90
0
Fully active, able to carry on all predisease activity
80
1
Cares for self; unable to carry on normal activity or to
do active work
Requires occasional assistance but is able to care for
most personal needs
70
Restricted in strenuous activity but ambulatory
and able to carry out work of a light or sedentary
nature
2
Requires considerable assistance and frequent
medical care
Disabled; requires special care and assistance
50
Out of bed > 50% of time; ambulatory and
capable of self-care but unable to carry out any
work activities
3
Severely disabled; hospitalization indicated, although
death not imminent
Very sick; hospitalization necessary; requires active
supportive treatment
Moribund; fatal processes progressing rapidly
Dead
30
In bed > 50% of time; capable of only limited
self-care
20
4
10
0
Bedridden; cannot carry out any self-care;
completely disabled
5
Deceased
Description: Karnofsky Scale
60
40
ECOG, Eastern Cooperative Oncology Group.
based on toxicity or the interval between cycles may be lengthened
to maintain quality of life.
Patient and tumor biology also affect how cancer therapy
is dosed. Patients with a uridine diphosphate–glucuronosyltransferase 1A1 enzyme (UGT1A1*28) deficiency can have lifethreatening diarrhea and complications from irinotecan related to
a decreased ability to metabolize the parent drug. The patient may
have a blood test before irinotecan therapy to determine if this
genetic mutation is present. In the case of some monoclonal antibodies and targeted agents, flow cytometry results reveal whether
the tumor has the receptor where the drug will bind and exert the
pharmacologic effect.13 The therapeutic uses of oncology drugs
with valid genomic biomarkers, called targeted therapies, will be
discussed briefly in this chapter and in more detail in the following chapters.
Another consideration of chemotherapy administration is the
patient. Factors that affect chemotherapy selection and dosing
are age, concurrent disease states, and performance status. Performance status can be assessed either with the Eastern Cooperative Oncology Group (ECOG) Scale or the Karnofsky Scale
(Table 88–4). Performance status is a very important prognostic
factor for many types of cancer. If a patient has renal dysfunction and the chemotherapy is eliminated primarily by the kidney,
dosing adjustments will need to be made. If a patient has had a
myocardial infarction recently or preexisting heart disease, the
clinician will weigh the risks of anthracycline therapy against the
benefit of the treatment of the cancer.
Another important consideration for treatment of cancers is
insurance coverage for off-label use. Off-label use is when a medication is used to treat a cancer that is not an FDA-approved indication. Because of rapid advancements in oncology, it is estimated
that up to 75% of chemotherapy agents are prescribed “off-label.”
Drugs used according to FDA-approved indications are usually
paid for by insurance. If sufficient supportive literature exists and
Chisholm_Ch088_p1389-1420.indd 1396
the use is supported by one of the Medicare-approved compendia
(eg, AHFS-DI, Clinical Pharmacology, Micromedex DrugDex,
and National Comprehensive Cancer Network [NCCN] Compendium), an insurer should cover the cost of the anticancer
treatment that does not have an FDA indication.
During the time of chemotherapy administration, patients
will likely experience various toxicities. The National Cancer
Institute (NCI) has provided a standardized system for evaluating and grading the toxicity from chemotherapy to provide
uniform grading of toxicity and evaluation of new agents and
regimens (Table 88–5).14
Combination Chemotherapy
The underlying principles of using combination therapy are to
use (a) agents with different pharmacologic actions, (b) agents
with different organ toxicities, (c) agents that are active against
the tumor and ideally synergistic when used together, and
(d) agents that do not result in significant drug interactions
(although these can be studied carefully and the interactions
addressed). When two or more agents are used together, the
risk of development of resistance may be lessened, but toxicity
may be increased.
Traditional chemotherapy agents have some similar
side effects, usually manifested on the most rapidly proliferating
cells of the body. However, there are unique toxicities of various
pharmacologic categories of antineoplastic agents. Anthracyclines (eg, doxorubicin) have the potential to cause cardiac toxicity, which is related to the cumulative dose. Microtubule-targeting
agents (eg, vincristine) are associated with various forms of neurotoxicity. Alkylating agents (eg, melphalan) are associated with
secondary malignancies.
Currently, anticancer agents are categorized by their mechanism of action. As depicted in Figure 88–3, different agents work
in different parts of the cell.15
11/10/21 4:42 PM
CHAPTER 88 | CANCER PRINCIPLES AND THERAPEUTICS 1397
Table 88–5
Selected National Cancer Institute Common Toxicity Criteria
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
General
Neutropenia
Mild
Lowest baseline:
1500/mm3
(1.5 × 109/L)
Lowest baseline:
75,000/mm3
(75 × 109/L)
Increase of less than
four stools per
day over baseline
or mild increase
in ostomy output
compared to
baseline
Moderate
< 1500–1000/mm3
(1.5–1 × 109/L)
Severe
< 1000–500/mm3
(1–0.5 × 109/L)
Life-threatening
< 500/mm3 (0.5 × 109/L)
–
< 75,000–50,000/mm3
(75–50 × 109/L)
< 50,000–25,000/mm3
(50–25 × 109/L)
< 25,000 mm3 (25 × 109/L)
–
Life-threatening
consequences (eg,
hemodynamic collapse);
urgent intervention
indicated
Death
Life-threatening
consequences; urgent
operative intervention
indicated
–
Death
Life-threatening
consequences
Death
Thrombocytopenia
Diarrhea
Esophagitis
Nausea
Vomiting
Increase of four to six
Increase of greater than
stools per day over
or equal to seven stools
baseline; moderate
per day over baseline;
increase in ostomy
hospitalization; severe
output compared with increase in ostomy
baseline; limiting ADLs output compared with
baseline; limiting self-care
ADL
Asymptomatic clinical Symptomatic altered
Severely altered eating
or diagnostic only;
eating or swallowing;
or swallowing; tube
intervention not
oral supplements
feedings, or TPN or
indicated
indicated
hospitalization indicated
Loss of appetite
Oral intake decreased
Inadequate oral caloric
without alteration in without significant
or fluid intake; tube
eating habits
weight loss,
feedings, TPN or
dehydration, or
hospitalization indicated
malnutrition
> 24 hours
Intervention not
Outpatient intravenous Tube feeding, TPN, or
indicated
hydration; medical
hospitalization indicated
intervention indicated
–
ADL, activity of daily living; IV, intravenous; TPN, total parenteral nutrition.
National Cancer Institute, Division of Cancer Treatment and Diagnosis | CTEP. Common Terminology Criteria for Adverse Events (CTCAE).
Available from: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf (accessed
October 14, 2020).
Table 88–6 lists the currently FDA-approved anticancer drugs
by drug class and name. The next section will describe the most
commonly used anticancer agents or those with unique mechanisms of action.
Antimetabolites: Pyrimidine Analogues
▶▶
5-Fluorouracil and Capecitabine
5-Fluorouracil (5-FU) is a fluorinated analogue of the pyrimidine uracil. Once administered, this prodrug is metabolized by
Patient Encounter 1, Part 2
The decision to treat the patient with a systemic hormonal
and chemotherapy regimen is made. He will be receiving
the standard regimen of leuprolide 22.5 mg intramuscularly
every 12 weeks indefinitely and docetaxel 75 mg/m2/day
(intravenous) IV infusion over 60 minutes on day 1 every
21 days × six cycles.
Before initiating this chemotherapy regimen in the patient,
what patient-specific issues need to be addressed?
What adverse effects will the patient likely experience with
these two drugs?
Chisholm_Ch088_p1389-1420.indd 1397
dihydropyrimidine dehydrogenase (DPD). 5-Fluorouracil ultimately is metabolized to fluorodeoxyuridine monophosphate
(FdUMP), which interferes with the function of thymidylate
synthase (TS), a requirement of thymidine synthesis. The triphosphate metabolite of 5-fluorouracil is incorporated into
ribonucleic acid (RNA) to produce the second cytotoxic effect.
Inhibition of TS occurs with the continuous infusion regimens,
whereas the triphosphate form is associated with bolus administration. Capecitabine is an orally active prodrug of 5-fluorouracil
and is enzymatically converted to 5-fluorouracil, sharing the
same mechanism of action. Patients with a low activity of DPD
appear to be at risk for life-threatening toxicities. Folates, such as
leucovorin, increase the stability of FdUMP–TS inhibition and
enhance the drug activity in certain cancers. These agents have
clinical activity in several solid tumors and are frequently used to
treat both breast and colon cancer. The most common toxicities
include myelosuppression when administered by intravenous
(IV) bolus and palmar–plantar erythrodysesthesia, and diarrhea,
when administered as continuous IV infusion or orally. Palmar–
plantar erythrodysesthesia, also called hand–foot syndrome
(HFS), refers to redness, itching, and blistering of the palms of
the hands and soles of the feet. Patients should be counseled to
notify the prescriber when this adverse effect occurs. Significant
increases in international normalization ratio (INR) and prothrombin time may occur within several days when capecitabine
is initiated in patients concomitantly receiving warfarin. The INR
11/10/21 4:42 PM
1398 SECTION 16 | ONCOLOGIC DISORDERS
6-MERCAPTOPURINE
6-THIOGUANINE
Purine
synthesis
Pyrimidine
synthesis
HYDROXYUREA
Inhibits ribonucleotide reductase
Inhibit purine ring biosynthesis
5-FLUOROURACIL
Ribonucleotides
Inhibit DNA synthesis
Inhibits thymidylate synthesis
PEMETREXED
METHOTREXATE
GEMCITABINE
CYTARABINE
FLUDARABINE
2-CHLORODEOXYADENOSINE
CLOFARABINE
Deoxyribonucleotides
Inhibit dihydrofolate reduction,
block thymidylate and
purine synthesis
Inhibits DNA synthesis
CAMPTOTHECINS
ETOPOSIDE
TENIPOSIDE
DAUNORUBICIN
DOXORUBICIN
PLATINUM ANALOGUES
ALKYLATING AGENTS
MITOMYCIN
TEMOZOLOMIDE
DNA
Block topoisomerase function
Form adducts with DNA
L-ASPARAGINASE
PROTEIN KINASE INHIBITORS
ANTIBODIES
RNA
(transfer, messenger, ribosomal)
Inhibits protein synthesis
Block activities of signaling pathways
IMMUNE CHECKPOINT
INHIBITORS
Block immune evasion
HORMONE ANTAGONISTS
Inhibit receptor function & expression
Deaminates asparagine
Proteins
Enzymes
Receptors
Microtubules
Response Differentiation
to antigens
Hormone
receptors
EPOTHILONES
TAXANES
VINCA ALKALOIDS
ESTRAMUSTINE
Inhibit function of microtubules
ATRA
ARSENIC TRIOXIDE
HISTONE DEACETYLASE INHIBITORS
Induce differentiation
FIGURE 88–3. The mechanisms of action of commonly used antineoplastic agents. (Reproduced with permission from Wellstein A.
General Principles of Chemotherapy. In: Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman’s The Pharmacologic Basis of
Therapeutics, 13th ed. New York, NY: McGraw-Hill; 2017.)
should be monitored closely or the patient may be switched to a
low-molecular-weight heparin. Other drug interactions can also
occur. Patients should be instructed to take capecitabine within
30 minutes after a meal to increase absorption of the drug.
▶▶
Cytarabine
Cytarabine is a structural analogue of cytosine and is phosphorylated intracellularly to the active triphosphate form, which inhibits
DNA polymerase. The triphosphate form also may be incorporated into DNA to result in chain termination to prevent DNA
elongation. The drug may be administered as a low-dose continuous infusion, high-dose intermittent infusion, and into the subdural space via intrathecal or intraventricular administration. A
liposomal formulation is also available for less frequent administration into the central nervous system (CNS). Cytarabine is
eliminated by the kidneys with a renal clearance of 90 mL/min
(1.5 mL/s). Cytarabine has shown efficacy in the treatment of
acute leukemias and some lymphomas. The toxicities of cytarabine in high doses include myelosuppression; cerebellar syndrome
(ie, nystagmus, dysarthria, and ataxia); and chemical conjunctivitis, an eye irritation that requires prophylaxis with steroid eye
drops. The risk of neurotoxicity is increased with high doses
(more than 1 g/m2), advanced age, and renal dysfunction. If cerebellar toxicity does occur, the drug needs to be discontinued
Chisholm_Ch088_p1389-1420.indd 1398
immediately, and decisions regarding further therapy need to be
carefully considered.16
▶▶
Gemcitabine
Gemcitabine is a deoxycytidine analogue that is structurally
related to cytarabine. Gemcitabine inhibits DNA polymerase
activity and ribonucleotide reductase to result in DNA chain
elongation. Gemcitabine has activity in several solid tumors and
some lymphomas. The toxicities include myelosuppression; flulike syndrome with fevers during the first 24 hours after administration; rash that appears 48 to 72 hours after administration; and
hemolytic uremic syndrome, a rare but life-threatening adverse
effect. Patients should be counseled to use acetaminophen to treat
the fevers during the first 24 hours; however, fevers occurring 7 to
10 days after gemcitabine are likely to be febrile neutropenia and
need prompt treatment with broad-spectrum antibiotics.
▶▶
Azacitidine and Decitabine
Azacitidine and decitabine are nucleoside analogues approved
for the treatment of patients with myelodysplastic syndrome
(MDS), a hematopoietic disorder that can transform into acute
myeloid leukemia (AML). Both of these agents cause cytotoxicity by directly incorporating in the DNA and inhibiting DNA
methyltransferase, which causes hypomethylation of DNA.
11/10/21 4:42 PM
CHAPTER 88 | CANCER PRINCIPLES AND THERAPEUTICS 1399
Table 88–6
Anticancer Drugs
Drug Class
Alkylating agents
Alkyl sulfonate
Nitrogen mustards
Nitrosoureas
Nonclassical
Platinum complexes
Triazenes and hydrazine
Anthracene derivatives
Antitumor antibiotics
Antimetabolites
Cytidine deaminase
inhibitor
Folate Antagonists
Purine analogs
Pyrimidine analogs
Histone deacetylase (HDAC)
inhibitors
Hormonal therapies
Antiandrogens
Androgen receptor antagonist
Antiestrogens
Aromatase inhibitors
Chisholm_Ch088_p1389-1420.indd 1399
Drug Name
Busulfan
Bendamustine
Chlorambucil
Cyclophosphamide
Ifosfamide
Melphalan
Mechlorethamine
Carmustine
Lomustine
Lurbinectedin
Mitomycin C
Thiotepa
Trabectedin
Carboplatin
Cisplatin
Oxaliplatin
Dacarbazine
Procarbazine
Temozolomide
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Mitoxantrone
Bleomycin
Drug Class
CYP17 inhibitor
Luteinizing hormone–releasing
hormone agonist
Luteinizing hormone–releasing
hormone antagonist
Immunomodulatory agents
Immunotherapy
Cell-based immunotherapy
CAR T cell
Checkpoint inhibitors
Miscellaneous immune
therapies
Microtubule-targeting agents
Taxanes
Vinca alkaloids
Cedazuridine
Methotrexate
Pemetrexed
Pralatrexate
Cladribine
Clofarabine
Fludarabine
6-Mercaptopurine
Pentostatin
Thioguanine
Azacitidine
Capecitabine
Cytarabine
Decitabine
5-Fluorouracil
Gemcitabine
Nelarabine
Trifluridine/(tipiracil)a
Belinostat
Panobinostat
Romidepsin
Tazemetostat
Vorinostat
Bicalutamide
Flutamide
Nilutamide
Apalutamide
Darolutamide
Enzalutamide
Raloxifene
Tamoxifen
Anastrozole
Exemestane
Letrozole
Other
Miscellaneous agents
Monoclonal antibodies
Drug Name
Abiraterone acetate
Goserelin
Leuprolide
Degarelix
Lenalidomide
Pomalidomide
Thalidomide
Sipuleucel-T
Tisagenlecleucel
Axicabtagene ciloleucel
Brexucabtagene autoleucel
Atezolizumab
Avelumab
Cemiplimab
Durvalumab
Ipilimumab
Nivolumab
Pembrolizumab
Interferons
Aldesleukin
Cabazitaxel
Docetaxel
Paclitaxel
Vinblastine
Vincristine
Vinorelbine
Eribulin
Estramustine
Ixabepilone
Asparaginase
Arsenic trioxide
Bexarotene
Calaspargase pegol
Hydroxyurea
Liposome encapsulated
doxorubicin-cytarabine
Omacetaxine mepesuccinate
Pegaspargase
Tagraxofusp
Tretinoin
Ziv-aflibercept
Alemtuzumab
Bevacizumab
Blinatumomab
Cetuximab
Daratumumab
Dinutuximab
Elotuzumab
Emapalumab
Isatuximab
Mogamulizumab
Obinutuzumab
Ofatumumab
Olaratumab
Necitumumab
Panitumumab
Pertuzumab
Ramucirumab
Rituximab
Tafasitamab
Trastuzumab
(Continued)
11/10/21 4:42 PM
1400 SECTION 16 | ONCOLOGIC DISORDERS
Table 88–6
Anticancer Drugs (Continued)
Drug Class
Antibody–drug conjugate
Drug Name
Drug Class
Trastuzumab and hyaluronidase
Ado-trastuzumab emtansine
Brentuximab vedotin
Belantamab mafodotin
Fam-trastuzumab deruxtecan
Inotuzumab ozogamicin
Gemtuzumab ozogamicin
Moxetumomab pasudotox
Polatuzumab vedotin
Sacituzumab govitecan
Ibritumomab tiuxetan
Hedgehog pathway inhibitors
Antibody–
radioimmunotherapy conjugate
Topoisomerase inhibitors
Camptothecin derivatives
Irinotecan
Topotecan
Epipodophyllotoxins
Etoposide
Tyrosine kinase inhibitors
Anaplastic lymphoma kinase Alectinib
(ALK)
Brigatinib
Ceritinib
Crizotinib
Lorlatinib
B-cell lymphoma 2 (Bcl-2)
Venetoclax
BCR-ABL
Bosutinib
Dasatinib
Imatinib
Nilotinib
Ponatinib
BRAF
Cobimetinib
Dabrafenib
Encorafenib
Vemurafenib
Bruton’s tyrosine kinase (BTK) Acalabrutinib
Ibrutinib
Zanubrutinib
Cyclin-dependent kinase (CDK) Abemaciclib
Palbociclib
Ribociclib
Epidermal growth factor
Afatinib
receptor (EGFR)
Dacomitinib
Erlotinib
Gefitinib
Osimertinib
Vandetanib
EGFR/HER2
Lapatinib
Neratinib
Tucatinib
Drug Name
Glasdegib
Sonidegib
Vismodegib
Fibroblast growth factor
Erdafitinib
receptor (FGFR)
Pemigatinib
Isocitrate dehydrogenase 2
Enasidenib
(IDH2)
Ivosidenib
Janus-associated kinase (JAK)
Fedratinib
Ruxolitinib
Binimetinib
Capmatinib
Mitogen-activated extracellular Cobimetinib
kinase (MEK)
Selumetinib
Trametinib
Multikinase
Axitinib
Brigatinib
Cabozantinib
Gilteritinib
Lenvatinib
Midostaurin
Pazopanib
Pexidartinib
Regorafenib
Ripretinib
Sorafenib
Sunitinib
Vandetanib
Mammalian target of rapamycin Everolimus
(mTOR)
Temsirolimus
Neurotrophic tyrosine receptor Entrectinib
kinase (NTRK)
Larotrectinib
Phosphoinositide 3-kinase (PI3K) Alpelisib
Copanlisib
Duvelisib
Idelalisib
Platelet-derived growth factor
Avapritinib
receptor (PDGFR)
Pralsetinib
Poly ADP ribose polymerase
Niraparib
(PARP)
Olaparib
Rucaparib
Bortezomib
Proteasome inhibitors
Carfilzomib
Ixazomib
Selpercatinib
RET tyrosine kinase (RET)
Selinexor
Selective inhibitor of nuclear
export antagonist
Tipiracil is a thymidine phosphorylase inhibitor used to increase bioavailability of trifluridine.
a
Hypomethylation of DNA appears to normalize the function
of the genes that control cell differentiation and proliferation
to promote normal cell maturation. Major side effects reported
are myelosuppression and infections. Most recently an oral formulation of azacitidine was approved by the FDA.17,18 Additionally, a combination product of an oral formulation of decitabine,
along with the cytidine deaminase inhibitor cedazuridine, was
approved for use in MDS. Cedazuridine prevents the breakdown
of decitabine, thereby increasing its bioavailability and efficacy.
Adverse events of these oral hypomethylating agents are similar
to their IV counterparts.
Chisholm_Ch088_p1389-1420.indd 1400
Antimetabolites: Purine Analogues
▶▶
Mercaptopurine
6-Mercaptopurine (6-MP) is an oral purine analogue that is
converted to ribonucleotides that inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are
catabolized by thiopurine S-methyltransferase (TPMT). TPMT is
subject to genetic polymorphisms and may cause severe myelosuppression; therefore, TPMT status may be assessed before
therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. 6-MP is used in the treatment
11/10/21 4:42 PM
CHAPTER 88 | CANCER PRINCIPLES AND THERAPEUTICS 1401
of acute lymphocytic leukemia (ALL) and chronic myeloid leukemia (CML). Significant side effects include myelosuppression,
mild nausea, skin rash, cholestasis, and rarely, veno-occlusive
disease. Mercaptopurine is metabolized by xanthine oxidase, an
enzyme that is inhibited by allopurinol. This represents a major
drug–drug interaction. To avoid toxicities of mercaptopurine
when these drugs are used concomitantly, the dose of mercaptopurine must be reduced by 66% to 75%.
▶▶
Fludarabine
Fludarabine is an analogue of the purine adenine. It interferes
with DNA polymerase to cause chain termination and inhibits transcription by its incorporation into RNA. Fludarabine is
dephosphorylated rapidly and converted to 2-fluoro-Ara-AMP
(2-FLAA), which enters the cells and is phosphorylated to
2-fluoro-Ara-ATP, which is cytotoxic. Fludarabine is used in the
treatment of chronic lymphocytic leukemia (CLL), some lymphomas, and refractory AML. Significant and prolonged myelosuppression may occur, along with immunosuppression, so patients
are susceptible to opportunistic infections. Prophylactic antibiotics and antivirals are recommended until cluster of differentiation
(CD) 4 counts return to normal. Mild nausea and vomiting and
diarrhea have been observed. Rarely, interstitial pneumonitis has
occurred.
Antimetabolites: Folate Antagonists
Folates carry one-carbon groups in transfer reactions required for
purine and thymidylic acid synthesis. Dihydrofolate reductase is
the enzyme responsible for supplying reduced folates intracellularly for thymidylate and purine synthesis.
▶▶
Methotrexate
Methotrexate inhibits dihydrofolate reductase of both malignant
and nonmalignant cells. When high doses of methotrexate are
given, the “rescue drug” leucovorin, a reduced folate, is administered to bypass the methotrexate inhibition of dihydrofolate
reductase of normal cells and is usually initiated 24 hours after
methotrexate administration. This is done to prevent potentially
fatal myelosuppression and mucositis. For safety purposes, the
term folinic acid, another term used for leucovorin, should
not be used because of the potential for a medication error in
which folic acid might be given instead. Methotrexate concentrations should be monitored to determine when to stop leucovorin administration. Generally, leucovorin administration
may be stopped when methotrexate concentrations decrease to
5 × 10−8 M, although this may vary by the chemotherapy regimen. Higher doses of methotrexate may place an individual at
risk for methotrexate to crystallize in the acidic environment of
the urine, often resulting in acute renal failure and decreased
methotrexate clearance. Administration of IV hydration with
sodium bicarbonate to maintain urinary pH greater than or
equal to 7 is necessary to prevent methotrexate-induced renal
dysfunction. Methotrexate is eliminated by tubular secretion;
therefore, concomitant drugs (eg, probenecid, salicylates, penicillin G, and ketoprofen) that may inhibit or compete for tubular secretion should be avoided. Methotrexate doses must be
adjusted for renal dysfunction and close monitoring of methotrexate concentrations is advised. In patients with toxic levels
of methotrexate (> 1 μmol/L) because of impaired renal function, the antidote glucarpidase can be administered. However,
efficacy can be compromised so it is not used in patients with
normal or slightly elevated levels. Side effects of methotrexate
Chisholm_Ch088_p1389-1420.indd 1401
include myelosuppression, nausea and vomiting, and mucositis.
Methotrexate may also be administered via the intrathecal route
or via an Ommaya reservoir in very low doses as small as 12 mg,
so it is crucial for the clinician to know the correct dose by the
correct route in order to avoid substantial toxicity. The methotrexate used for intrathecal and intraventricular injection must
be preservative-free to prevent CNS toxicity.
▶▶
Pemetrexed
Pemetrexed inhibits four pathways in thymidine and purine
synthesis. Pemetrexed has shown activity in the treatment of
mesothelioma and non–small cell lung cancer (NSCLC). Side
effects include myelosuppression, rash, diarrhea, and nausea
and vomiting. Patients should receive folic acid and cyanocobalamin to reduce bone marrow toxicity and diarrhea. Doses of
folic acid of at least 400 mcg/day starting 7 days before treatment and continuing throughout therapy, as well as for 21 days
after the last pemetrexed dose, have been used.18 Cyanocobalamin 1000 mcg is given intramuscularly the week before pemetrexed and then every three cycles thereafter. Dexamethasone
4 mg twice daily the day before, the day of, and the day after
pemetrexed administration helps to decrease the incidence and
severity of rash.
Microtubule-Targeting Agents
▶▶
Vinca Alkaloids (Vincristine, Vinblastine, and
Vinorelbine)
The vinca alkaloids (vincristine, vinblastine, and vinorelbine)
are derived from the periwinkle (vinca) plant and cause cytotoxicity by binding to tubulin, disrupting the normal balance
between polymerization and depolymerization of microtubules,
and inhibiting the assembly of microtubules, which interferes
with the formation of the mitotic spindle. As a result, cells are
arrested during the metaphase of mitosis. The vinca alkaloids
are used in several malignancies, primarily hematologic. Even
though these agents have similar structures, the incidence and
severity of toxicities vary. The dose-limiting toxicity of vincristine is neurotoxicity, which can consist of depressed tendon reflexes, paresthesias of the fingers and toes, toxicity to
the cranial nerves, or autonomic neuropathy (constipation or
ileus, abdominal pain, and/or orthostatic hypotension). In contrast, the dose-limiting toxicity associated with vinorelbine and
vinblastine is myelosuppression. All of the vinca alkaloids are
vesicants and can cause tissue damage; therefore, extravasation
needs to be prevented. Biliary excretion accounts for a significant portion of elimination of vincristine and its metabolites, so
doses need to be adjusted for obstructive liver disease.
Vincristine, vinblastine, and vinorelbine have similar sounding names, which is a potential cause of medication errors. As
with all chemotherapy prescribing, dispensing, and administration, the clinician must be very careful with sound-alike, lookalike medications. Unfortunately, vincristine has been involved
in numerous cases of fatal chemotherapy errors, including
inadvertent intrathecal administration. When administered
intrathecally, widespread tissue damage and potentially deaths
can occur. An example of a strategy that health systems can
use to decrease the likelihood of an error such as this is for
the pharmacy to only dispense vincristine in a mini-bag for
IV administration. Many clinicians cap IV vincristine doses at
2 mg to prevent severe neuropathic side effects; however, if the
intent of chemotherapy is curative, the vincristine dose may be
dosed above the 2-mg cap.19
11/10/21 4:42 PM
1406 SECTION 16 | ONCOLOGIC DISORDERS
vector containing anti-CD19 CAR transgene. The transduced
T cells are then expanded and formulated into a suspension that is
cryopreserved. Once passing a sterility test, it is shipped back in a
patient-specific infusion bag to the institution for administration.
Axicabtagene ciloleucel is approved for large B-cell lymphoma;
brexucabtagene autoleucel is approved for mantle cell lymphoma;
and tisagenlecleucel is approved for us in ALL and diffuse large
B-cell lymphoma. The most common side effect is a cytokinerelease syndrome (CRS), which can be fatal. CRS occurs when the
cytokines are released by activated T cells, producing a systemic
inflammatory response. Patients may initially present with a lowgrade fever, fatigue, and anorexia which can quickly progress to
high fever, hypoxia, and organ failure. Immediate identification
and treatment is necessary to prevent death. Another potentially
serious side effect is neurotoxicity which often manifests within
4 to 10 days and can be mild such as headache and dizziness but
can progress to delirium, aphasia, seizures, and encephalopathy.
NCCN has guidelines on monitoring and treating CRS, neurologic symptoms, and other CAR T-cell therapy toxicities.25 Other
side effects include decreased appetite, headache, nausea/vomiting,
infections, and diarrhea.
Many monoclonal antibodies now have biosimilar products
approved in the United States for cancer treatment. A biosimilar is a type of biological product that is highly similar to the
originator product and is expected to have no meaningful clinical difference. They are thought to be interchangeable from the
innovator product. New biologics approved by the FDA now
have a four-letter suffix to differentiate innovator and biosimilar
products.
Monoclonal Antibodies
Bevacizumab is a humanized monoclonal antibody that binds
to vascular endothelial growth factor (VEGF), which prevents it
from binding to its receptors, ultimately resulting in inhibition
of angiogenesis. Bevacizumab has shown clinical activity in the
treatment of breast, colorectal, glioblastoma, gynecologic, head
and neck, kidney, and lung cancer. Patients treated with bevacizumab products may develop hypertension requiring chronic
medication during therapy. Impaired wound healing, thromboembolic events, proteinuria, bleeding, and bowel perforation are
serious side effects that occur with this drug.
The cell surface contains molecules, which are referred to as CD.
The antibodies are produced against a specific antigen. When
administered, usually by an IV injection, the antibody binds to
the antigen, which may trigger the immune system to result in
cell death through complement-mediated cellular toxicity, or the
antigen–antibody cell complex may be internalized to the cancer cell, which results in cell death. Monoclonal antibodies may
also carry radioactivity, sometimes referred to as hot antibodies,
and are referred to as radioimmunotherapy, so the radioactivity is
delivered to the cancer cell. Antibodies that contain no radioactivity are referred to as cold antibodies.
All monoclonal antibodies end in the suffix -mab. The syllable before -mab indicates the source of the monoclonal antibody (Table 88–7).26 When administering an antibody for the
first time, one should consider the source. The less humanized
an antibody, the greater the chance for the patient to have an
allergic-type reaction to the antibody. The more humanized the
antibody, the lower the risk of a reaction. The severity of the reactions may range from fever and chills to life-threatening allergic
reactions. Premedication with acetaminophen and diphenhydramine is common before the first dose of any antibody. If a severe
reaction occurs, the infusion should be stopped and the patient
treated with antihistamines, corticosteroids, or other supportive
measures.
Table 88–7
Syllable Source Indicators for Monoclonal Antibodiesa
U
O
Xi
Axo
Xizu
Human
Mouse
Chimeric: A cross between humanized and animal source
Rat/mouse hybrid
Combination of humanized and chimeric chains
These letters appear before mab, which stands for monoclonal
antibody.
Data from American Medical Association. Monoclonal Antibodies.
Available from: https://www.antibodysociety.org/wordpress/
wp-content/uploads/2017/07/INN-2017-Reference-20.pdf (accessed
October 10, 2020).
a
Chisholm_Ch088_p1389-1420.indd 1406
▶▶
Alemtuzumab
Alemtuzumab is an antibody to the CD52 receptor present on B
and T lymphocytes. Alemtuzumab has shown clinical activity in
the treatment of CLL. Severe and prolonged (6 months) immunosuppression may result, which necessitates Pneumocystis jiroveci
pneumonia (PJP) prophylaxis and antifungal and antiviral prophylaxis to prevent opportunistic infections. Infusion-related
reactions typically occur with the first dose and can be severe.
Premedication with antihistamines and acetaminophen is recommended. SC administration will also alleviate the severity of infusion reactions.
▶▶
▶▶
Bevacizumab
Blinatumomab
Blinatumomab is a bispecific CD19-directed CD3 T-cell therapy.
It activates T cells by connecting the CD3 antigen in the receptor complex with the CD19 surface antigen on both benign and
malignant B cells, activating inflammatory cytokine release and
T-cell proliferation resulting in apoptosis of CD19+ cells. It is
effective in patients with Philadelphia negative B-cell precursor
ALL. Common side effects include pyrexia, neutropenia, infections, and infusion-related reactions. Patients should receive
dexamethasone before infusion and when restarting an infusion if interrupted for more than 4 hours. Rare but serious side
effects include CRS and neurologic toxicity, such as paresthesia,
confusion, dizziness, and tremor. Thus, patients are typically hospitalized for the first cycle and first 2 days of the second cycle.
Medication errors can occur when preparing and administering
blinatumomab because preparation instructions are more complicated than most other IV drugs. Doses are based on weight,
dose, and duration of infusion. Additionally, specific instructions
for use of an IV solution stabilizer are provided rather than mixing with the drug for reconstitution and the volume for infusion.
▶▶
Cetuximab, Necitumumab, and Panitumumab
Cetuximab is a chimeric antibody that binds to the EGFR to
block its stimulation. Panitumumab binds to the EGFR to prevent receptor autophosphorylation and activation of receptorassociated kinases, which results in inhibition of cell growth and
induction of apoptosis. Necitumumab is an anti-EGFR recombinant human monoclonal antibody. Cetuximab has shown clinical
activity in the treatment of colorectal and head and neck cancers,
necitumumab in non–small cell lung cancer, and panitumumab
11/10/21 4:42 PM
1402 SECTION 16 | ONCOLOGIC DISORDERS
▶▶
Taxanes (Cabazitaxel, Docetaxel, Nanoparticle
Albumin-Bound Paclitaxel, and Paclitaxel)
Taxane plant alkaloids are similar to the vinca alkaloids, exhibiting cytotoxicity during the M phase of the cell cycle by binding
to tubulin. Unlike the vinca alkaloids, however, the taxanes do
not interfere with tubulin assembly. Rather, the taxanes promote
microtubule assembly and inhibit microtubule disassembly. Once
the microtubules are polymerized, the taxanes stabilize against
depolymerization.
Hepatic metabolism and biliary excretion account for
the majority of paclitaxel’s elimination. Paclitaxel has demonstrated activity in several solid tumors. The diluent for
paclitaxel, Cremophor EL, is composed of ethanol and castor oil. Infusions must be prepared and administered in non–
polyvinyl chloride–containing bags and tubing, and solutions
must be filtered. Patients receive dexamethasone, diphenhydramine, and an histamine (H)2 blocker to prevent hypersensitivity reactions caused by Cremophor EL. Patients also may
have asymptomatic bradycardia during the infusion. Approximately 3 to 5 days after administration, patients may complain
of myalgias and arthralgias that may last several days. Myelosuppression, flushing, neuropathy, ileus, and total-body alopecia are other common side effects. Because paclitaxel is a
substrate for cytochrome P450 (CYP)-3A4, patients receiving
phenytoin (a strong CYP3A4 inducer) had lower steady-state
concentration of paclitaxel than patients not receiving phenytoin and this combination should be avoided. In addition,
paclitaxel clearance is decreased by 33% when it was administered after cisplatin, so for regimens containing both agents,
paclitaxel is administered before cisplatin.
A nanoparticle albumin-bound nab-paclitaxel product is also
available for the treatment of metastatic breast cancer resistant to
conventional chemotherapy. The nab-paclitaxel formulation uses
nanotechnology to combine human albumin with paclitaxel allowing for the delivery of an insoluble drug in the form of nanoparticles. This unique formulation allows for an increased bioavailability
and higher intracellular concentrations of the drug. It does not have
the serious hypersensitivity reactions encountered with paclitaxel
solubilized in Cremophor EL, so premedication with H1 and H2
blockers and steroids is not necessary. Also, a significantly lower
incidence of severe neutropenia occurs with nab-paclitaxel. The
dose is infused over 30 minutes and does not require a special IV
bag, tubing, or filter. The dosing of this product is also different
from that of the original paclitaxel and the formulation needs to
be clearly indicated when prescribed. The pharmacokinetics of the
albumin-bound paclitaxel displays a higher clearance and larger
volume of distribution than paclitaxel. The drug is eliminated primarily via fecal excretion. Bone marrow suppression, neuropathy,
ileus, arthralgias, and myalgias still occur.
Docetaxel has activity in the treatment of several solid tumors.
Dexamethasone, 8 mg twice daily for 3 days starting the day before
treatment, is used to prevent the fluid-retention syndrome associated with docetaxel and possible hypersensitivity reactions. The
fluid-retention syndrome is characterized by edema and weight
gain that is unresponsive to diuretic therapy and is associated with
cumulative doses greater than 800 mg/m2. Myelosuppression,
alopecia, and neuropathy are other side effects associated with
docetaxel treatment.
Cabazitaxel is a newer taxane used in combination with prednisone for the treatment of metastatic hormone-refractory prostate cancer. Cabazitaxel has shown to have similar adverse effects
as paclitaxel and docetaxel. Premedication with an antihistamine,
Chisholm_Ch088_p1389-1420.indd 1402
corticosteroid, and H2 antagonist to prevent hypersensitivity reactions is required.
▶▶
Eribulin
Eribulin mesylate is a nontaxane microtubule dynamics inhibitor. It is a synthetic analogue of halichondrin B, which is a
product isolated from the sea sponge Halichondria okadai.
While taxanes inhibit cell division by stabilizing microtubules,
eribulin arrests the cell cycle through inhibition of the growth
phase of microtubules without interfering with microtubule
shortening. The cytotoxicity results from its effects via a tubulin-based antimitotic mechanism, resulting in G2/M cell cycle
arrest and mitotic blockage. Apoptotic cell death results from
prolonged mitotic blockage. Eribulin mesylate is an IV medication that is specifically indicated for the treatment of patients
with metastatic breast cancer and liposarcoma. The most common adverse effects reported are neutropenic fever, anemia,
asthenia or fatigue, alopecia, peripheral neuropathy, nausea,
and constipation. Eribulin has been reported to cause significant neutropenia and QTc interval prolongation. It has vesicant
properties. Dosages should be adjusted in renal and hepatic
impairment.
▶▶
Ixabepilone
Ixabepilone, an epothilone analogue, binds to β-tubulin subunits on microtubules, which results in suppression of microtubule dynamics. Ixabepilone is primarily eliminated by the liver
by oxidation through the CYP3A4 system. Ixabepilone, in combination with capecitabine or alone if resistant to capecitabine,
is indicated for the treatment of metastatic or locally advanced
breast cancer. Studies have shown a possible synergy when used
in combination with capecitabine. Side effects include hypersensitivity reactions, myelosuppression, and peripheral neuropathy. To minimize the occurrence of hypersensitivity reactions,
patients must receive both H1 and H2 antagonists before therapy.
If a reaction still occurs, corticosteroids should be added to the
premedications.
Topoisomerase Inhibitors
Topoisomerase is responsible for relieving the pressure on the
DNA structure during unwinding by producing strand breaks.
Topoisomerase I produces single-strand breaks, whereas topoisomerase II produces double-strand breaks.
▶▶
Epipodophyllotoxins (Etoposide)
Etoposide is a semisynthetic podophyllotoxin derivative that
inhibits topoisomerase II, causing multiple DNA double-strand
breaks. Etoposide has shown activity in the treatment of several
types of lymphoma, testicular and lung cancer, retinoblastoma,
and carcinoma of unknown primary. Oral bioavailability is
approximately 50%, so oral dosages are approximately two times
those of IV doses. It should be slowly administered to prevent
hypotension. Side effects include mucositis, myelosuppression,
alopecia, phlebitis, hypersensitivity reactions, and secondary leukemias. Hypersensitivity reactions are caused by the solubilizing
agents, polysorbate 80 and may be life-threatening.
▶▶
Camptothecin Derivatives (Irinotecan and Topotecan)
Irinotecan and topotecan, both camptothecins, inhibit the topoisomerase I enzyme to interfere with DNA synthesis through the
active metabolite SN-38. Topoisomerase I enzymes stabilize DNA
single-strand breaks and inhibit strand resealing. Irinotecan has
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CHAPTER 88 | CANCER PRINCIPLES AND THERAPEUTICS 1403
shown activity in the treatment of cancers of the colon, rectum,
cervix, and lung. Irinotecan-induced diarrhea is a serious complication and may be life-threatening. One form of diarrhea (early)
can occur during or immediately after the infusion. This is a
result of a cholinergic process in which the patient may experience facial flushing, diaphoresis, and abdominal cramping. IV
atropine should be administered to treat diarrhea that occurs any
time during the first 24 hours of administration. Another form
of diarrhea (late) can occur several days after administration and
can result in severe dehydration. This adverse effect should be
treated immediately with loperamide at a dosage of 2 mg every
2 hours or 4 mg every 4 hours until diarrhea has stopped for
12 hours. Other side effects include myelosuppression, fatigue,
and alopecia. Individuals homozygous for UGT1A1*28 have an
increased risk of febrile neutropenia and diarrhea and should be
considered for an empiric dose reduction of one level; heterozygotes should receive closer monitoring, including more frequent
CBCs to detect myelosuppression.
Topotecan has shown clinical activity in the treatment of ovarian and lung cancer, MDS, and AML. The IV infusion may be
scheduled daily for 5 days or once weekly. Side effects include
myelosuppression, mucositis, and diarrhea. Diarrhea is less common than with irinotecan.
Anthracene Derivatives
▶▶
Daunorubicin, Doxorubicin, Idarubicin, and Epirubicin
Anthracyclines (daunorubicin, doxorubicin, idarubicin, and epirubicin) are also referred to as antitumor antibiotics or topoisomerase inhibitors when considering their mechanism of action. All
of the anthracyclines contain a four-membered anthracene ring,
a chromophore, with an attached sugar portion. This chromophore results in red-orange urine after administration, which is
an important counseling point for patients. Free radicals formed
from the anthracyclines combine with oxygen to form superoxide, which can make hydrogen peroxide. These agents are able to
insert between base pairs of DNA to cause structural changes in
DNA. However, the primary mechanism of cytotoxicity appears
to be the inhibition of topoisomerase II. These drugs are widely
used in a variety of cancers.
Oxygen-free-radical formation is a cause of cardiac damage
and extravasation injury, which is common with these drugs.
The anthracyclines can cause cardiac toxicity as manifested by
a congestive heart failure or cardiomyopathy symptomatology,
alopecia, nausea or vomiting, mucositis, myelosuppression, and
urinary discoloration. These drugs are vesicants.
To reduce the risk of cardiotoxicity associated with doxorubicin, the maximum lifetime cumulative dose is 550 mg/m2; similarly, the other anthracyclines have maximum lifetime cumulative
doses. Ventricular ejection fractions should be measured before
therapy and periodically if therapy is continued. Therapy should
be halted if there is a 10% to 20% decrease from baseline in ejection fraction. Patients at increased risk of cardiotoxicity include
patients reaching the upper limit of cumulative lifetime dose;
those taking concomitant or previous cardiotoxic drugs, concurrent paclitaxel, or bolus administration; patients with preexisting
cardiac disease or mediastinal radiation; and the very young and
elderly. Cardioprotectants (eg, dexrazoxane) have been used to
decrease risk in some cases. Clinical guidelines for cardioprotective agents’ use are available.20
Liposomal doxorubicin is an irritant, not a vesicant, and is
dosed differently from doxorubicin and formulation must be
clearly specified when prescribing. Liposomal doxorubicin may
Chisholm_Ch088_p1389-1420.indd 1403
also be less cardiotoxic than doxorubicin. Liposomal doxorubicin has significant activity in the treatment of breast and ovarian
cancer along with multiple myeloma (MM) and Kaposi sarcoma.
Side effects include mucositis, myelosuppression, alopecia, and
palmar–plantar erythrodysesthesia.
Liposomal daunorubicin is also available but only in a combination product with liposomal cytarabine used in the treatment
of AML. This product uses a synergistic ratio of daunorubicin to
cytarabine (1:5) in a liposomal formulation to enhance exposure
within the bone marrow. The dosing of this drug is different than
traditional daunorubicin and cytarabine.
▶▶
Mitoxantrone
Mitoxantrone is a royal blue–colored anthracenedione that inhibits DNA topoisomerase II. Mitoxantrone has clinical activity in
the treatment of acute leukemias, breast and prostate cancer, and
non-Hodgkin lymphomas with myelosuppression, mucositis,
nausea and vomiting, and cardiac toxicity its major adverse effect.
The total cumulative dose limit is 160 mg/m2 for patients who
have not received prior anthracycline or mediastinal radiation.
Patients with prior doxorubicin or daunorubicin therapy should
not receive a cumulative dose greater than 120 mg/m2 of mitoxantrone. Patients should be counseled that their urine will turn
a blue-green color.
Alkylating Agents
Although still widely used for many malignancies, the alkylating agents are the oldest class of anticancer drugs. The agents
cause cytotoxicity via transfer of their alkyl groups to nucleophilic groups of proteins and nucleic acids. The major site of
alkylation within DNA is the N7 position of guanine, although
alkylation does occur to a lesser degree at other bases. These
interactions can either occur on a single strand of DNA
(monofunctional agents) or on both strands of DNA through a
cross-link (bifunctional agents), which leads to strand breaks.
The major toxicities of the alkylating agents are myelosuppression, alopecia, nausea or vomiting, sterility or infertility, and
secondary malignancies.
▶▶
Nitrogen Mustards (Cyclophosphamide
and Ifosfamide)
Cyclophosphamide and ifosfamide are bifunctional alkylating
agents with similar adverse effects and activity and are used in
a variety of solid and hematologic cancers. Both are prodrugs,
requiring activation by mixed hepatic oxidase enzymes to phosphoramide and ifosfamide mustard. During the activation process, additional byproducts (acrolein and chloroacetaldehyde)
are formed. Acrolein has no cytotoxic activity but is responsible
for the hemorrhagic cystitis associated with ifosfamide and
high-dose cyclophosphamide. Acrolein produces cystitis by
directly binding to the bladder wall. Prophylaxis is necessary
with aggressive hydration, administration of 2-mercaptoethane sulfonate sodium (mesna, which binds to and inactivates
acrolein in the bladder), frequent voiding, and monitoring in
patients receiving ifosfamide and high-dose cyclophosphamide.
Patients should be counseled to drink plenty of fluids; void
frequently; and report any hematuria, irritation, or flank pain.
Dosing regimens of mesna range from an equal milligram dose
to the ifosfamide mixed in the same IV bag to 20% of the dose
administered before ifosfamide and 20% of the dose repeated at
4 and 8 hours after the ifosfamide dose.
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1404 SECTION 16 | ONCOLOGIC DISORDERS
Chloroacetaldehyde, a metabolite of ifosfamide, can result in
encephalopathy, especially in patients with renal dysfunction or
advanced age. This adverse effect can occur within 48 to 72 hours
of administration and is usually reversible.
▶▶
Busulfan
Busulfan is an alkylating agent that forms DNA–DNA and DNA–
protein cross-links to inhibit DNA replication. Oral busulfan is
well absorbed, has a terminal half-life of 2 to 2.5 hours, and is
eliminated primarily by hepatic metabolism. It is also available
in an IV formulation, which is commonly used for high doses, to
reduce pill burden. Busulfan has significant clinical activity in the
treatment of AML and CML and has been used as a conditioning
regimen before hematopoietic stem cell transplantation (HSCT).
Side effects include bone marrow suppression; hyperpigmentation of skin creases; and rarely, pulmonary fibrosis. High doses
used for HSCT preparatory regimens can cause severe nausea and
vomiting, tonic–clonic seizures, and sinusoidal obstruction syndrome and require anticonvulsant prophylaxis. A discussion of
busulfan adaptive dosing can be found in Chapter 98.
▶▶
Nitrosoureas (Carmustine and Lomustine)
Carmustine (BCNU) and lomustine (CCNU) are lipophilic nitrosureas that can cross the blood–brain barrier. Carmustine may
be administered IV or as a biodegradable wafer formulation that
is implanted during surgical resection of brain tumors. Lomustine is available in an oral formulation. Carmustine has shown
clinical activity in the treatment of lymphoma, MM, and brain
tumors. Lomustine has shown clinical activity in the treatment of
non-Hodgkin lymphoma and brain tumors. Side effects include
myelosuppression, severe nausea and vomiting, and pulmonary
fibrosis with long-term therapy.
▶▶
Nonclassic Alkylating Agents (Dacarbazine
and Temozolomide)
Although the exact mechanism of action remains unclear,
dacarbazine and temozolomide appear to inhibit DNA, RNA,
and protein synthesis. Dacarbazine is used to treat melanoma,
Hodgkin lymphoma, and soft tissue sarcomas. Side effects
include myelosuppression, severe nausea and vomiting, and a
flu-like syndrome that starts about 7 days after treatment and
lasts 1 to 3 weeks.
Temozolomide is a well-absorbed orally active agent that
also crosses the blood–brain barrier. Temozolomide is converted via pH-dependent hydrolysis to the active metabolite
5-(3-methyltriazeno)-imidazole-4-carboxamide. Temozolomide
may be used in the treatment of melanoma, refractory anaplastic
astrocytoma, and glioblastoma multiforme. Nausea may be minimized by administering the drug at bedtime. Because patients
receiving temozolomide may have confusion secondary to their
brain tumors and dosing can consist of multiple capsule sizes,
care must be taken by all providers to simplify regimens to prevent chemotherapy overdose.21
▶▶
Procarbazine
Although the exact mechanism of action of procarbazine is
unknown, it does inhibit DNA, RNA, and protein synthesis.
Procarbazine is used most often in the treatment of lymphoma.
Myelosuppression is the major side effect. Nausea, vomiting,
and a flu-like syndrome occur initially with therapy. Patients
must be counseled to avoid tyramine-rich foods because procarbazine is a monoamine oxidase inhibitor. Patients should be
Chisholm_Ch088_p1389-1420.indd 1404
provided a list of foods and beverages to avoid a hypertensive
crisis. A disulfiram-like reaction can occur with the ingestion
of alcohol.
Heavy Metal Compounds
Platinum drugs form reactive platinum complexes that bind
to cells, so the pharmacokinetics of the individual drug may
be of the platinum, both free and bound, rather than of the
parent drug.
▶▶
Cisplatin
Cisplatin forms inter- and intrastrand DNA cross-links to inhibit
DNA synthesis. Cisplatin has clinical activity in the treatment
of numerous tumor types and remains front-line therapy for
lung and ovarian cancers. Cisplatin is highly emetogenic, even
when low doses are given daily for 5 days, and causes delayed
nausea and vomiting as well; patients require aggressive antiemetic regimens for both delayed and acute emesis. Significant
nephrotoxicity and electrolyte abnormalities can occur if inadequate hydration occurs. Ototoxicity, which manifests as a highfrequency hearing loss, and a glove-and-stocking neuropathy
may limit therapy.
▶▶
Carboplatin
Carboplatin has the same mechanism of action as cisplatin; however, its side effects are similar but less intense than those of cisplatin. Many chemotherapy regimens dose carboplatin based on
an area under the curve (AUC), also called the Calvert equation.
According to the Calvert equation for adults, the dose in milligrams of carboplatin = (creatinine clearance [CrCl] + 25) × AUC
desired, where CrCl is expressed in mL/min.22 Carboplatin has
shown clinical activity in the treatment of several solid tumors
and lymphoma. Thrombocytopenia, nausea and vomiting, and
hypersensitivity reactions are common adverse effects.
▶▶
Oxaliplatin
Oxaliplatin is commonly used to treat colorectal cancer. Its
adverse effect profile is similar to cisplatin with hypersensitivity reactions and moderate nausea and vomiting commonly
observed.23 In addition, oxaliplatin can cause cold-induced
neuropathy. Patients should be counseled to avoid cold beverages, to use gloves to remove items from the freezer, and to
wear protective clothing in cold climates for the first week after
treatment. A glove-and-stocking neuropathy also occurs with
long-term administration.
Miscellaneous Agents
▶▶
Bleomycin
Bleomycin is a mixture of peptides with drug activity expressed
in units, where 1 U equals to 1 mg. Bleomycin causes DNA strand
breakage. Bleomycin has activity in testicular cancer and malignant
effusions, squamous cell carcinomas of the skin, and Kaposi sarcoma. Hypersensitivity reactions and fever may occur, so premedication with acetaminophen may be required. The most serious side
effect of bleomycin is pulmonary toxicity that presents as a pneumonitis with a dry cough, dyspnea, rales, and infiltrates. Pulmonary
function studies show decreased carbon monoxide diffusing capacity and restrictive ventilatory changes. “Bleomycin lung” is associated with cumulative dosing greater than 400 U and occurs rarely
with a total dose of 150 U and is potentiated by thoracic radiation
and by hyperoxia. Additional side effects include fever with or without chills, mild-to-moderate alopecia, and nausea and vomiting.
11/10/21 4:42 PM
CHAPTER 88 | CANCER PRINCIPLES AND THERAPEUTICS 1405
Bleomycin is also used to manage malignant plural effusions at
doses of 15 to 60 U through installation into the affected area. The
drainage tube of the effusion is clamped off for some period of time
after administration of bleomycin and then the amount of drainage
is monitored to determine efficacy of the treatment.23
▶▶
Hydroxyurea
Hydroxyurea is an oral drug that inhibits ribonucleotide reductase, which converts ribonucleotides into the deoxyribonucleotides used in DNA synthesis and repair. Hydroxyurea has activity
in CML, polycythemia vera, sickle cell disease, and thrombocytosis. The major side effects are myelosuppression, nausea and
vomiting, diarrhea, and constipation. Rash, mucositis, and renal
tubular dysfunction occur rarely.
▶▶ l-Asparaginase
l-Asparaginase is an enzyme that may be produced by Escherichia
coli. Asparaginase hydrolyzes the reaction of asparagine to aspartic acid and ammonia to deplete lymphoid cells of asparagine,
which inhibits protein synthesis. l-Asparaginase has activity in
ALL and childhood AML. Severe allergic reactions may occur
when the interval between doses is 7 days or greater, so while
a skin test result may be negative, patients should be observed
closely after asparaginase administration. If the patient suffers
an allergic reaction to l-asparaginase, alternatively formulated
agents, such as pegaspargase or calaspargase pegol, may be given.
These drugs include l-asparaginase modified through a linkage with polyethylene glycol or monomethoxypolyethylene glycol, respectively, which extends the half-life and allows for lower
doses and less-frequent administration. Cost and limited availability limit their use in the front line setting.
▶▶
Tretinoin
Tretinoin, also referred to as all-trans-retinoic acid (ATRA), is
used to treat acute promyelocytic leukemia (APL). ATRA is a
retinoic acid that is not cytotoxic but promotes the maturation
of early promyelocytic cells that have the charatersitic t(15;17)
translocation. A severe side effect of ATRA is retinoic acid syndrome, which may occur anytime during treatment and consists
of fever, respiratory distress, and hypotension. Chest radiographs
are consistent with a pneumonia-like process and it is important
to differentiate pneumonia from APL syndrome, as the treatment
for retinoic acid syndrome is dexamethasone 10 mg IV every
12 hours, which may be detrimental to administer to a neutropenic patient with pneumonia.
▶▶
Immunomodulatory Agents (Thalidomide,
Lenalidomide, and Pomalidomide)
Thalidomide was initially approved in Europe on October 1, 1957, as
a sedative–hypnotic. Some children born to women who had taken
thalidomide were born with severe limb deformities (phocomelia)
which led to its removal from the market. Thalidomide was subsequently identified an angiogenesis inhibitor, with clinical activity in
the treatment of MM. Patients receiving thalidomide are enrolled
in the Risk Evaluation and Mitigation Strategies (REMS) program
and counseled on the risks of phocomelia should they become pregnant. Common adverse effects include somnolence, constipation,
peripheral neuropathy, and deep vein thrombosis (DVT). Recommendations for DVT prophylaxis for all thalidomides is based upon
a risk-assessment model whereby prophylaxis with low-molecularweight heparin or dose-adjusted warfarin is recommended for
high-risk patients and aspirin for low-risk patients.24
Chisholm_Ch088_p1389-1420.indd 1405
Lenalidomide is approved for the treatment of MDS when the
5q deletion is present and MM. Because lenalidomide is an analogue of thalidomide, all of the same precautions must be taken
to prevent phocomelia. However, lenalidomide has fewer adverse
effects than thalidomide. Dosing adjustments are necessary for
renal dysfunction. Other side effects are neutropenia, thrombocytopenia, DVT, and pulmonary embolus.
Pomalidomide is also used in treatment of refractory or progressive MM and Kaposi’s sarcoma. Similar precautions to prevent phocomelia are also required. Adverse effects include
myelosuppression and infections. The use of the immunomodulatory agents in the treatment of MM is discussed thoroughly in
Chapter 96.
▶▶
Omacetaxine Mepesuccinate
Omacetaxine mepesuccinate is an alkaloid from Cephalotaxus
harringtonia. The agent reversibly inhibits protein synthesis, causing cell death in both malignant and nonmalignant cells. It is a
subcutaneous (SC) injection and is indicated for the treatment of
CML patients (including those patients with the T315I mutation)
showing resistance and/or intolerance to two or more tyrosine
kinase inhibitors (TKIs). The most common nonhematological
adverse effects are gastrointestinal (GI) disruption, fatigue, and
hyperglycemia. Rare but serious adverse reactions include febrile
neutropenia, infections, and cerebral hemorrhage.
▶▶
Histone Deacetylase (HDAC) Inhibitors
(Belinostat, Panobinostat, Romidepsin,
Tazemetostat, and Vorinostat)
Histone deacetylase (HDAC) inhibitors agents catalyze the
removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. Belinostat,
romidepsin, and vorinostat are used for the treatment of cutaneous T-cell lymphoma; panobinostat for MM; and tazemetostat
for epithelioid sarcoma and follicular lymphoma. Panobinostat,
tazemetostat, and vorinostat are orally available agents, and belinostat and romidepsin are only available in an IV formulation.
These drugs are metabolized by CYP3A4 and have potential drug
interactions strong CYP3A inducers and inhibitors. Side effects
include fatigue, myelosuppression, and GI toxicities. Tazemetostat and vorinostat are associated with hypercholesterolemia,
hypertriglyceridemia, and hyperglycemia. Despite anemia,
thrombocytopenia, and neutropenia, patients receiving vorinostat have developed pulmonary embolism and DVT while on
therapy. Panobinostat carries a boxed warning for severe diarrhea
(occurring in 25% of patients) and cardiac events, severe arrhythmia and electrocardiogram changes that can be exacerbated by
electrolyte abnormalities. Tazemetostat has a risk of a developing
a second primary hematologic malignancy.
Immunotherapy
▶▶
Chimeric Antigen Receptor (CAR) T-Cell Therapies
(Axicabtagene ciloleucel, Brexucabtagene autoleucel,
Tisagenlecleucel)
One of the newer immunotherapy classes is the chimeric antigen
receptor (CAR) T-cell therapies that are autologous T-cell immunotherapies comprising T cells that are genetically modified using
a vector to encode an anti-CD19 CAR. Axicabtagene ciloleucel,
brexucabtagene autoleucel and tisagenlecleucel are prepared
from the patient’s own peripheral mononuclear cells, which are
obtained through a leukapheresis procedure.18 The cells are sent
to a laboratory whereby they are enriched with the lentiviral
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CHAPTER 88 | CANCER PRINCIPLES AND THERAPEUTICS 1407
in colorectal cancers. Tumors that have RAS mutations do not
respond to treatment with cetuximab or panitumumab; therefore, tumors should be tested for RAS mutations before initiating therapy. An acne-like rash may appear on the face and upper
torso 1 to 3 weeks after the start of therapy. Preventive therapies
with topical corticosteroids with moisturizer, sunscreen, and oral
doxycycline are recommended. Other side effects include hypersensitivity reactions, fever, nausea and vomiting, and interstitial
lung disease. Electrolyte disturbances, such as hypomagnesemia
and hypocalcemia, can occur; these are more common with necitumumab and panitumumab.
▶▶
Daratumumab and Isatuximab
Daratumumab and isatuximab are monoclonal antibodies to the
CD38 receptor, highly expressed on myeloma cells and weakly
on other hematopoietic stem cells. They are used in patients with
MM. Infusion-related reactions are common so patients must be
pretreated with acetaminophen, an antihistamine, and IV methylprednisolone. Additionally, with daratumumab, an oral corticosteroid is administered for each of the 2 days following infusion
to prevent delayed reactions. Also, these drugs also interact with
cross matching and red blood cell antibody screening, by causing
a positive indirect Coombs test that can persist for 6 months after
discontinuation of therapy. Thus, patients should be typed and
screened before therapy, and blood banks should be informed
when a patient has received either of these drugs.
▶▶
Elotuzumab
Elotuzumab is a humanized recombinant monoclonal antibody
that specifically targets signaling lymphocytic activation molecule family member 7 protein. It works by directly activating
natural killer cells to mediate the killing of myeloma cells through
antibody-dependent cellular cytotoxicity (ADCC). Premedications to prevent infusion-related reactions should include dexamethasone, H1 blocker, H2 blocker, and acetaminophen. The most
common side effects are fatigue, diarrhea, pyrexia, constipation,
and cough.
▶▶
Obinutuzumab, Ofatumumab, and Rituximab
Obinutuzumab, ofatumumab, and rituximab are monoclonal
antibodies to the CD20 receptor expressed on the surface of B
lymphocytes; the presence of the antibody is determined during
flow cytometry of the tumor cells. Cell death results from ADCC.
All of these drugs have shown clinical activity in the treatment
of B-cell lymphomas that are CD20 positive. Side effects include
infusion-related reactions, hypotension, fevers, chills, rash, headache, and mild nausea and vomiting. Premedication with acetaminophen and an antihistamine is recommended for rituximab
to minimize the first-dose infusion reaction. Acetaminophen,
an antihistamine, and a glucocorticoid are administered prior to
obinutuzumab and ofatumumab. In patients with extensive disease, prevention of tumor lysis syndrome is also recommended.
Serious adverse events, including fatal infections, progressive
multifocal leukoencephalopathy, and reactivation of hepatitis B,
have been reported. Thus, all patients should be tested for hepatitis B
and treated before therapy commences.
▶▶
Pertuzumab, Trastuzumab, and
Trastuzumab/Hyaluronidase
Pertuzumab and trastuzumab-based products are humanized
monoclonal antibodies directed against human epidermal receptor
2 (HER-2). When compared to trastuzumab products, pertuzumab
Chisholm_Ch088_p1389-1420.indd 1407
recognizes different extracellular epitopes, binds uniquely, which
causes structural changes and, therefore, interrupts receptor dimerization. These differences were thought to be able to provide greater
inhibition of HER-2 when compared to trastuzumab, but this has
not been proven to be the case. Cancer tissue must be tested for
the presence of HER-2 because patients who do not express HER-2
do not respond to trastuzumab. Trastuzumab hyaluronidase is
trastuzumab combined with an enzyme hyaluronidase-oysk that
allows the drug to be delivered subcutaneously, reducing potential
for infusion-related reactions and shorter administration. Trastuzumab-products and pertuzumab are used for certain patients with
HER-2 positive breast cancers; trastuzumab (but not all products)
can also be used in other solid tumors that are HER-2 positive (eg,
gastric cancer). Trastuzumab products are not interchangeable and
may have different dose, schedules, and indications.
Severe congestive heart failure may occur with concurrent
HER-2 monoclonal antibody and anthracycline administration.
Cardiac toxicity may be seen when the drug is administered
months after anthracycline administration, so patients must be
counseled on the signs and symptoms of heart failure. A common
side effect associated with trastuzumab is a first-dose infusionrelated reaction which includes chills. The patient may be given
acetaminophen and diphenhydramine and/or the infusion may
be slowed. Other side effects that are rare include hypersensitivity
reactions, abnormal liver function tests, and pulmonary reactions.32
Pertuzumab has similar adverse effects as trastuzumab. When
used in combination with trastuzumab, it does not appear to
increase the incidence of cardiac toxicity. A more detailed discussion of the use of trastuzumab products and pertuzumab in breast
cancer can be found in Chapter 89.
Antibody Conjugates
Antibody conjugates contain both an antibody and either a drug
or radioisotope. In many cases, the antibody is used as a drug
vehicle to deliver an anticancer agent either an antineoplastic
agent or the radioisotope. In some cases, a linking agent is also
used to link the antibody and anticancer drug. Antibody–drug
conjugates are often referred to as ADCs.
▶▶
Ado-Trastuzumab Emtansine (Trastuzumab
Emtansine) and Fam-Trastuzumab Deruxtecan
Ado-trastuzumab emtansine combines trastuzumab and the anticancer agent emtansine (a maytansine derivative). Fam-trastuzumab
deruxtecan is composed of fam-trastuzumab (which has same
basic structure of trastuzumab), a topoisomerase I inhibitor
exatecan derivative (DXd), and a compound that links the drugs,
deruxtecan. The most common serious adverse effect with adotrastuzumab emtansine was thrombocytopenia. The platelet nadir
usually occurs about 7 days after treatment and recovers within a
week. Other side effects are similar to trastuzumab products. See
more detail in Chapter 89.
▶▶
Belantamab Mafodotin
Belantamab mafodotin is composed of the monoclonal antibody
belantamab directed against B-cell maturation antigen (BMCA)
and the conjugate mafodotin, an auristatin analogue and microtubule inhibitor monomethyl auristatin phenylalanine (MMAF)
that has antineoplastic activity. It is used in MM. It has boxed
warning regarding corneal epithelium changes including severe
vision loss and corneal ulcer. Ophthalmologic exams are, therefore, required at baseline and throughout therapy. Additionally
infusion-related reactions and fatigue may occur.
11/10/21 4:42 PM
1408 SECTION 16 | ONCOLOGIC DISORDERS
▶▶
Brentuximab Vedotin
Brentuximab vedotin is a CD30-directed antibody, a microtubule
disrupting agent called monomethyl auristatin E (MMAE), and
a protease-cleavable linker that covalently attaches MMAE to
the antibody. It is reported that the cytotoxic activity is a result
of the binding of the ADC to CD30-expressing cells followed by
internalization of the ADC–CD30 complex, and then proteolytic
cleavage and release of MMAE into the cell. Binding of MMAE to
tubulin disrupts the microtubule network, resulting in cell cycle
arrest and apoptosis. This IV agent is indicated for some Hodgkin
lymphoma and non-Hodgkin lymphoma patients. In vitro data
suggests that MMAE is a substrate and an inhibitor of CYP3A4/5;
therefore, patients need to be monitored for drug–drug interactions. The most common adverse effects are neutropenia, peripheral neuropathy, fatigue, nausea and vomiting, diarrhea, anemia,
thrombocytopenia, and upper respiratory infection.
▶▶
Ibritumomab Tiuxetan
Ibritumomab tiuxetan, a “hot antibody,” is linked to yttrium and
binds to the CD20 receptor of B lymphocytes. Hematologic toxicity may occur several weeks after administration and may take
weeks to resolve.
▶▶
Polatuzumab Vedotin
Polatuzumab vedotin is an ADC directed against CD79B via a
proteas-cleavable peptide linker to MMAE, an auristatin derivative and potent microtubule inhibitor. This drug is used for
diffuse large B-cell lymphoma and is associated with myelosuppression, peripheral neuropathy, serious infections, and infusionrelated reactions. Thus, an antihistamine and antipyretic are used
for premedications and patients should receive prophylaxis for
herpes virus and PJP.
▶▶
Sacituzumab Govitecan
Sacituzumab govitecan is an antibody against tumor-associated
calcium signal transducer 2 linked to an irinotecan metabolite,
SN-38. This drug is indicated for metastatic triple-negative breast
cancer. It is has boxed warnings for neutropenia and severe diarrhea. It is associated with nausea, anorexia, fatigue, and infusionrelated reactions. Prior to each dose, premedicate with antipyretics
and H1/H2 antagonists; corticosteroids may be administered if an
infusion-related reaction occurred with a prior dose that required
premedications. Patients with UGT1A1*28 deficiency are at an
increased risk of neutropenia and other adverse events.
Checkpoint Inhibitors
The immune system is in a continual state of balance between tolerating “normal” tissue and attacking foreign substances. Immunological tolerance is regulated by immune cells, suppressive
cytokines, and immune checkpoint pathways.27 Immune checkpoints become involved following immune activation, creating
an inhibitory feedback loop to reduce involvement of normal tissues. Inhibitors of the immune checkpoints act by inhibiting key
regulatory steps, promoting activation and proliferation of T cells
to induce tumor infiltration and regression. Tumor responses
to checkpoint inhibitors differ from those observed with other
anticancer therapies. Responses can be seen long after the start
of treatment, and pseudoprogression can be seen immediately
after starting therapy which, instead of representing a tumor
progression, can represent inflammation only within the tumor
area. Checkpoint inhibitors are now approved for use not only in
many solid tumors but also in some hematologic tumors and can
Chisholm_Ch088_p1389-1420.indd 1408
be administered alone or in combination with each other, chemotherapy and targeted therapies.
Adverse effects of checkpoint inhibitors are related to their
effect on the immune system, whereby they attack normal cells
as well. This can result in severe and fatal immune-mediated
adverse reactions, including enterocolitis, hepatitis, toxic epidermal necrolysis, neuropathy, pneumonitis, and endocrine abnormalities. Thus a physical examination and review of systems is
important to quickly identify and treat toxicity. Complete blood
counts (CBCs) with differentials, comprehensive metabolic panel,
and liver function tests should be performed at baseline and cortisol and thyroid function tests periodically. Patients should be
monitored for symptoms of inflammatory responses (eg, diarrhea
as early sign of colitis, shortness of breath as early sign of pneumonitis). These symptoms can occur during treatment or weeks
to months after discontinuation of the drug. If any of these reactions occur, treatment should be initiated with systemic corticosteroids, which are tapered once symptoms improve, and the drug
should be held until symptoms resolve. Severe toxicities require
permanent discontinuation. Unlike other anticancer agents, dose
reductions are not used as a toxicity management strategy with
checkpoint inhibitors. Typically, these side effects can be more
severe with the cytotoxic T lymphocyte–associated antigen 4
(CTLA-4) inhibitor than PD-1 or PD-ligand (PD-L)-1 inhibitors.
NCCN publishes guidelines for management of immunotherapy
toxicities and more details can be found in the Supportive Care
(Chapter 99).25
▶▶
Ipilimumab
Ipilimumab is a recombinant, human monoclonal antibody that
binds to the CTLA-4, which is a molecule on T cells that causes
a suppression of the immune response. CTLA-4 is a negative
regulator of T-cell activation. Ipilimumab binds to CTLA-4 and
blocks the interaction of CTLA-4 with its ligands. This blockage
has been reported to enhance T-cell activation and proliferation.
The antitumor effects appear to be T-cell–mediated immune
responses and are the highest with this drug of all the available
checkpoint inhibitors.
▶▶
Cemiplimab, Nivolumab, and Pembrolizumab
Cemiplimab, nivolumab, and pembrolizumab are human
monoclonal antibodies that block the interaction of the binding to PD-1 and its ligands, PD-L1 and PD-L2. Cemiplimab is
approved for patients with cutaneous squamous cell carcinoma.
Both nivolumab and pembrolizumab are active in many solid
and some hematologic tumors. Pembrolizumab is also the first
monoclonal antibody to be approved as a tumor agnostic therapy.
That is, it is approved for patients with any cancer that have high
microsatellite instability or high mutational tumor burden. Side
effects are much less common with PD-1 inhibitors compared
with the CTLA-4 inhibitor ipilimumab.
▶▶
Atezolizumab, Avelumab, and Durvalumab
Atezolizumab, avelumab, and durvalumab are recombinant,
human monoclonal antibodies that bind PD-L1 and block interaction with the PD-1 receptors. These drugs are active in many
solid tumors. Side effects are much less common with PD-L1
inhibitors compared with the CTLA-4 inhibitor ipilimumab.
Tyrosine Kinase Inhibitors (TKI)
More than 100 different types of tyrosine kinases are present
in the body. TKIs have been developed to block either several
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CHAPTER 88 | CANCER PRINCIPLES AND THERAPEUTICS 1409
or a specific tyrosine kinase (see Table 88–6). They are used to
treat solid tumors, leukemias, and lymphomas and can be used
as alone or in combination with IV chemotherapy, surgery, and/
or radiation. Some are continuously administered until disease
progression occurs or intolerance develops whereas others are
given cyclically (eg, 2 weeks on, 1 week off; then repeat). Side
effects often limit use if uncontrolled and typically are different
than those observed from traditional chemotherapy or immunotherapy. Drug interactions are common as many of these drugs
are metabolized through the CYP450 and P-glycoprotein systems
and can have decreased concentrations in the presence of antacids, H2 blockers, and/or proton pump inhibitors.
▶▶
Anaplastic Lymphoma Kinase (ALK) Inhibitors
(Alectinib, Brigatinib, Ceritinib, Crizotinib, and
Lorlatinib)
These small molecules primarily inhibit anaplastic lymphoma
kinase (ALK) and often will inhibit others such as mesenchymal epithelial transition growth factor c-MET, (crizotinib), Ret
proto-oncogene (RET), (alectinib); or insulin-like growth factor
1 receptor, insulin receptor, and ROS proto-oncogene 1 (ROS1),
(brigatinib and lorlatinib). These orally available agents are
approved for the treatment of NSCLC, that is ALK positive (about
2%–7% of NSCLC patients) as detected by an FDA-approved test.
Adverse effects include mild GI symptoms and elevated liver
function tests. Visual changes, pulmonary disease, and QTc prolongation can also occur as well as creatine kinase elevations specifically with alectinib. Lorlatinib is associated with CNS effects
such as changes in cognitive function, mood, sleep, and seizures.
▶▶
B-cell Lymphoma 2 (Bcl-2) Inhibitor (Venetoclax)
Venetoclax selectively inhibits the anti-apoptotic protein Bcl-2,
which is over-expressed in CLL and AML, thus restoring the
apoptotic process. This drug can work quickly and put patients at
risk for tumor lysis syndrome. Thus, the dose is escalated slowly
with tumor lysis monitoring and prophylaxis required. A reduced
renal function increases the risk of tumor lysis syndrome. Myelosuppression, nausea, and diarrhea can occur.
▶▶
BCR-ABL TKIs (Bosutinib, Dasatinib, Imatinib,
Nilotinib, and Ponatinib)
Imatinib was the first FDA-approved TKI. Imatinib inhibits phosphorylation during cell proliferation. The drug was designed to
block the breakpoint cluster region tyrosine kinase (BCR-ABL)
produced by the Philadelphia chromosome associated with CML
and ALL. Imatinib also has shown activity against GI stromal
tumors (GIST) that are positive for c-kit (CD117). Imatinib is
usually well tolerated, but common adverse effects include myelosuppression, rash, GI upset, edema, fatigue, arthralgias, myalgias,
and headaches. A cumulative cardiotoxicity is a serious but rare
adverse effect; therefore, it is recommended to closely monitor
patients with preexisting cardiac conditions.
Advanced generation BCR-ABL TKIs are more potent than
imatinib and can overcome most BCR-ABL mutations that lead
to imatinib resistance. Bosutinib, dasatinib, and nilotinib are
second-generation BCR-ABL TKIs and are used frontline in the
treatment of CML and in CML with resistance or intolerance
to imatinib. Side effects of dasatinib and nilotinib are similar
to imatinib and include myelosuppression, nausea and vomiting, headache, fluid retention, and hypocalcemia. Pleural effusions have been reported with dasatinib and imatinib but not
with nilotinib. QTc prolongation can occur with dasatinib and
Chisholm_Ch088_p1389-1420.indd 1409
nilotinib. Abnormalities in indirect bilirubin have been reported
with nilotinib and is more common in patients with (TA)7/(TA)7
genotype (UGT1A1*28).28 Bosutinib appears to have a milder
side effect profile than other TKIs, with GI disturbances and rash
being most common.
Ponatinib is a third-generation multikinase inhibitor and the
only advanced generation TKI that overcomes the T315I mutation. The serious adverse effects thrombosis, hepatotoxicity (rare),
and death (rare) are included as boxed warnings. Less serious
adverse effects include abdominal pain, dry skin, and rash.
▶▶
BRAF Inhibitors (Dabrafenib, Encorafenib,
and Vemurafenib)
Dabrafenib, encorafenib, and vemurafenib are inhibitors of BRAF
kinases. They most often are used to treat melanoma and also
some colon cancers that have BRAF V600E mutations. Common
adverse effects of BRAF inhibitors include arthralgias, alopecia,
GI symptoms, and fatigue. Other adverse effects of vemurafenib
include rash, keratoacanthoma or squamous cell cancer, and photosensitivity. Adverse effects associated with dabrafenib include
headache, palmar–plantar erythrodysesthesia syndrome, elevated
liver enzymes, pyrexia, and papilloma. Encorafenib is associated with electrolyte disturbances, including hyperglycemia and
increased serum creatinine.
▶▶
Bruton’s Tyrosine Kinase (BTK) Inhibitors
(Acalabrutinib, Ibrutinib, and Zanubrutinib)
Bruton’s tyrosine kinase (BTK) is an integral component of the
B-cell receptor. Constitutive activation of B-cell receptor signaling
allows the survival of malignant B cells. BTK inhibitors decrease
malignant B-cell proliferation and survival and are used in CLL
and some types of non-Hodgkin lymphomas. A noninfectious,
transient lymphocytosis should be expected and can last for weeks
but does not signify disease progression. Myelosuppression and
mild GI toxicities are the most common adverse effects. Infection risk is high; hepatitis B reactivation can occur, thus testing at
baseline for hepatitis B is recommended. Secondary cancers, primarily skin malignancies, have also been reported. BTK inhibitors
can increase the risk of bleeding, particularly in patients receiving
antiplatelet or anticoagulant medications. Additionally, cardiac
toxicity, including new-onset atrial fibrillation, hypertension, and
ventricular tachyarrhythmias can, occur but are more frequent
with ibrutinib. Acalabrutinib is associated with headaches that are
typically resolved after 1 to 2 months of therapy and can be managed with acetaminophen and caffeine. Zanubrutinib is associated
with rashes.
▶▶
Cyclin-Dependent Kinase (CDK) Inhibitors
(Abemaciclib, Palbociclib, and Ribociclib)
Abemaciclib, palbociclib, and ribociclib all inhibit cyclin-dependent
kinases (CDKs) 4 and 6, which prevent phosphorylation and
subsequent inactivation of the retinoblastoma tumor suppressor protein, ultimately causing cell cycle arrest and inhibiting
cancer cell proliferation. Each of the available CDK4/6 inhibitors is used in the treatment of postmenopausal women with
hormone receptor positive but HER-2 negative breast cancer.
Palbociclib and ribociclib are administered daily for 21 days,
followed by 7 days off, whereas abemaciclib is administered
daily. Common side effects include neutropenia, GI toxicities,
and hair loss. Rarely, abemaciclib is associated with venous
thromboembolism, ribociclib with QTc prolongation, and both
with hepatotoxicity.
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1410 SECTION 16 | ONCOLOGIC DISORDERS
▶▶
EGFR Pathway Inhibitors (Afatinib, Dacomitinib,
Erlotinib, Gefitinib, Lapatinib, Neratinib, Osimertinib,
and Tucatinib)
Patients with NSCLC in which the tumors have mutations in exon
19 and/or 21 in the EGFR pathway will likely respond to EGFR
TKIs such as afatinib, dacomitinib, and erlotinib. Those with
EGFR T790M mutations will likely respond to osimertinib. These
agents are believed to inhibit the intracellular phosphorylation of
the EGFR. Food increases bioavailability to almost 100% but is
variable; experts recommend administering erlotinib on an empty
stomach. Smoking increases the clearance of erlotinib by 24%,
which may result in treatment failure and different doses are used
for smokers versus nonsmokers.29 Side effects of EGFR inhibitors
include acneiform rash, diarrhea, dry skin, fatigue, anorexia, pruritus, conjunctivitis, and rarely interstitial lung disease. Diarrhea
and rash are highest among afatinib and dacomitinib.
Lapatinib, neratinib, and tucatinib inhibit the intracellular
kinase domains of both EGFR and HER-2 and have been shown to
retain activity against breast cancer cells that have become resistant
to trastuzumab. These are indicated for the treatment of patients
with breast cancer whose tumors overexpress HER-2. Common
side effects include diarrhea, nausea/vomiting, fatigue, and HFS.
▶▶
Fibroblast Growth Factor Receptor (FGFR)
(Erdafitinib and Pemigatinib)
Fibroblast growth factor receptor (FGFR) inhibitors bind to and
inhibit FGFR, which may be overexpressed on certain tumor cells.
Erdafitinib is indicated for urothelial carcinoma patients with
FGFR-2 or -3 genetic alterations; whereas pemigatinib is indicated
for those with cholangiocarcinoma and an FGFR-2 fusion or other
gene rearrangement. FGFR inhibitors can cause hyperphosphatemia, stomatitis, fatigue, dry mouth/skin, alopecia, onycholysis,
liver function enzyme elevations and rarely ocular disorders such
as serous retinopathy/retinal pigment epithelial detachment.
▶▶
Hedgehog Inhibitors (Glasdegib, Sonidegib,
and Vismodegib)
The Hedgehog pathway is a signaling pathway that regulates selfrenewal and differentiation of cells. It is abnormally activated
in basal cell carcinoma, medulloblastoma, and leukemia. These
inhibitors bind to smoothened (SMO), a transmembrane protein,
and prevents downstream signaling and activation of the Hedgehog pathway thus preventing tumor growth. Glasdegib is indicated
for AML treatment and sonidegib and vismodegib are indicated for
basal cell carcinoma. Because the Hedgehog pathway is essential for
embryogenesis, these drugs have boxed warnings for severe birth
defects and embryo–fetal death and have strict recommendations
for contraception for both males and females and pregnancy tests
within 7 days of starting therapy. Patients are also advised to not
donate blood during and for 30 days to 24 months following the last
dose, depending on the drug. The most common adverse effects of
sonidegib and vismodegib include muscle spasms, alopecia, dysgeusia, weight loss, fatigue, and GI toxicities. Glasdegib is also associated with myelosuppression, GI toxicities, edema, and dyspnea
and may cause QTc prolongation. Sonidegib can increase serum
creatine kinase levels, leading to severe musculoskeletal events.
▶▶
Isocitrate Dehydrogenase (IDH) Inhibitors
(Enasidenib and Ivosidenib)
Isocitrate dehydrogenase (IDH) enzymes are part of the citric acid
cycle, which is responsible for cellular respiration. In cancer, IDH1
and IDH2 are recurrently mutated and produce 2-hydroxglutarate
that alters DNA methylate and leads to the inhibition of cellular
Chisholm_Ch088_p1389-1420.indd 1410
differentiation. Enasidenib is a potent selective inhibitor of mutant
IDH2 and ivosidenib is a selective reversible inhibitor of mutant
IDH1 and are used for IDH-mutated AML. The most common
adverse events include hyperbilirubinemia without concurrent
transaminase elevation. Enasidenib is associated with nausea and
vomiting and requires a prophylactic antiemetic and can cause
leukocytosis and tumor lysis syndrome. Ivosidenib is associated
with fatigue, noninfectious leukocytosis, arthralgia, diarrhea, and
QTc prolongation.
▶▶
Mitogen-Activated Extracellular Kinases (MEK)
Inhibitors (Binimetinib, Cobimetinib, Selumetinib,
and Trametinib)
Binimetinib, cobimetinib, and trametinib are reversible inhibitor
of mitogen-activated extracellular kinases (MEK)-1 and MEK-2
and are active against BRAF V600-mutated forms of BRAF kinases
in melanoma cells. They most often are used in combination with
BRAF inhibitors for malignant melanoma. Rash, diarrhea, fatigue,
acneiform dermatitis, and peripheral and lymph edema are commonly reported. Cardiomyopathy (defined as heart failure) and
bleeding have also been reported. Selumetinib is approved for a
pediatric with neurofibromatosis type 1. Most common adverse
effects are nausea, vomiting, diarrhea, rash, dry skin, and fatigue.
▶▶
Mammalian Target of Rapamycin (mTOR) Inhibitors:
Temsirolimus and Everolimus
The mammalian target of rapamycin (mTOR) is a downstream
mediator in the phosphatidylinositol 3-kinase/Akt signaling
pathway that controls translation of proteins that regulate not
only cell growth and proliferation but also angiogenesis and cell
survival. The mTOR is an intracellular component that stimulates
protein synthesis by phosphorylating translation regulators and
contributes to protein degradation and angiogenesis.
Temsirolimus is approved for the treatment of advanced kidney
cancer. Temsirolimus and its metabolite sirolimus are substrates
of the CYP3A4/5 isoenzyme system. The primary side effects of
temsirolimus include mucositis, diarrhea, maculopapular rash,
nausea, leucopenia, thrombocytopenia, and hyperglycemia. Noninfectious pneumonitis can occur and must be identified immediately for best outcomes.
Everolimus is an oral inhibitor of mTOR that is approved for the
treatment of patients with advanced kidney cancer, breast cancer,
and neuroendocrine tumors. Drug interactions and adverse reactions are similar to those of temsirolimus.
▶▶
Multikinase Inhibitors (Axitinib, Cabozantinib,
Sorafenib, Sunitinib, and Pazopanib)
Multikinase inhibitors inhibit multiple tyrosine kinases and are
used for many different cancers. A full list of available multikinase inhibitors is found in Table 88–6. Some of the more common
ones are described here. Sorafenib is a multikinase inhibitor that
inhibits both intracellular and extracellular kinases and is used
in the treatment of hepatic, kidney, and thyroid cancers. The primary side effects of sorafenib include rash, diarrhea, pruritus, and
elevations in serum lipase. Hand–foot skin reaction (HFSR) can
also occur with those drugs that affect the VEGF receptor. HFSR
differs than HFS in that it initially develops as erythema and soreness, progressing to blisters, and eventually hyperkeratosis.
Cabozantinib and pazopanib both primarily inhibit VEGF
receptor-1 (VEGFR)-1, VEGFR-2, VEGFR-3, and several other
tyrosine kinases. Cabozantinib is available in two dosage forms:
tablets and capsules. The tablet formulation is used for patients
with advanced kidney cancer, whereas the capsules are a larger
11/10/21 4:42 PM
CHAPTER 88 | CANCER PRINCIPLES AND THERAPEUTICS 1411
dose for patients with medullary thyroid cancer. Pazopanib is
used to treat advanced kidney cancer and sarcomas. Common
side effects of these drugs are diarrhea, nausea, anorexia, HFSR
syndrome, hypertension, and fatigue. Pazopanib also is associated
with hair color changes. Serious toxicities that have been observed
are fatal hepatotoxicity, prolonged QTc intervals and torsade’s de
pointes, hemorrhagic events, arterial thrombotic events, GI perforation, and proteinuria.
Regorafenib is another small molecule inhibitor of multiple
membrane-bound and intracellular kinases used in the treatment of metastatic colorectal cancer and GI stromal tumor. The
proposed mechanism of action is through inhibition of VEGFR
involved in angiogenesis. GI effects, hypertension, mucositis,
infection, rash, and fever are commonly occurring adverse effects.
Hepatotoxicity is listed as a black-box warning; therefore, hepatic
function should be monitored closely. It is an orally administered
agent given for the first 21 days per 28-day cycle and should be
taken with a low-fat breakfast (30 g or less).
▶▶
Neurotrophic Tyrosine Receptor Kinase (NTRK)
(Entrectinib and Larotrectinib)
Neurotrophic tyrosine receptor kinase (NTRK) inhibitors are the
first oral anticancer agents approved pan-tumor, meaning they are
used to treat a specific genetic mutation rather than a tumor type.
Both entrectinib and larotrectinib are used adults and pediatric
patients with solid tumors that have a NTRK gene fusion without a
known acquired resistance. Entrectinib is also approved for ROS1positive NSCLC. The most common adverse reactions include
fatigue, nausea/vomiting, diarrhea, constipation, and dizziness.
Elevations in transaminases may occur. Rarely, entrectinib is associated with reductions in left ventricular ejection fraction (LVEF), QTc
prolongation, vision disorders, hyperuricemia, and skeletal fractures.
▶▶
Phosphoinositide 3-Kinase (PI3-K) Inhibitors (Alpelisib,
Copanlisib, Duvelisib, and Idelalisib)
Phosphoinositide 3-kinase (PI3-K), an essential lipid kinase, is
the target of inhibition for alpelisib, copanlisib, duvelisib, and
idelalisib. Alpelisib is indicated for breast cancer patients with
a PI3KCA mutation and the other drugs are used in the treatment of follicular lymphoma and CLL. Adverse effects associated
with copanlisib are hyperglycemia, hematologic abnormalities,
fatigue, diarrhea, and hypertension. Duvelisib is associated with
hepatotoxicity, diarrhea, cutaneous reactions, and myelosuppression. Idelalisib causes GI disturbances, rash, hematological side
effects, fatigue, and musculoskeletal pain. Idelalisib caries boxed
warnings for hepatotoxicity, colitis, pneumonitis, infections, and
intestinal perforation. Because the PI3-K pathway regulates the
immune system, PI3K inhibitors result in immunosuppression,
placing patients receiving these medications at risk for immunocompromising infections such as PJP and cytomegalovirus; thus
close monitoring and consideration of prophylactic antibacterials
and antivirals is warranted.
▶▶
Poly ADP Ribose Polymerase (PARP) Inhibitors
(Niraparib, Olaparib, and Rucaparib)
PARP enzymes are involved in normal cellular function, including DNA transcription and repair. PARP inhibitors prevent
DNA repair, allow apoptosis to occur and inhibit tumor growth.
Niraparib is used to treat ovarian, fallopian tube, or peritoneal
cancer; olaparib is used to treat some breast, ovarian, pancreatic,
and prostate cancers, and rucaparib is used to treat some ovarian and prostate cancers. Common side effects include myelosuppressive side effects, GI toxicities, fatigue, upper respiratory
Chisholm_Ch088_p1389-1420.indd 1411
tract infections, and arthralgias and myalgias. Rarely, patients can
develop MDS or AML and pneumonitis. Niraparib also causes
hypertension and patients must undergo heart rate (HR) and
blood pressure (BP) monitoring monthly for the first year.
▶▶
Proteasome Inhibitors (Bortezomib,
Carfilzomib, and Ixazomib)
The proteasome is an enzyme complex that exists in all cells and
plays an important role in degrading proteins that control the cell
cycle. When the proteasome is inhibited, the numerous pathways
that are necessary for the growth and survival of cancer cells are
disrupted. Bortezomib specifically inhibits the 26S proteasome,
which is a large protein complex that degrades ubiquitinated proteins. This pathway plays an essential role in regulating the intracellular concentration of specific proteins, causing the cells to
maintain homeostasis. Inhibition of the 26S proteasome prevents
this from occuring, ultimately causing a disruption in the homeostasis and cell death. Both carfilzomib and ixazomib inhibit 20S
proteasome, which is the proteolytic core with the 26S proteasome.
Bortezomib is approved for the treatment of MM and mantle
cell lymphoma. It is administered either as an IV or SC injection. The most commonly reported adverse effects are asthenia,
GI disturbances (nausea, diarrhea, decreased appetite, constipation, vomiting), thrombocytopenia, peripheral neuropathy, anemia, headache, insomnia, and edema. Peripheral neuropathy is
much lower with the SC injection. Prophylactic anticoagulation
is not routinely required. Reactivation of varicella zoster infection
is also common with bortezomib, and antiviral prophylaxis with
acyclovir should be considered.
Carfilzomib and ixazomib are second-generation proteasome
inhibitors. Carfilzomib is administered by IV, whereas ixazomib
is a capsule that should be taken on an empty stomach. Both of
these drugs used in the treatment of refractory cases of MM and
have similar but fewer side effects compared with bortezomib.
▶▶
RET Inhibitors (Pralsetinib and Selpercatinib)
RET inhibitors inhibit wild-type RET and oncogenic RET fusions
and mutations that are found in 1%–2% of NSCLCs and some
thyroid cancers. These drugs are commonly associated with elevations in transaminases, myelosuppression, fatigue, and hypertension. Impairment of wound healing and hemorrhage can occur.
Optimization of hypertension is recommended before initiation.
Less commonly selpercatinib can cause QTc prolongation and
hypersensitivity. Pralsetinib can cause interstitial lung disease.
▶▶
Selective Inhibitor of Nuclear Export
Antagonist (Selinexor)
Selinexor is an orally available, small molecular inhibitor of chromosome region maintenance 1 protein, also known as exportin 1
(XOP1). Essentially, selinexor inhibits tumor suppressor proteins,
growth regulators, and mRNA of oncogenic proteins, resulting in
accumulation of these cell cycle arrest and cancer apoptosis. It
is used in non-Hodgkin lymphoma and MM. Common adverse
events include myelosuppression, GI toxicity including nausea
and vomiting that requires prophylactic antiemetics, hyponatremia, dizziness, and mental status changes.
Hormonal Therapies
Hormonal or endocrine therapies have activity in the treatment
of cancers whose growth is affected by gonadal hormonal control.
Hormonal treatments either block or decrease the production of
endogenous hormones. These agents are covered extensively in
Chapters 89 and 92, in the breast and prostate cancer chapters.
11/10/21 4:42 PM
1412 SECTION 16 | ONCOLOGIC DISORDERS
▶▶
Antiandrogens (Bicalutamide, Flutamide,
and Nilutamide)
The antiandrogens block androgen receptors (ARs) and inhibit
the action of testosterone and dihydrotestosterone in prostate
cancer cells. Side effects common to these agents are hot flashes,
gynecomastia, and decreased libido. Flutamide tends to be associated with more diarrhea and requires three times daily administration, whereas bicalutamide is dosed once daily. Nilutamide
may cause interstitial pneumonia and is associated with the visual
disturbance of delayed adaptation to darkness.
▶▶
Pure AR Antagonists (Apalutamide, Darolutamide,
and Enzalutamide)
Pure antagonists competitively inhibit androgen binding to
ARs and AR nuclear translocation and coactivator recruitment
of the ligand-receptor complex. All three are indicated for nonmetastatic castrate-resistant prostate cancer; both apalutamide
and enzalutamide are indicated for the treatment of metastatic
hormone sensitive prostate cancer; and enzalutamide is also
approved for metastatic castration-resistant prostate cancer. The
most common side effect of these therapies is fatigue and hypertension, but overall are they well tolerated. Apalutamide is also
associated with rash and hypothyroidism.
▶▶
Luteinizing Hormone–Releasing Hormone Agonists
(Goserelin and Leuprolide)
Initially, luteinizing hormone–releasing hormone (LHRH) agonists
increase levels of luteinizing hormone and follicle-stimulating
hormone, but testosterone and estrogen levels are decreased
because of continuous negative-feedback inhibition. Major side
effects are testicular atrophy, decreased libido, gynecomastia, and
hot flashes. Goserelin is injected as a pellet under the skin; therefore, SC injection of lidocaine around the injection site before
administration helps to decrease the pain associated with administration. Numerous dosage forms are available for leuprolide
with varying strengths and dosing intervals. Antiandrogens may
be administered during initial therapy to decrease symptoms of
tumor flare (eg, bone pain and urinary tract obstruction).
▶▶
Gonadotropin-Releasing Hormone
Antagonist (Degarelix)
Degarelix is a gonadotropin-releasing hormone (GnRH) receptor
antagonist that reversibly binds to the pituitary GnRH receptors,
thereby reducing the release of gonadotropins and consequently
testosterone. Degarelix is indicated for the treatment of advanced
prostate cancer. Adverse effects include hot flashes, injection
site reactions, and an increase in liver enzymes. An advantage of
degarelix over LHRH agonists is the lack of the tumor flare.30
▶▶
Abiraterone
Abiraterone is an orally available androgen biosynthesis inhibitor that inhibits 17α-hydroxylase/C17,20-lyase (CYP17), which
is expressed in testicular, adrenal, and prostatic tumor tissues.
Abiraterone is indicated in combination with prednisone for the
treatment of metastatic prostate cancer. Two formulations are
available: abiraterone acetate and micronized abiraterone. Both
the dose and the administration are different between formulations. The conventional formulation of abiraterone is taken on
an empty stomach; however, the micronized formulation can be
taken without respect to food. Adverse effects include hypokalemia, edema, muscle discomfort, fatigue, hot flashes, nocturia,
urinary frequency, and hypertension.
Chisholm_Ch088_p1389-1420.indd 1412
▶▶
Aromatase Inhibitors (AIs) (Anastrozole,
Exemestane, Letrozole)
Three AIs are currently available: anastrozole, letrozole, and
exemestane. All three agents work by inhibiting aromatase, which
prevents the conversion of androstenedione to estrone and testosterone to estradiol in adipose tissue, which is the primary source
of estrogens in post menopausal women. All three agents are used
to treat breast cancer in postmenopausal women and are considered interchangeable in terms of activity. When compared to
tamoxifen, there are less endometrial and uterine cancers, vaginal bleeding, and thrombosis with AI therapy. Common adverse
effects associated with the AI therapy include hot flashes and
arthralgias. Serious adverse effects include osteoporosis, skeletalrelated events, and atherosclerotic cardiovascular disease. More
information on the pharmacology and clinical use of AI therapy
can be found in Chapter 89.
▶▶
Antiestrogens (Fulvestrant, Raloxifene,
and Tamoxifen)
Antiestrogens bind to ERs and block the effect of estrogen on tissue. Two classes of antiestrogens exist: SERMs (tamoxifen, raloxifene) and selective estrogen-receptor downregulators (SERDs,
fulvestrant). SERDs were developed in an effort to eliminate the
unwanted estrogenic side effects from the SERMs. Tamoxifen is
used for the treatment of ER positive premenopausal or postmenopausal metastatic hormone receptor–positive breast cancer,
as adjuvant and primary treatment of breast cancer, and in the
prevention of breast cancer in high-risk women. The agent has a
beneficial effect on bone density and the lipid profile. Unwanted
side effects include hot flashes, fluid retention, and mood swings.
Thrombosis, endometrial and uterine cancer, corneal changes,
and cataracts are harmful adverse effects that occur more frequently with this agent. Although uncommon, there is a disease/
tumor flare that can occur during the initiation of therapy in
metastatic breast cancer patients with bone metastases. Because
tamoxifen is a substrate of CYP3A4, decreased tamoxifen levels
have occurred with use of St. John’s wort and rifampin. Tamoxifen is also a substrate for CYP450 2D6 and evidence suggests
that those who are CYP2D6*4/*4 may have a poorer response
and more toxicity with tamoxifen.31 Routine pharmacogenomics
screening of these patients is not currently recommended. Significant drug interactions exist and drug–drug interactions affecting
this enzyme should be avoided if possible.
Raloxifene is another SERM and is used for the treatment of osteoporosis in postmenopausal women and is the
Patient Encounter 1, Part 3
The patient has progressed following therapy with initial
treatment with docetaxel and subsequently was found to
have a BRCA1 mutation. He now will be receiving a new
prescription for olaparib 300 mg orally, twice daily.
What education and training should be provided to the
patient to ensure his understanding of safe handling
procedures as well as thorough knowledge of proper
administration?
How should the patient be instructed to take this medication,
in regards to meals or the time of day?
11/10/21 4:42 PM
CHAPTER 88 | CANCER PRINCIPLES AND THERAPEUTICS 1413
chemopreventive agent of choice for the prevention of breast
cancer in high-risk women. When compared head to head with
tamoxifen for breast cancer prevention, it was demonstrated to
have equal efficacy with less toxicity. Raloxifene was not studied
in premenopausal women; therefore, tamoxifen is still the preventative agent of choice in these women. Hot flashes, arthralgias, and peripheral edema occur frequently with raloxifene, but
thrombosis and endometrial cancer is less common than with
tamoxifen.
Fulvestrant is used as second-line treatment in hormone
receptor–positive metastatic breast cancer, postmenopausal
women with disease progression following antiestrogen therapy.
Fulvestrant is given as a monthly intramuscular injection, which
might be a deterrent to some patients.
ADMINISTRATION ISSUES
Extravasation
Extravasation, or the leakage of an anticancer outside the blood
vessel into the surrounding tissue is a concern for a number of
anticancer agents. Antineoplastic agents that cause severe tissue
damage when they escape from the vasculature are called vesicants. The tissue damage may be severe, with tissue sloughing and
loss of mobility, depending on the area of extravasation. Patients
need to be educated to alert clinic staff immediately if there is
any pain on administration. If extravasation of a vesicant occurs,
the injection should be stopped and any fluid aspirated out of the
injection site. The prevention, risk factors, signs and symptoms,
causative agents, and treatment will be discussed thoroughly in
Chapter 99.
Hypersensitivity Reactions
Hypersensitivity reactions to cancer treatments are problematic because of cross-reactivity between agents and the desire to
continue active therapies against the cancer.32 For documented
immediate hypersensitivity reactions to a particular agent, further
administration of the agent may be achieved through extensive
premedication with H1 and H2 antihistamines and corticosteroids
and through the use of desensitization protocols which include
escalating doses of the offending agent given at doses of onehundredth, one-tenth, and the balance of the dose (so the total
dose administered is equivalent to the normally prescribed dose)
administered over a much longer period of time. These treatments must be given in an environment where resuscitation is
readily available in case of medical emergency.
Secondary Malignancies
Chemotherapy and radiation therapy treatments may cause cancers later in life; these are referred to as secondary malignancies.
The most common types of secondary malignancies are MDS
and AML. The antineoplastic agents most commonly associated
with secondary malignancies are alkylating agents, etoposide,
topoisomerase inhibitors, and anthracyclines. Although the risk
for secondary cancers is extremely low, it must outweigh the risk
of survival produced by treatment of the primary malignancy.
Because secondary malignancies may not occur for several years
after treatment, patients with relatively short-term survival expectancy related to their current cancer should consider the more
immediate benefits of chemotherapy. Radiation therapy may
also cause secondary malignacies decades after treatment. The
most common example of radiation therapy–induced secondary
malignancy is breast cancer, which rarely occurs after mantle field
radiation therapy for Hodgkin disease.
Chisholm_Ch088_p1389-1420.indd 1413
CHEMOTHERAPY SAFETY
One of the first Institute of Medicine (IOM) reports, the health
arm of the National Academy of Sciences, starts out with a patient
who died from an overdose of chemotherapy; the patient did not
have an immediately life-threatening cancer, so her death was
hastened by a medication error. Chemotherapy agents may cause
harm to patients, healthcare professionals, and the environment
if not handled correctly.
Because of the risk of severe toxicities associated
with many of the chemotherapy agents, safety precautions must
be in place to prevent chemotherapy errors or accidental chemotherapy exposures of healthcare professionals or patients. The
American Society of Clinical Oncology (ASCO), Hematology/
Oncology Pharmacy Association, Oncology Nursing Society, and
the American Society of Health-System Pharmacists have information to assist in the safe handling of chemotherapy agents.19,33,34
National, state, and local regulations regarding the safe disposal of
chemotherapy agents and the equipment used to administer them
need to be followed to protect the environment.
Each organization should have chemotherapy safety
checks built into the prescribing, preparation, and administration of chemotherapy.19,33 Dosing based on patient-specific information should be included on every order for chemotherapy,
whether it is oral or parenteral. Many chemotherapy regimens are
referred to by acronyms (eg, AC, which is doxorubicin and cyclophosphamide); these should not be allowed as the only reference
to drugs in the prescribing of chemotherapy. Also, abbreviations
for the names of chemotherapy agents should be avoided because
one abbreviation may stand for two different drug entities. For
drugs such as doxorubicin and liposomal doxorubicin, the names
should be written out fully, and in this case, the addition of the
brand name may help to prevent a mistake.
The measured height and weight, along with the body surface area (BSA), if applicable, should be readily available, along
with the dosage in milligrams per meter squared or kilogram,
so that the dosage may be checked. If a chemotherapy regimen
is a continuous infusion of 800 mg/m2/day for 4 days, an added
safety feature would be to include the total dosage of 3200 mg
in order to prevent any ambiguity. In cases where the clinician
wants to decrease the dosage based on a laboratory value or side
effect, it is recommended that the clinician include that information with the order so the clinical team caring for the patients
understands the correct dosage for that patient. Chemotherapy
dosages should be checked for route and dose to determine
that the dosages prescribed are correct and do not exceed dosing guidelines. Appropriate laboratory values should be checked
Patient Encounter 2
A 68-year-old woman is receiving nivolumab 1 mg/kg and
ipilimumab 3 mg/kg as treatment for intermediate-risk
metastatic renal cell carcinoma. While receiving treatment,
her aspartate aminotransferase (AST) has risen from 16 to
156 IU/L and alanine aminotransferase (ALT) has risen from
42 to 175 IU/L.
What is the likely diagnosis?
What is the most appropriate treatment?
What measures should be taken by patients while receiving
checkpoint inhibitors?
11/10/21 4:42 PM
1414 SECTION 16 | ONCOLOGIC DISORDERS
prior to administration so the dose can be adjusted for organ
dysfunction or toxicity if needed. See examples in Table 88–8.
Additionally, drug interactions should be scrutinized closely and
whether the patient has the appropriate indication (eg, presence
of EGFR mutation for use of erlotinib).18 Healthcare professionals administering chemotherapy should check the dosage calculation for the patient’s weight or BSA along with the five Rs of
administering medication (ie, right patient, right medication,
right dose, and right route, at the right time). If there is any question about the safe dosage or safe administration of a chemotherapy agent, the chemotherapy should not be administered until the
question is resolved.
In addition, a controversy related to chemotherapy dosing is
whether actual or ideal body weight should be used for calculating
Table 88–8
Examples of Dose Modifications in Patients With Hepatic and/or Renal Dysfunction
Agent
Organ Dysfunction
Bleomycin
Baseline and during therapy
CrCl > 50 mL/min
CrCl = 40–50 mL/min
CrCl = 30–40 mL/min
CrCl = 20–30 mL/min
CrCl = 10–20 mL/min
CrCl = 5–10 mL/min
Hepatic dysfunction
Baseline
CrCl > 51 mL/min
CrCl = 30–50 mL/min
CrCl < 30 mL/min
Mild-moderate hepatic impairment
Severe hepatic impairment
During therapy
SCr > ULN to 1.5 ULN
SCr > 1.5–3 × baseline to > 1.5–3 × ULN
SCr > 3 × baseline to > 3–6 × ULN
SCr > 6 × ULN
Total bilirubin > 3–10 × ULN if baseline was normal or
> 3–10 × baseline if baseline as abnormal
Baseline and during therapy
CrCl = 30–89 mL/min
CrCl < 30 mL/min
Baseline
Mild hepatic impairment
Moderate hepatic impairment (total bilirubin
> 1.5–≤ 3 × ULN and any AST elevation)
Severe hepatic impairment (total bilirubin > 3 × ULN and
any AST elevation)
During therapy
ALT or AST > 5 × ULN with total bilirubin ≤ 1.5 × ULN
Capecitabine
Crizotinib
Idarubicin
Pembrolizumab
ALT or AST > 3 × ULN with total bilirubin ≥ 1.5 × ULN
Baseline and during therapy
CrCl > 50 mL/min
CrCl = 10–50 mL/min
CrCl < 10 mL/min
Bilirubin 2.6–5 mg/dL
Bilirubin > 5 mg/dL
Baseline
Renal dysfunction
Mild hepatic impairment
Moderate-severe hepatic impairment
During therapy
SCr 1.5–2 × above baseline or increase of ≥ 0.3 mg/dL
SCr 2–3 × above baseline
SCr > 3 × above baseline or > 4 mg/dL
ALT or AST > 3–5 × ULN with total bilirubin
≥ 1.5–3 × ULNa
ALT or AST > 5 × ULN with total bilirubin ≥ 3 × ULNa
Dose Modification
No dosage adjustment
70% of normal dose
60% of normal dose
55% of normal dose
45% of normal dose
40% of normal dose
No dosage adjustments required
Initial: no dosage adjustment
Initial: 75% of normal dose
Contraindicated
No initial dosage adjustment
Not studied
No dosage adjustment
No dosage adjustment at first instance
75% dosage adjustment at first instance
Discontinue therapy
Interrupt therapy until total bilirubin ≤ 3 × ULN; dosage
adjustment is based on dosing guidelines for toxicity
No dosage adjustment
Decrease dose to 250 mg once daily
No dosage adjustment
Decrease dose to 200 mg twice daily
Decrease dose to 250 mg once daily
Withhold therapy until recovery until baseline or ≤ 3 × ULN,
then resume at reduced dose
Discontinue therapy
No dosage adjustment
75% of normal dose
50% of normal dose
50% of normal dose
Do not use
No dosage adjustment
No dosage adjustment
Has not been studied
Consider holding therapy
Withhold therapy and start prednisone 0.5–1 mg/kg/day
Permanently discontinue and start prednisone 1–2 mg/kg/day
Withhold therapy and start prednisone 0.5–1 mg/kg/day;
resume after taper complete and toxicity resolved
Permanently discontinue and start prednisone 1–2 mg/kg/day
In patients without hepatocellular or renal cell carcinoma; recommendations are different for these cancers.
AST, aspartate aminotransferase; ALT, alanine aminotransferase; CrCl, creatinine clearance; SCr, serum creatinine; ULN, upper limit of normal.
a
Chisholm_Ch088_p1389-1420.indd 1414
11/10/21 4:42 PM
CHAPTER 88 | CANCER PRINCIPLES AND THERAPEUTICS 1415
chemotherapy doses for obese individuals. ASCO guidelines currently recommend the use of actual body weight.35
errors and the potential for drug and/or food interactions well as
accidental exposure to other individuals. Healthcare professionals
have an important role in ensuring safe handling of oral anticancer
agents, and should be properly trained and perform competently
within guidelines for the storage, handling, and disposal of oral
agents. The healthcare professionals are also expected to provide
proper training and education on safe handling and proper administration (see Table 88–9) to the patient and caregivers.33,34,36
ORAL ANTICANCER AGENTS
Over the past decade, self-administration of oral anticancer agents has increased. Although oral anticancer agents have
many potential advantages, including convenience and quality of
life for patients, oral administration increases the risk of medication
Table 88–9
Oral Anticancer Therapy Administration With Respect to Food
With Food
6-Mercaptopurine
Abemaciclib
Abiraterone
Acalabrutinib
Afatinib
Alectinib
Alpelisib
Anastrozole
Apalutamide
Avapritinib
Axitinib
Azacitidine
Bexarotene
Bicalutamide
Binimetinib
Brigatinib
Bosutinib
Busulfan
Cabozantinib
Capecitabine
Capmatinib
Ceritinib
Chlorambucil
Crizotinib
Cyclophosphamide
Cobimetinib
Dabrafenib
Dacomitinib
Darolutamide
Dasatinib
Decitabine/Cedazuridine
Duvelisib
Enasidenib
Encorafenib
Entrectinib
Enzalutamide
Erdafitinib
Erlotinib
Estramustine
Etoposide
Everolimus
Exemestane
Fedratinib
Flutamide
Gefitinib
Glasdegib
Gilteritinib
Hydroxyurea
Ibrutinib
Idelalisib
Imatinib
Ivosidenib
Empty Stomach
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xa
X
X
X
X
X
X
X
X
X
X
X
With or Without Food
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X (avoid high-fat meal)
(Continued)
Chisholm_Ch088_p1389-1420.indd 1415
11/10/21 4:42 PM
1416 SECTION 16 | ONCOLOGIC DISORDERS
Table 88–9
Oral Anticancer Therapy Administration With Respect to Food (Continued)
With Food
Ixazomib
Lapatinib
Larotrectinib
Lenalidomide
Lenvatinib
Letrozole
Lomustine
Lorlatinib
Melphalan
Methotrexate
Midostaurin
Neratinib
Nilotinib
Nilutamide
Niraparib
Olaparib
Osimertinib
Palbociclib
Panobinostat
Pazopanib
Pemigatinib
Pexidartinib
Pomalidomide
Ponatinib
Pralsetinib
Procarbazine
Regorafenib
Ribociclib
Ripretinib
Rucaparib
Ruxolitinib
Selinexor
Selpercatinib
Selumetinib
Sonidegib
Sorafenib
Sunitinib
Talazoparib
Tamoxifen
Tazemetostat
Temozolomide
Thalidomide
Thioguanine
Toremifene
Trametinib
Tretinoin
Trifluridine/Tipiracil
Tucatinib
Vandetanib
Vemurafenib
Venetoclax
Vismodegib
Vorinostat
Zanubrutinib
Empty Stomach
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X (avoid tyramine-containing foods)
X (low fat meal)
X
X
X
X
X
X
X
X
X
X
X
X
X
X (must be consistent)
X
X
X
X
X
X
X
X
X
X
X
With or Without Food
X
X
X
X
X
X
X
X
X
X
Preferably on an empty stomach; but most importantly consistently with or without food.
a
CANCER SURVIVORSHIP
As early detection of cancers and effective therapies
have improved over the last several years, the number of cancer
survivors has increased. A cancer survivor by definition, according to the National Coalition for Cancer Survivorship, starts
at the point of diagnosis. It is estimated that two out of every
three people with cancer live at least 5 years after diagnosis.
Chisholm_Ch088_p1389-1420.indd 1416
In 2005, the IOM released a report, “From Cancer Patient to
Cancer Survivor: Lost in Transition,” which emphasized a lack of
definitive guidance and proposed increased efforts were needed
to raise awareness regarding the care of cancer survivors.37 In
addition to facing a risk of a cancer recurrence, secondary malignancy, and an increased risk of developing other health conditions, cancer survivors often face physical, emotional, financial,
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CHAPTER 88 | CANCER PRINCIPLES AND THERAPEUTICS 1417
Patient Care Process
Collect Information:
•• Patient characteristics (eg, age, race, sex, patient preferences)
•• Patient history (lifestyle factors—alcohol use, tobacco use,
diet, physical activity)
•• Patient medical and family history (eg, ECOG performance
status, concurrent disease states)
•• Clinical presentation signs and symptoms (eg, changes in
bowel habits, unusual bleeding, weight loss, recurrent fevers)
•• Current medications (prescription, over the counter, and
complimentary alternative, medical marijuana)
•• Objective data
•• BP, heart rate, height, weight, and BSA
•• Labs (eg, serum electrolytes, renal function, liver
chemistries, complete blood count, coagulation studies,
tumor markers)
•• Other diagnostic test (eg, left ventricular ejection fraction)
•• Physical examination data (eg, hepatomegaly,
lymphadenopathy)
•• Cancer staging
•• Tumor genomics (eg, BRAF, HER-2, PIK3CA, RAS)
Assess the Information:
•• Risk factors for treatment-related toxicities (eg, UGT1A1*28
genotype, poor nutritional intake, uncontrolled BP or
hypertension, baseline peripheral neuropathy)
•• Type of and response to prior treatments
•• Potential for disease responsiveness to specific agents and
risk factors for disease recurrence
•• Patient characteristics (eg, social history/situation, insurance
coverage, pregnancy) and treatment preferences
•• Potential problems with medication adherence to oral
treatment regimens
•• Goals of treatment
and social challenges as a result of the cancer diagnosis and treatment. The American Cancer Society (ACS), Centers for Disease
Control, ASCO, and the NCCN all have guidelines that describe
strategies to meet the needs of these individuals who experience
the long-term effects of cancer and its treatment.38-40
OUTCOME EVALUATION
Once a pathologic diagnosis of cancer is made, the patient may
be evaluated by a radiation oncologist, a surgical oncologist,
and a medical oncologist. Options for treatment are presented
that may include surgery, radiation, pharmacologic therapy, or
some combination of these modalities. The goals of treatment
vary by the cancer and the stage of disease. For example, the
patient who has metastatic kidney cancer could be presented
with several options. They may have a possible cure with highdose aldesleukin or receive palliative therapy with pazopanib
or sunitinib, or the patient may decline any therapy because of
fears of significant toxicity that would decrease quality of life.
In this case, if the patient’s performance status is poor, such as
Chisholm_Ch088_p1389-1420.indd 1417
•• Need for drug dose reductions or supportive care
Develop a Care Plan*:
•• Drug therapy regimen including specific anticancer agent(s),
dose (calculated correctly for patient characteristics and
disease), route, frequency, and duration
•• Supportive care plan (eg, antiemetics, prophylactic
antidiarrheals, infusion reaction prophylaxis)
•• Monitoring parameters including efficacy (eg, cancer
imaging studies-chest, abdominal, and/or pelvic CT scans
and radiographs, tumor markers if previously elevated,
symptoms of recurrence), safety (medication-specific
adverse effects, including major dose-limiting toxicities), and
timeframe
•• Patient education (eg, goals of treatment; expected and
potential serious toxicities; drug therapy; monitoring and
management plan; safe administration, storage, and disposal)
Implement the Care Plan*:
•• Provide patient education regarding all elements of
treatment plan
•• Survivorship care plan (eg, primary prevention of other
diseases, such as infections, and other cancers, support
systems for maintaining healthy lifestyle choices and BMI)
Follow-up: Monitor and Evaluate:
•• Determine disease response to treatment and occurrence of
disease progression or recurrence (cancer imaging studies,
tumor markers previously elevated)
•• Presence of adverse effects
•• Patient adherence to treatment plan using multiple
sources of information (eg, patient self-report, medication
administration records or refill data)
•• Patient’s satisfaction with treatment, including understanding
of adherence
Collaborate with patient, caregivers, and other healthcare professionals
*
an ECOG performance status 3, then the patient would not be a
candidate for aldesleukin therapy because of significant toxicity
or even death from treatment. The patient with the poor performance status will receive palliative therapy to control symptoms
of the disease to improve the quality of life at the end of life.
For the patient with a poor performance status and extensive
metastatic disease, no treatment of the cancer may be appropriate, and the patient may be enrolled in a hospice program or
provided comfort care.
Abbreviations Introduced
in This Chapter
2-FLAA
5-FU
6-MP
ACS
ADC
ADCC
2-Fluoro-Ara-AMP
5-Fluorouracil
6-Mercaptopurine
American Cancer Society
Antibody–drug conjugate
Antibody-dependent cellular cytotoxicity
11/10/21 4:42 PM
1418 SECTION 16 | ONCOLOGIC DISORDERS
AI
ALK
ALL
ALT
AML
APL
AR
ASCO
ATRA
AST
AUC
BSA
Bcl-2
BCNU
BP
BTK
c-MET
CAR
CBC
CCNU
CD
CDK
CLL
CML
CNS
CrCl
CRS
CT
CTLA-4
CYP
CYP17
DNA
DPD
DVT
ECOG
EGFR
ER
FDA
FdUMP
FGFR
G-CSF
GI
GIST
GnRH
H
HDAC
HER-2
HFS
HFSR
HPV
HR
HSCT
IDH
IOM
INR
IV
LDH
LHRH
MDS
MEK
MM
MMAE
MMAF
MRI
mTOR
NCI
NCCN
NSCLC
NTRK
Aromatase inhibitor
Anaplastic lymphoma kinase gene
Acute lymphocytic leukemia
Alanine aminotransferase
Acute myeloid leukemia
Acute promyelocytic leukemia
Androgen receptor
American Society of Clinical Oncology
All-trans-retinoic acid
Aspartate aminotransferase
Area under the curve
Body surface area
B-cell lymphoma 2
Carmustine
Blood pressure
Bruton’s tyrosine kinase
Mesenchymal epithelial transition growth factor
Chimeric antigen receptor
Complete blood count
Lomustine
Cluster of differentiation
Cyclin-dependent kinase
Chronic lymphocytic leukemia
Chronic myeloid leukemia
Central nervous system
Creatinine clearance
Cytokine-release syndrome
Computed tomography
Cytotoxic T-lymphocytic-associated antigen 4
Cytochrome P450
17α-hydroxylase/C17,20-lyase
Deoxyribonucleic acid
Dihydropyrimidine dehydrogenase
Deep vein thrombosis
Eastern Cooperative Oncology Group
Epidermal growth factor receptor
Estrogen receptor
Food and Drug Administration
Fluorodeoxyuridine monophosphate
Fibroblast growth factor receptor
Granulocyte–colony stimulating factor
Gastrointestinal
Gastrointestinal stromal tumor
Gonadotropin-releasing hormone
Histamine
Histone deacetylase
Human epidermal receptor-2
Hand–foot syndrome
Hand–foot–skin reaction
Human papillomavirus
Heart rate
Hematopoietic stem cell transplantation
Isocitrate dehydrogenase
Institute of Medicine
International normalization ratio
Intravenous
Lactate dehydrogenase
Luteinizing hormone–releasing hormone
Myelodysplastic syndrome
Mitogen-activated extracellular kinases
Multiple myeloma
Monomethyl auristatin E
Monomethyl auristatin phenylalanine
Magnetic resonance imaging
Mammalian target of rapamycin
National Cancer Institute
National Comprehensive Cancer Network
Non–small cell lung cancer
Neurotrophic tyrosine receptor kinase
Chisholm_Ch088_p1389-1420.indd 1418
OTC
PARP
PCR
PD
PD-L
PET
PI3-K
PSA
RAS
RECIST
REMS
RNA
SC
SERDs
SERMs
SMO
SPF
TKI
TNM
TPMT
TS
UGT1A1*28
VEGF
VEGFR
XOP1
Over-the-counter
Poly ADP ribose polymerase
Polymerase chain reaction
Programmed cell death
Programmed cell death ligand
Positron emission tomography
Phosphoinositide 3-kinase
Prostate-specific antigen
Reticular activing system
Response evaluation criteria in solid tumors
Risk Evaluation and Mitigation Strategies
Ribonucleic acid
Subcutaneous
Selective estrogen-receptor downregulators
Selective estrogen receptor modulator
Smoothened
Sun protection factor
Tyrosine kinase inhibitor
Tumor, nodes, metastases
Thiopurine S-methyltransferase
Thymidylate synthase
Uridine diphosphate–glucuronosyltransferase
1A1 enzyme
Vascular endothelial growth factor
Vascular endothelial growth factor receptor
Exportin 1
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