REPORT

Overview of Chemotherapy-Induced Nausea

and Vomiting and Evidence-Based Therapies
Nelly Adel, PharmD, BCOP, BCPS

P
atients with cancer often fearfully anticipate the prospect
ABSTRACT
of many potential negative consequences resulting
from antineoplastic chemotherapy. At or near the top Among patients with cancer, chemotherapy-induced nausea and vomiting
of their concerns is the common adverse effect (AE) of (CINV) is a common adverse effect that not only impacts quality of life,
chemotherapy-induced nausea and vomiting (CINV).1-3 When CINV but also treatment outcomes. It is important to address these issues
from both prevention and treatment standpoints so that patients remain
goes untreated, it affects upwards of 60% to 80% of patients with
adherent to their regimens. With CINV being classified into 5 different
cancer.4 CINV not only negatively impacts the quality of life (QOL)
types, the primary medication options for prevention and treatment
of the patient,4-6 but also the QOL of the patient’s family.7 Without include 5-HT3 receptor antagonists, NK1 receptor antagonists, and
prevention and control of CINV, patients may experience many corticosteroids. Other medications used, but to a lesser extent, include
undesirable events that can affect their QOL and/or treatment dopamine antagonists, benzodiazepines, cannabinoids, and olanzapine.
outcomes, 8-10
including discontinuation of chemotherapy, which
3 In addition, those patients who express interest in alternative or
nonpharmacologic therapies may have options as well. With the array
highlights the need for adequate prevention and control measures.
of medications available for patients with cancer, pharmacists play an
CINV is a substantial issue in oncology that requires active
integral role in optimizing patient outcomes. Therefore, it is important
management for both prevention and treatment. In CINV, the that pharmacists stay up-to-date on the most current guidelines available
focus is clearly on prevention to avoid clinical, QOL, and economic for CINV treatment.
issues that arise when CINV is not well controlled. With updated
Am J Manag Care. 2017;23:S259-S265
antiemesis protocols and newer antiemetic agents, healthcare
For author information and disclosures, see end of text.
providers and pharmacists can be ready to implement the most
appropriate prevention and treatment strategies.

Definition and Classifications of CINV

Definition of CINV
Although nausea and vomiting are grouped together in CINV and they
often do occur together, the symptoms can occur independently.11
Nausea occurs more frequently in cancer chemotherapy11 and
is described as the subjective sensation or feeling of unsettled
stomach in the epigastrium and/or throat, coupled with a sensation
that vomiting is impending. Vomiting, as a separate effect, is the
physical expulsion of stomach contents via the mouth.12,13 Despite
progress in controlling emesis, nausea remains a problem for many
patients. In this activity, the sequelae of nausea and vomiting will
be discussed together unless otherwise noted.

Classifications of CINV
CINV can be classified into 5 types (Table 114-19): acute, delayed,
anticipatory, breakthrough, and refractory. Acute CINV occurs
within 24 hours of the initial administration of an antineoplastic

THE AMERICAN JOURNAL OF MANAGED CARE® Supplement VOL. 23, NO. 14 S259
 REPORT
TABLE 1. Classifications of CINV14-19
Type of CINV Description
Nausea and/or vomiting occurring within 24
Acute
hours of chemotherapy administration
Nausea and/or vomiting occurring at least 24
Delayed hours post chemotherapy administration; often
peaks between 48 and 72 hours
Nausea and/or vomiting that occurs within 5
days post chemotherapy despite optimal anti-
Breakthrough
emetic regimen used; requires rescue therapy
with other antiemetics
Nausea and/or vomiting that occurs in subse-
Refractory quent chemotherapy cycles despite maximum
antiemetic protocol
Nausea and/or vomiting that is triggered by
Anticipatory sensory stimuli associated with chemotherapy
administration
CINV indicates chemotherapy-induced nausea and vomiting.
agent, while delayed CINV occurs after 24 hours and may peak 2 to
3 days post administration. 14-16
Once a patient experiences CINV, he
or she may then experience anticipatory CINV, which occurs when
a sensory experience (eg, smell, sound, taste) triggers an episode
of nausea and/or vomiting prior to subsequent administration of
a chemotherapy regimen.16-18 Breakthrough CINV can be defined as
nausea and/or vomiting that occurs within 5 days of chemotherapy
treatment despite the use of a guideline-recommended antiemetic
protocol, which requires the addition of more agents referred to
as “rescue medications.” 17,19
Refractory CINV can be described as
nausea and/or vomiting that consistently occurs in subsequent
chemotherapy cycles despite the use of a guideline-recommended
antiemetic regimen.19
Pathophysiology
The pathophysiology of CINV includes both peripheral and central
nervous system (CNS) pathways with different mechanisms involved
in acute CINV and delayed CINV.10,20,21 In acute CINV, free radicals
generated by toxic chemotherapeutic agents stimulate entero-
chromaffin cells in the gastrointestinal tract, causing the release
of serotonin.10,22 Subsequently, serotonin binds to intestinal vagal
afferent nerves via 5-HT3 receptors, which trigger the vomiting reflex
via the nucleus of the solitary tract (NTS) and chemoreceptor trigger
zone (CTZ) in the CNS.10,22 5-HT3 receptor signaling may also play
a role in delayed CINV, but to a lesser extent than in acute CINV.10
Substance P is considered to be the principal neurotransmitter
involved in delayed CINV. Chemotherapy drugs trigger the release
of substance P from neurons in the central and peripheral nervous
systems, which then binds to neurokinin-1 (NK1) receptors mainly
in the NTS to induce vomiting.10,22 In both acute and delayed CINV,
coordination of nausea and vomiting occurs in the vomiting center
S260   SEPTEMBER 2017 www.ajmc.com
in the medulla oblongata via signals from the NTS, CTZ, or afferent
vagal nerves.10 The recommended antiemetic agents for acute
and delayed CINV flow from the differences in pathophysiology.
However, there is evidence of “cross-talk” between 5-HT3 and NK1
pathways that may guide treatment and prevention strategies.10
Anticipatory CINV is generally regarded as a conditioned
response to a prior episode of CINV.16-18 A sensory stimulus (eg,
sight, sound, smell) present at the time of an episode of CINV
conditions the patient to associate the stimulus with nausea and
vomiting. Subsequent exposure to the stimulus then triggers the
conditioned response of nausea and vomiting.13,23 The classic example
is the patient who becomes nauseated simply upon arriving in the
chemotherapy infusion suite. Prevention of acute and delayed
CINV is the best approach to anticipatory CINV so that a sensory
stimulus is not established.
Risk Factors
The risk factors for developing CINV can be categorized as patient-
related or treatment-related.24 While there may be some variability
in patient risk factors based on chemotherapy regimen, the common
patient factors include age, gender, history of motion sickness and/
or pregnancy-related nausea and vomiting, a history of alcohol use,
and emesis with prior chemotherapy. Patients who are younger
than 50 years have a higher risk for CINV.15,24,25 Gender appears to
be a factor with a higher risk generally associated with females15,24;
however, a recent multivariate analysis suggests a less prominent
role of gender on CINV risk.25 Patients who have a history of motion
sickness and/or pregnancy-related nausea and vomiting have a
higher risk of developing CINV. A history of high alcohol intake
(eg, ≥5 drinks per week) tends to lower the risk of CINV,15,24 possibly
because of desensitization of the CTZ.15 The bases for some risk
factors span patient and treatment elements. A risk factor that can
be mitigated through preventive measures is previous episodes
of CINV, and this is particularly true of anticipatory CINV.15,24,25
Related to previous episodes of CINV, another risk factor is failure to
adhere to antiemetic treatment guidelines,25 a factor that is clearly
dependent on healthcare providers.
Emetogenic Risk
One of the most reliable risk factors for CINV is the type of anti-
neoplastic regimen that is being administered. Along with varying
mechanisms of action, chemotherapy agents also vary with respect
to their relative ability to incite emesis, ie, the emetogenic risk,
which is influenced by the drug, dose, route, schedule, and the
combination with other chemotherapy agents.26,27 For the purposes
of this activity, the focus will be on the treatment of CINV in the high
and moderate emetic risk groups. In the high-risk category, the drug
has the potential to elicit CINV in >90% of patients in the absence
of antiemetic prophylaxis, while in the moderate-risk category, the
 OVERVIEW OF CINV AND EVIDENCE-BASED THERAPIES

potential to elicit CINV ranges from 30% to 90% TABLE 2. High and Moderate Emetogenic Risk Classification of Single Cancer
of patients.26 In Table 226, single therapy agents, Chemotherapy Agents26,a
whether administered intravenously or orally, Emetic Risk Intravenously Administered Orally Administered
Group Agentsb Agentsb
are categorized with their relative emetogenic
risk potential.26 • Carboplatin (dose of an AUC of 4) • Procarbazine
• Carmustine
Pharmacologic and Integrative • Cisplatin
• Cyclophosphamide (dose ≥1500 mg/m2)
Medical Therapies for CINV High • Dacarbazine
Pharmacologic Therapies (risk in >90%
• Doxorubicin (dose >60 mg/m2)
of patients)
Prevention and treatment of CINV is based on • Epirubicin (dose >90 mg/m2)
its underlying subtype. The primary goal is to • Ifosfamide (dose ≥2000 mg/m2)
prevent CINV from occurring so that subsequent • Mechlorethamine
episodes of nausea and vomiting and the potential • Streptozocin
for anticipatory CINV are avoided. Uncontrolled • Azacitidine • Cyclophosphamide
nausea and vomiting have potential effects on the • Bendamustine • Imatinib
patient’s QOL and adherence to chemotherapy. • Carboplatin • Temozolomide
The various antiemetic guidelines available for • Clofarabine
CINV describe in detail the numerous options for • Cyclophosphamide (dose <1500 mg/m2)
crafting a regimen to fit a patient’s needs.17,27,28 Moderate • Cytarabine (dose >1000 mg/m2)
(risk in 30% to • Daunorubicin
When devising an antiemetic regimen, the level
90% of patients) • Doxorubicin
of treatment is based on the chemotherapy drug
• Epirubicin
with the highest potential for emesis. Therefore,
• Idarubicin
if a chemotherapy regimen includes drugs with
• Ifosfamide (dose <2000 mg/m2)
low or minimal emetic risks, as well as a drug • Irinotecan
with high emetic risk, such as anthracyclines, • Oxaliplatin
the antiemetic regimen should be tailored to a
For a more comprehensive list of emetogenic potentials of chemotherapy agents, please refer to the
the drug with the highest emetic risk. Emesis Additional Resources sidebar.
b
Agents are listed in alphabetical order within each category.
control should be individualized to patient Adapted from reference 26.
need and, depending on the chemotherapeutic
agents used, duration of regimen, the route of
administration for the antiemetic, and considerations regarding differences in half-lives influence dosing and possibly indication.
the AEs of the antiemetic agents. Ondansetron, dolasetron, and granisetron are most commonly used
The main pharmacologic classes of drugs used in preventing in acute CINV.30,31 Palonosetron demonstrates efficacy in delayed
and treating CINV (Table 327) are 5-HT3 receptor antagonists, NK1 CINV as well.32-35 Common AEs for 5-HT3 antagonists include
receptor antagonists, and corticosteroids; they also include, to a headache and gastrointestinal effects such as constipation, as
lesser extent, dopamine antagonists, benzodiazepines, cannabi- well as elevation of liver aminotransferase levels.36-39 Of particular
noids, and the atypical antipsychotic, olanzapine. With different note, ondansetron and dolasetron should be given with caution
mechanisms of action, the agents are typically administered in in patients with long QT syndrome.36,38
combination protocols to provide maximum antiemetic control,
particularly when patients are undergoing high or moderate emetic NK1 Receptor Antagonists
risk chemotherapy regimens. The NK1 receptor antagonists act peripherally and centrally by
blocking the binding of substance P at the NK1 receptor.40 The
5-HT3 Receptor Antagonists approved drugs in this class include aprepitant, fosaprepitant (a
The 5-HT3 receptor antagonists act on serotonin receptors both prodrug of aprepitant for injection), and rolapitant.41,42 Another NK1
peripherally in the intestine and centrally in the CTZ. This 29
receptor antagonist, netupitant, is formulated with the 5-HT3 receptor
class includes the first-generation 5-HT3 receptor antagonists, antagonist, palonosetron, in a fixed-dose combination product for
ondansetron, dolasetron, and granisetron, with half-lives between acute and delayed CINV.43 The NK1 antagonists are not used as sole
3 and 9 hours. The second-generation compound in this class, antiemetic agents in acute CINV, but rather typically in combination
palonosetron, has a half-life of approximately 40 hours.29 The with a 5-HT3 antagonist and dexamethasone. Aprepitant may also

THE AMERICAN JOURNAL OF MANAGED CARE® Supplement VOL. 23, NO. 14    S261
 REPORT

TABLE 3. Antiemetic Agents by Pharmacologic Class27
Pharmacologic Class Agentsa
• Dolasetron mesylate (Anzemet)
• Granisetron hydrochloride
(Granisol, Kytril, Sancuso)
5-HT3 receptor
antagonists
• Ondansetron base (Zofran ODT, Zuplenz)
• Ondansetron hydrochloride (Zofran)
• Palonosetron hydrochloride (Aloxi)
• Aprepitant (Emend)
NK1 receptor
• Fosaprepitant dimeglumine (Emend) –
antagonists prodrug of aprepitant for IV injection
in patients receiving thioridazine and concomitant administration
should be avoided with other CYP2D6 substrates, such as pimozide,
but no dose adjustment is needed with dexamethasone.42
For the netupitant/palonosetron (NEPA) combination product,
AEs include asthenia, dyspepsia, fatigue, hiccups, and erythema,
and severe AEs reported in clinical trials include neutropenia and
leukopenia.53,54 Netupitant is a moderate inhibitor of CYP3A4 and
drug interactions are possible in patients receiving drugs that
are metabolized by CYP3A4, but no contraindications are listed.43
NEPA, however, should be avoided in patients with severe renal
or hepatic impairment.43

• Rolapitant (Varubi)
NK1/5-HT3 • Netupitant/palonosetron
combination hydrochloride (Akynzeo)
Corticosteroid • Dexamethasone (Decadron)
Atypical antipsychotic • Olanzapine (Zyprexa)
Dopamine • Metoclopramide (Reglan)
antagonists • Prochlorperazine (Compazine)
• Alprazolam (Xanax)
Benzodiazepines
• Lorazepam (Ativan)
• Dronabinol (Marinol)
Cannabinoids
• Nabilone (Cesamet)
IV indicates intravenous; ODT, orally disintegrating tablet.
a
Agents are listed in alphabetical order within each class and brand names
are listed in parentheses where applicable.
be used in delayed CINV.17,27,28 AEs of NK1 receptor antagonists are
generally limited to diarrhea, fatigue, and nausea,44-48 but individual
agents have specialized AEs of note. Aprepitant is metabolized by
and is a moderate inhibitor of CYP3A4, which may lead to drug-drug
interactions. Of particular importance in CINV, aprepitant causes
an increase in plasma dexamethasone levels; therefore, reduction
in dexamethasone doses are necessary when used in combination
antiemetic regimens. 29,49-51
Aprepitant and fosaprepitant are also
contraindicated in patients receiving pimozide because inhibition
of metabolism can lead to increased pimozide levels that can cause
severe or life-threatening reactions, including QT prolongation.41 In
addition, aprepitant and fosaprepitant should be used with caution
in patients receiving warfarin, due to a potential decrease in the
international normalized ratio; drug-drug interactions are possible
with CYP3A4 substrates, CYP3A4 inhibitors, and CYP3A4 inducers.41
Rolapitant is generally well tolerated, with fewer than 10% of
patients experiencing treatment-related AEs.44,45 The most common
AEs with rolapitant were similar to those of control groups and include
neutropenia, hiccups, and dizziness.42 Although rolapitant is not an
inhibitor or inducer of CYP3A4, it is metabolized by the enzyme, and
52
CYP3A4 inducers, such as rifampin, can reduce rolapitant blood levels
and efficacy.42 As a CYP2D6 inhibitor, rolapitant is contraindicated
Corticosteroids
While the mechanism of action of corticosteroids as antiemetics is not
entirely clear, their use in CINV dates to the 1980s.29 Dexamethasone
is the corticosteroid of choice for CINV, and it is often used in
combination with other agents to increase antiemetic efficacy
in acute and delayed CINV. Dexamethasone may also be used as
monotherapy in low–emetic risk chemotherapy regimens.17,27,28
Other Agents
Dopamine receptor antagonists (eg, metoclopramide, prochlorpera-
zine) were used in early attempts to alleviate CINV. These drugs
still have their place in current CINV treatment regimens.17,27,28 It is
important to emphasize that these agents are used in breakthrough
CINV, and as a rescue medication, they exhibit many AEs, with the
most worrisome being extrapyramidal symptoms. Although an off-
label use, the atypical antipsychotic, olanzapine, has gained a role
for its antiemetic effects, particularly for breakthrough CINV.17,27,28
Common AEs associated with olanzapine include sedation, fatigue,
headache, dry mouth, hyperglycemia, and diarrhea.55-57 Olanzapine can
also increase the risk of extrapyramidal symptoms.57 Benzodiazepines
are most often used in treating anticipatory CINV, but may also be
included in regimens to treat breakthrough or refractory CINV.17,27,28
Antiemetic guidelines are published by several major cancer
organizations, including the American Society of Clinical Oncology
(ASCO), the National Comprehensive Cancer Network (NCCN), and
jointly by the European Society of Medical Oncology (ESMO) and the
Multinational Association of Supportive Care in Cancer (MASCC).17,27,28
One notable difference among the guidelines is the consideration
of cannabinoids. In the ASCO and MASCC/ESMO guidelines, can-
nabinoids are not listed as antiemetic alternatives, while the NCCN
guidelines list cannabinoids as options for breakthrough/refractory
CINV.17,27,28 Also, in the ASCO and NCCN guidelines, palonosetron is
considered the preferred 5-HT3 antagonist for moderate emetogenic
chemotherapy regimens, while the MASCC/ESMO guidelines do not
specify any particular 5-HT3 antagonist.17,27,28,58 A generalized scheme
for antiemetic protocols from the various guidelines can be found
in Table 4.10,17,22,27,28,59

S262   SEPTEMBER 2017 www.ajmc.com

 OVERVIEW OF CINV AND EVIDENCE-BASED THERAPIES

Integrative Medical Treatments TABLE 4. Generalized Antiemetic Guidelines10,17,22,27,28,59,a

Given the increasing preferences for integrative medicine using Chemotherapy Emetic Risk Recommended Antiemeticsb
complementary and alternative therapies, patients may express an Acute CINV
interest in alternatives to standard pharmacologic treatments for • NK1 + 5-HT3 + DEX
CINV. Pharmacists and other healthcare providers should be aware • Netupitant/palonosetron + DEX
of nonpharmacologic or alternative treatments so they can provide High • Olanzapine + palonosetron + DEX
the proper counsel to patients. As is common with alternative • Aprepitant or fosaprepitant +
medical treatments, there tends to be a dearth of well-controlled 5-HT3 + DEX + olanzapine

trials to properly evaluate such alternative treatments. Pharmacists • 5-HT3 + DEX

and other healthcare providers may find it helpful to engage their • NK1 + 5-HT3 + DEX
Moderate
• Netupitant/palonosetron + DEX
patients in conversations regarding nonpharmacologic or alternative
• Olanzapine + palonosetron + DEX
treatments. Even if the clinical evidence is lacking, patients may
Low • DEX or DRA or 5-HT3
derive other benefits from such treatments. Pharmacists should
also ensure that the nonpharmacologic or alternative treatments Minimal • No routine prophylaxis

do not interact with pharmacologic therapies in a negative manner. Delayed CINV

• Aprepitant + DEX
Behavioral Treatments • DEX
High
Anticipatory CINV, as a learned response to a stimulus, may • Olanzapine
respond to nonpharmacologic treatments, particularly behavioral • Aprepitant + DEX + olanzapine

modification approaches.10,13,23,60 Antiemetic therapies may actually • DEX

exacerbate nausea and vomiting in anticipatory CINV. Behavioral
61 • 5-HT3 monotherapy
Moderate • Aprepitant +/– DEX
approaches to anticipatory CINV may be preferable; they include
• DEX
hypnosis, muscle relaxation with guided imagery, music therapy,
• Olanzapine
systematic desensitization, and biofeedback.13,27 Particularly for
Low • DEX or DRA or 5-HT3
anticipatory CINV, patients and healthcare providers may also
Minimal • No routine prophylaxis
opt for the use of acupuncture or acupressure, in which needles or
external pressure are placed at critical pressure points of the body Add 1 agent from a different drug
class to current regimen, such as:
to relieve the symptoms of nausea and vomiting. 27,62
• Olanzapine
Breakthrough/refractory • Benzodiazepine
Alternative Treatments (all risk groups) • Cannabinoid
Two of the most common alternative CINV treatments are ginger • DRA
and cannabis, including its various forms and synthetic deriva- • 5-HT3
tives. Ginger (Zingiber officinale) has a long history as an agent to • DEX
treat gastrointestinal ailments and it is a relatively popular home • Prevention first
remedy for nausea and vomiting. Studies suggest that ginger • Behavioral therapy
Anticipatory
contains bioactive compounds that bind to 5-HT3 receptors and • Acupuncture/acupressure
thus may alleviate symptoms of nausea and vomiting.62,63 While • Benzodiazepine
controlled clinical trials studying ginger for CINV have produced CINV indicates chemotherapy-induced nausea and vomiting; DEX, dexametha-
sone; DRA, dopamine receptor antagonist; NK1, neurokinin-1; 5-HT3, 5-HT3
mixed results, ginger, at doses up to 4 grams per day, is classified receptor antagonist.
in the “generally regarded as safe” category by the FDA. Patients a
Order of regimens or agents does not indicate preferential status.
b
Specific dosing recommendations can be found in antiemetic guidelines.17,27,28,59
should discuss with their physician the doses of ginger they are
taking, especially for the potential risk of bleeding in patients with
thrombocytopenia.62 Most clinical success appears to be seen when commercial form of the synthetic cannabinoid, dronabinol, has
ginger is used as a supplemental treatment along with standard been on the market since 1985, and in 2016, a newer, oral solution
antiemetic protocols.62 formulation was approved that includes CINV as an indication.64
In addition, the FDA approved the capsule formulation of another
Cannabinoids for CINV synthetic cannabinoid, nabilone, in 1985.65 After the original nabilone
With increasing public debate on medicinal cannabis and legalized manufacturer withdrew it from the market, a different manufac-
cannabis, patients may express interest in its use for CINV. A turer received marketing approval again in 2005.65 The synthetic

THE AMERICAN JOURNAL OF MANAGED CARE® Supplement VOL. 23, NO. 14    S263
 REPORT
cannabinoids, dronabinol and nabilone, are generally accepted
for the treatment of CINV, particularly breakthrough or refractory
types.27 It is important to note that dronabinol is a schedule III drug
and nabilone is a schedule II drug.66-68
Role of Pharmacists
Antiemetic drugs are often used to prevent CINV caused by che-
motherapy regimens that frequently include multiple drugs. With
the polypharmacy typically required in chemotherapy and CINV,
pharmacists can become crucial partners with other healthcare
professionals and patients to optimize clinical outcomes. Pharmacists
can assist with adherence to standard CINV guidelines, which
can greatly assist with preventing CINV in the first place. Eligible
pharmacists can also aspire to board certification in oncology,69
which can enhance their ability to provide advanced clinical
expertise to patients and the medical team.
Summary
CINV remains a common AE of chemotherapy that can profoundly
impact the lives of patients with cancer. Diligent adherence to
antiemetic guidelines can reduce the incidence of CINV. Even with
firm adherence, breakthrough or refractory CINV can occur that will
require additional clinical evaluation. Pharmacists knowledgeable
in CINV treatment guidelines are an important resource for patients,
caregivers, and other healthcare professionals. n
Additional Resources
2017 NCCN Guidelines
www.nccn.org/professionals/physician_gls/f_guidelines.asp
2016 MASCC and ESMO Guidelines
Roila F, Molassiotis A, Herrstedt J, et al; participants of the MASCC/
ESMO Consensus Conference Copenhagen 2015. 2016 MASCC and ESMO
guideline update for the prevention of chemotherapy- and radiotherapy-
induced nausea and vomiting and of nausea and vomiting in advanced
cancer patients. Ann Oncol. 2016;27(suppl 5):v119-v133. doi: 10.1093/
annonc/mdw270.
2011 ASCO Guidelines and 2016 Focused Update
Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society
of Clinical Oncology clinical practice guideline update [erratum in: J
Clin Oncol. 2014;32(19):2117. Dosage error in article text]. J Clin Oncol.
2011;29(31):4189-4198. doi: 10.1200/JCO.2010.34.4614.
Hesketh PJ, Bohlke K, Lyman GH, et al; American Society of Clinical
Oncology. Antiemetics: American Society of Clinical Oncology Focused
Guideline Update. J Clin Oncol. 2016;34(4):381-386. doi: 10.1200/
JCO.2015.64.3635.
National Cancer Institute
www.cancer.gov
American Cancer Society
www.cancer.org
Board of Pharmacy Specialties Board
Certified Oncology Pharmacist program
www.bpsweb.org/bps-specialties/oncology-pharmacy/
S264   SEPTEMBER 2017 www.ajmc.com
Author affiliation: Touro College of Pharmacy, New York, NY.
Funding source: This activity is supported by educational grants from
Eisai Inc and Tesaro, Inc.
Author disclosure: Dr Adel has no relevant financial relationships with
commercial interests to disclose.
Authorship information: Concept and design; analysis and interpreta-
tion of data; supervision.
Address correspondence to: nelly.adel@touro.edu.
REFERENCES
1. Hofman M, Morrow GR, Roscoe JA, et al. Cancer patients’ expectations of experiencing treatment-
related side effects: a University of Rochester Cancer Center-Community Clinical Oncology Program
study of 938 patients from community practices. Cancer. 2004;101(4):851-857. doi: 10.1002/cncr.20423.
2. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358(23):2482-2494. doi:
10.1056/NEJMra0706547.
3. Hernandez Torres C, Mazzarello S, Ng T, et al. Defining optimal control of chemotherapy-induced
nausea and vomiting—based on patients’ experience. Support Care Cancer. 2015;23(11):3341-3359. doi:
10.1007/s00520-015-2801-y.
4. Sommariva S, Pongiglione B, Tarricone R. Impact of chemotherapy-induced nausea and vomiting
on health-related quality of life and resource utilization: a systematic review. Crit Rev Oncol Hematol.
2016;99:13-36. doi: 10.1016/j.critrevonc.2015.12.001.
5.Bloechl-Daum B, Deuson RR, Mavros P, Hansen M, Herrstedt J. Delayed nausea and vomiting con-
tinue to reduce patients’ quality of life after highly and moderately emetogenic chemotherapy despite
antiemetic treatment. J Clin Oncol. 2006;24(27):4472-4478. doi: 10.1200/JCO.2006.05.6382.
6. Haiderali A, Menditto L, Good M, Teitelbaum A, Wegner J. Impact on daily functioning and indirect/
direct costs associated with chemotherapy-induced nausea and vomiting (CINV) in a U.S. population.
Support Care Cancer. 2011;19(6):843-851. doi: 10.1007/s00520-010-0915-9.
7. O’Brien BJ, Rusthoven J, Rocchi A, et al. Impact of chemotherapy-associated nausea and vomiting
on patients’ functional status and on costs: survey of five Canadian centres. CMAJ. 1993;149(3):296-
302. Accessed June 6, 2017.
8. Vidall C, Dielenseger P, Farrell C, et al. Evidence-based management of chemotherapy-induced nau-
sea and vomiting: a position statement from a European cancer nursing forum. Ecancermedicalscience.
2011;5:211. doi: 10.3332/ecancer.2011.211.
9. Fernández-Ortega P, Caloto MT, Chirveches E, et al. Chemotherapy-induced nausea and vomiting in
clinical practice: impact on patients’ quality of life. Support Care Cancer. 2012;20(12):3141-3148. doi:
10.1007/s00520-012-1448-1.
10. Janelsins MC, Tejani MA, Kamen C, Peoples AR, Mustian KM, Morrow GR. Current pharmaco-
therapy for chemotherapy-induced nausea and vomiting in cancer patients. Expert Opin Pharmacother.
2013;14(6):757-766. doi: 10.1517/14656566.2013.776541.
11. Singh P, Yoon SS, Kuo B. Nausea: a review of pathophysiology and therapeutics. Therap Adv
Gastroenterol. 2016;9(1):98-112. doi: 10.1177/1756283X15618131.
12. Hasler WL, Chey WD. Nausea and vomiting. Gastroenterology. 2003;125(6):1860-1867.
13. PDQ Supportive and Palliative Care Editorial Board. Treatment-related nausea and vomiting (PDQ®):
health professional version. In: National Cancer Institute. PDQ Cancer Information Summaries [Internet].
Bethesda, MD: National Cancer Institute; 2002-2017. www.ncbi.nlm.nih.gov/books/NBK66056/.
14. Jordan K, Schmoll HJ, Aapro MS. Comparative activity of antiemetic drugs. Crit Rev Oncol Hematol.
2007;61(2):162-175. doi: 10.1016/j.critrevonc.2006.08.003.
15. Aapro M, Jordan K, Feyer P. Pathophysiology and classification of chemotherapy-induced nausea
and vomiting. In: Aapro M, Jordan K, Feyer P, eds. Prevention of Nausea and Vomiting in Cancer Patients,
London, UK: Springer Healthcare, Ltd; 2015:5-14.
16. Lohr LK. Current practice in the prevention and treatment of chemotherapy-induced nausea and
vomiting in adults. J Hematol Oncol Pharm. 2011;1(4):13-21.
17. Roila F, Molassiotis A, Herrstedt J, et al; participants of the MASCC/ESMO Consensus Conference
Copenhagen 2015. 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and
radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients.
Ann Oncol. 2016;27(suppl 5):v119-v133. doi: 10.1093/annonc/mdw270.
18. Roscoe JA, Morrow GR, Aapro MS, Molassiotis A, Olver I. Anticipatory nausea and vomiting. Support
Care Cancer. 2011;19(10):1533-1538. doi: 10.1007/s00520-010-0980-0.
19. Navari RM. Treatment of breakthrough and refractory chemotherapy-induced nausea and vomiting.
Biomed Res Int. 2015;2015:595894. doi: 10.1155/2015/595894.
20. Darmani NA. Mechanisms of broad-spectrum antiemetic efficacy of cannabinoids against
chemotherapy-induced acute and delayed vomiting. Pharmaceuticals (Basel). 2010;3(9):2930-2955. doi:
10.3390/ph3092930.
21. Hesketh PJ, Van Belle S, Aapro M, et al. Differential involvement of neurotransmitters through the
time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur
J Cancer. 2003;39(8):1074-1080.
22. Rapoport BL. Delayed chemotherapy-induced nausea and vomiting: pathogenesis, incidence, and
current management. Front Pharmacol. 2017;8:19. doi: 10.3389/fphar.2017.00019.
23. Ahrari S, Chow R, Goodall S, DeAngelis C. Anticipatory nausea: current landscape and future direc-
tions. Ann Palliat Med. 2017;6(1):1-2. doi: 10.21037/apm.2016.10.01.
24. Hesketh PJ, Aapro M, Street JC, Carides AD. Evaluation of risk factors predictive of nausea and
vomiting with current standard-of-care antiemetic treatment: analysis of two phase III trials of apre-
pitant in patients receiving cisplatin-based chemotherapy. Support Care Cancer. 2010;18(9):1171-1177.
doi: 10.1007/s00520-009-0737-9.

25. Molassiotis A, Aapro M, Dicato M, et al. Evaluation of risk factors predicting chemotherapy-related
nausea and vomiting: results from a European prospective observational study. J Pain Symptom Manage.
2014;47(5):839-848.e4. doi: 10.1016/j.jpainsymman.2013.06.012.
26. Grunberg SM, Warr D, Gralla RJ, et al. Evaluation of new antiemetic agents and definition of anti-
neoplastic agent emetogenicity—state of the art. Support Care Cancer. 2011;19(suppl 1):S43-S47. doi:
10.1007/s00520-010-1003-x.
27. NCCN Clinical Practice Guidelines in Oncology: Antiemesis, version 2.2017. National Comprehensive
Cancer Network website. www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/pro-
fessionals/physician_gls/pdf/antiemesis.pdf. Published March 28, 2017. Accessed August 11, 2017.
28. Basch E, Prestrud AA, Hesketh PJ, et al; American Society of Clinical Oncology. Antiemetics:
American Society of Clinical Oncology clinical practice guideline update [erratum in J Clin Oncol.
2014;32(19):2117. Dosage error in article text]. J Clin Oncol. 2011;29(31):4189-4198. doi: 10.1200/
JCO.2010.34.4614.
29. Rao KV, Faso A. Chemotherapy-induced nausea and vomiting: optimizing prevention and manage-
ment. Am Heal Drug Benefits. 2012;5(4):232-240.
30. Geling O, Eichler HG. Should 5-hydroxytryptamine-3 receptor antagonists be administered beyond
24 hours after chemotherapy to prevent delayed emesis? systematic re-evaluation of clinical evidence
and drug cost implications. J Clin Oncol. 2005;23(6):1289-1294. doi: 10.1200/JCO.2005.04.022.
31. Hickok JT, Roscoe JA, Morrow GR, et al. 5-hydroxytryptamine-receptor antagonists versus prochlor-
perazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial.
Lancet Oncol. 2005;6(10):765-772. doi: 10.1016/S1470-2045(05)70325-9.
32. Botrel TE, Clark OA, Clark L, Paladini L, Faleiros E, Pegoretti B. Efficacy of palonosetron (PAL) com-
pared to other serotonin inhibitors (5-HT3R) in preventing chemotherapy-induced nausea and vomiting
(CINV) in patients receiving moderately or highly emetogenic (MoHE) treatment: systematic review and
meta-analysis. Support Care Cancer. 2011;19(6):823-832. doi: 10.1007/s00520-010-0908-8.
33. Balu S, Buchner D, Craver C, Gayle J. Palonosetron versus other 5-HT(3) receptor antagonists for
prevention of chemotherapy-induced nausea and vomiting in patients with cancer on chemotherapy in
a hospital outpatient setting. Clin Ther. 2011;33(4):443-455. doi: 10.1016/j.clinthera.2011.04.009.
34. Schwartzberg L, Barbour SY, Morrow GR, Ballinari G, Thom MD, Cox D. Pooled analysis of phase
III clinical studies of palonosetron versus ondansetron, dolasetron, and granisetron in the prevention
of chemotherapy-induced nausea and vomiting (CINV). Support Care Cancer. 2014;22(2):469-477. doi:
10.1007/s00520-013-1999-9.
35. Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versus granisetron plus
dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-
dummy, randomised, comparative phase III trial [erratum in Lancet Oncol. 2010;11(3):226]. Lancet Oncol.
2009;10(2):115-124. doi: 10.1016/S1470-2045(08)70313-9.
36. Zofran [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2017.
37. Sancuso [package insert]. Bedminster, NJ: ProStrakan Inc; 2015.
38. Anzemet [package insert]. Bridgewater, NJ: Sanofi-Aventis US LLC; 2009.
39. Aloxi [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2013.
40. Diemunsch P, Grélot L. Potential of substance P antagonists as antiemetics. Drugs. 2000;60(3):533-546.
41. Emend [package insert]. Whitehouse Station, NJ: Merck & Co Inc; 2017.
42. Varubi [package insert]. Waltham, MA: Tesaro, Inc; 2015.
43. Akynzeo [package insert]. Iselin, NJ: Helsinn Therapeutics Inc; 2016.
44. Rapoport B, Chua D, Poma A, Arora S, Wang Y, Fein LE. Study of rolapitant, a novel, long-acting,
NK-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting (CINV) due
to highly emetogenic chemotherapy (HEC). Support Care Cancer. 2015;23(11):3281-3288. doi: 10.1007/
s00520-015-2738-1.
45. Schwartzberg LS, Modiano MR, Rapoport BL, et al. Safety and efficacy of rolapitant for preven-
tion of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic
chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised,
active-controlled, double-blind, phase 3 trial. Lancet Oncol. 2015;16(9):1071-1078. doi: 10.1016/S1470-
2045(15)00034-0.
46. Saito H, Yoshizawa H, Yoshimori K, et al. Efficacy and safety of single-dose fosaprepitant in the
prevention of chemotherapy-induced nausea and vomiting in patients receiving high-dose cisplatin: a
multicentre, randomised, double-blind, placebo-controlled phase 3 trial. Ann Oncol. 2013;24(4):1067-
1073. doi: 10.1093/annonc/mds541.
47. Weinstein C, Jordan K, Green SA, et al. Single-dose fosaprepitant for the prevention of
chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy:
THE AMERICAN JOURNAL OF MANAGED CARE® Supplement
OVERVIEW OF CINV AND EVIDENCE-BASED THERAPIES
results of a randomized, double-blind phase III trial. Ann Oncol. 2016;27(1):172-178. doi: 10.1093/
annonc/mdv482.
48. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al; Aprepitant Protocol 054 Study Group. Addition
of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control
of chemotherapy-induced nausea and vomiting. results from a randomized, double-blind, placebo-
controlled trial in Latin America. Cancer. 2003;97(12):3090-3098. doi: 10.1002/cncr.11433.
49. Chawla SP, Grunberg SM, Gralla RJ, et al. Establishing the dose of the oral NK1 antagonist aprepi-
tant for the prevention of chemotherapy-induced nausea and vomiting. Cancer. 2003;97(9):2290-2300.
doi: 10.1002/cncr.11320.
50. Aapro MS, Walko CM. Aprepitant: drug-drug interactions in perspective. Ann Oncol. 2010;21(12):2316-2323.
doi: 10.1093/annonc/mdq149.
51. Takahashi T, Nakamura Y, Tsuya A, Murakami H, Endo M, Yamamoto M. Pharmacokinetics of
aprepitant and dexamethasone after administration of chemotherapeutic agents and effects of plasma
substance P concentration on chemotherapy-induced nausea and vomiting in Japanese cancer patients.
Cancer Chemother Pharmacol. 2011;68(3):653-659. doi: 10.1007/s00280-010-1519-2.
52. Goldberg T, Fidler B, Cardinale S. Rolapitant (Varubi): a substance P/neurokinin-1 receptor antago-
nist for the prevention of chemotherapy-induced nausea and vomiting. P T. 2017;42(3):168-172.
53. Aapro M, Rugo H, Rossi G, et al. A randomized phase III study evaluating the efficacy and
safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemo-
therapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol.
2014;25(7):1328-1333. doi: 10.1093/annonc/mdu101.
54. Hesketh PJ, Rossi G, Rizzi G, et al. Efficacy and safety of NEPA, an oral combination of netupitant
and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly
emetogenic chemotherapy: a randomized dose-ranging pivotal study. Ann Oncol. 2014;25(7):1340-1346.
doi: 10.1093/annonc/mdu110.
55. Navari RM, Aapro M. Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl
J Med. 2016;374(14):1356-1367. doi: 10.1056/NEJMra1515442.
56. Tan L, Liu J, Liu X, et al. Clinical research of olanzapine for prevention of chemotherapy-induced
nausea and vomiting. J Exp Clin Cancer Res. 2009;28:131. doi: 10.1186/1756-9966-28-131.
57. Zyprexa [package insert]. Indianapolis, IN: Eli Lilly and Company; 2017.
58. Hesketh PJ. Prevention and treatment of chemotherapy-induced nausea and vomiting in adults.
UpToDate website. www.uptodate.com/contents/prevention-and-treatment-of-chemotherapy-induced-
nausea-and-vomiting-in-adults. Updated July 24, 2017. Accessed August 17, 2017.
59. Hesketh PJ, Bohlke K, Lyman GH, et al; American Society of Clinical Oncology. Antiemetics:
American Society of Clinical Oncology Focused Guideline Update. J Clin Oncol. 2016;34(4):381-386. doi:
10.1200/JCO.2015.64.3635.
60. Mustian KM, Darling TV, Janelsins MC, Jean-Pierre P, Roscoe JA, Morrow GR. Chemotherapy-
induced nausea and vomiting. US Oncol. 2008;4(1):19-23.
61. Morrow GR, Roscoe JA, Kirshner JJ, Hynes HE, Rosenbluth RJ. Anticipatory nausea and vomiting in
the era of 5-HT 3 antiemetics. Support Care Cancer. 1998;6(3):244-247. doi: 10.1007/s005200050161.
62. Mustian KM, Devine K, Ryan JL, et al. Treatment of nausea and vomiting during chemotherapy. US
Oncol Hematol. 2011;7(2):91-97.
63. Marx W, Isenring EA, Lohning AE. Determination of the concentration of major active anti-emetic
constituents within commercial ginger food products and dietary supplements. Eur J Integr Med.
2017;10:19-24. doi: 10.1016/j.eujim.2017.02.001.
64. Insys Therapeutics announces FDA approval of Syndros [news release]. Phoenix, AZ:
Insys Therapeutics, Inc; July 5, 2016. investors.insysrx.com/phoenix.zhtml?c=115949&p=irol-
newsArticle&ID=2181815. Accessed June 30, 2017.
65. Valeant returns synthetic cannabinoid to USA. PharmaTimes Online website. www.pharmatimes.com/
news/valeant_returns_synthetic_cannabinoid_to_usa_996830. Published May 17, 2006. Accessed
June 30, 2017.
66. DEA schedules Insys Therapeutics’ Syndros (dronabinol oral solution) as Schedule II drug
[news release]. Phoenix, AZ: Insys Therapeutics, Inc; March 23, 2017. globenewswire.com/news-
release/2017/03/23/943459/0/en/DEA-Schedules-Insys-Therapeutics-Syndros-dronabinol-oral-solution-
as-Schedule-II-Drug.html. Accessed July 13, 2017.
67. Marinol [package insert]. North Chicago, IL: AbbVie Inc; 2017.
68. Cesamet [package insert]. Somerset, NJ: Meda Pharmaceuticals Inc; 2013.
69. Board of Pharmacy Specialties (BPS) Board Certified Oncology Pharmacist program. BPS website.
www.bpsweb.org/bps-specialties/oncology-pharmacy/. Accessed July 1, 2017.
VOL. 23, NO. 14    S265