Download Chemotherapy-Induced Nausea and Vomiting

Clinical Review
Chemotherapy-Induced Nausea and Vomiting:
Identifying and Addressing Unmet Needs
Ralph V. Boccia, MD
ABSTRACT
• Objective: To review current issues in chemotherapyinduced nausea and vomiting (CINV) management
and consider practical options to optimize antiemetic
use and improve outcomes.
• Methods: Practical review of current evidence and
examination of management strategies.
• Results: Management of CINV is primarily guided by
evidence-based recommendations from the American Society of Clinical Oncology (ASCO), the Multinational Association of Supportive Care in Cancer
(MASCC), and the National Comprehensive Cancer
Network (NCCN), which recommend selection of
antiemetics based on the emetogenicity of the chemotherapy regimen. 5-HT3 antagonists, often heralded as one of the most significant advances in
the treatment of CINV, and newer NK-1 antagonists
play a predominant role for moderately and highly
emetogenic chemotherapy. However, limited adherence to guidelines is a concern. Strategies to improve
outcomes therefore initially focus on ensuring optimal
selection and use of antiemetic agents. Beyond antiemetic selection, more sophisticated approaches can
be proposed to improve outcomes across the breadth
of supportive care by involving multidisciplinary expertise in integrated care strategies.
• Conclusion: Despite significant advances with anti-
emetics, CINV remains an important problem for many
cancer patients. Developing integrated approaches to
improve the care of at-risk patients represents a crucial
step towards improving outcomes.
N
ausea and vomiting have long been acknowledged to be among the most feared and distressing side effects of chemotherapy. Chemotherapy-induced nausea and vomiting (CINV) can have
significant effects on both quality of life and physical
functioning [1,2]; in severe cases, CINV can lead to serious complications or a clinical decision to delay, reduce,
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or even stop chemotherapy [1–4]. As a consequence,
control of CINV is a high priority for improving clinical
outcomes in patients with cancer.
Antiemetic prophylaxis has been improving continuously over the past decades; at the same time, chemotherapy agents have themselves changed, affecting the side
effect profile that patients experience. The introduction of
5-HT3 antagonists in the 1990s represents one of the most
significant advances in the treatment of CINV to date [5],
followed by more recent developments with NK-1 receptor
antagonists and evidence-based treatment strategies.
Nevertheless, there remain considerable unmet needs
in CINV. Crucially, observational studies indicate that
around one-third to one-half of patients at risk experience CINV despite prophylaxis, with concomitant
detrimental effects on quality of life [6–9]. This article
reviews the current evidence and treatment options for
CINV and considers integrated strategies to improve
outcomes for patients.
Overview of CINV
Incidence and Impact
The overall incidence of CINV is challenging to estimate,
as risks vary greatly depending on the emetogenicity of
chemotherapy and a number of risk factors. Nevertheless, it is generally accepted that without appropriate
prophylaxis, 70% to 80% of all cancer patients receiving
chemotherapy experience nausea and/or vomiting [10].
Even with prophylaxis, observational studies indicate that
as many as half of patients may experience uncontrolled
nausea or vomiting [6–9]; for example, Grunberg et al
reported that greater than 35% of patients experienced
nausea within 24 hours of chemotherapy, with 54%
experiencing nausea and 32% experiencing vomiting in
the following 4 days [7].
From the Center for Cancer and Blood Disorders, Bethesda,
MD.
Vol. 20, No. 8 August 2013 JCOM 377
CINV
While improvements in antiemetic therapy have enabled
improvements in quality of life for patients undergoing
emetogenic chemotherapy, unmet needs remain [11]. The
burden that uncontrolled CINV places on patients and
their families and carers can be substantial, impacting both
physical well-being and quality of life. The direct physiological effects of nausea and vomiting include metabolic
imbalances (hypokalemia, hyponatremia, hypochloremic
alkalosis), degeneration of functional ability and performance status, nutrient depletion, anorexia, and esophageal
tears [1,2]. Moreover, if the symptoms of severe emesis
are not recognized and treated, a number of potentially
serious complications could arise. These may include dehydration, weight loss, metabolic disorders, dental erosion,
wound dehiscence, and aspiration pneumonia [1,2].
Beyond its direct physiological effects, CINV can
affect diverse aspects of patients’ quality of life, such as
daily functioning, leisure activities, and the enjoyment
of food and drink [6,9]. Interestingly, there is some evidence to suggest that nausea often has a greater impact
on quality of life than vomiting in patients receiving
chemotherapy [6].
Moreover, consideration should be given to the knockon effects of CINV. Haiderali et al estimated the total
costs associated with CINV at $779 per patient following
the first chemotherapy cycle, with more severe CINV attracting higher costs [8]. Perhaps more worrisome, severe
CINV may lead to a clinical decision to delay, reduce, or
even stop chemotherapy [2,4,12]. Although continued
chemotherapy can substantially improve life expectancy
and quality of life, many patients fear that side effects will
reduce their overall quality of life, particularly during the
palliative care phase [13]; discontinuation of chemotherapy may therefore be a particular challenge in the
palliative stages of treatment.
Classification
CINV is typically classified based on the timing (or phase)
of the nausea and/or vomiting in relation to chemotherapy.
Anticipatory nausea and vomiting occurs prior to administration, and is thought to be a conditioned response to a
negative chemotherapy experience, occurring in up to 20%
of patients by the fourth treatment cycle [14,15]. Anticipatory nausea and vomiting is difficult to treat once developed [14]. Therefore, current guidelines emphasize the importance of effectively preventing acute or delayed CINV
(the negative experience) from the first time chemotherapy
is administered, thereby avoiding the subsequent develop378 JCOM August 2013 Vol. 20, No. 8
ment of a conditioned response. However, if anticipatory
nausea does occur, behavioral therapy with systematic desensitization is the primary treatment recommended [16].
Acute CINV typically occurs within 24 hours after
chemotherapy administration, while delayed CINV usually develops 24 to 120 hours after administration [2,17].
Delayed CINV has a higher incidence than acute CINV
and also has a pronounced impact on patient quality of
life [6,8,9,12]. Evidence suggests, however, that delayed
CINV is underreported by patients, and its incidence
is underestimated by most oncology physicians and
nurses [7]; while uncontrolled acute CINV is correlated
with escalation of antiemetic treatment, the same cannot
be said for delayed CINV [9].
Chemotherapy agents and regimens are classified based
on the risk of nausea and vomiting they carry. Such classification of emetogenicity provides a valuable framework
for guiding antiemetic treatment decisions in practice [14].
In the mid-1990s, Hesketh and colleagues developed a
classification scheme in which individual chemotherapy
agents were assigned to 1 of 5 emetogenic levels [18]. An
algorithm was then devised to determine the emetogenicity of multiple-agent regimens by identifying the most
emetogenic agent in the combination and assessing the
relative contribution of the other agents [18]. More recently, a 4-level classification for single antineoplastic agents
has been agreed by the major expert bodies in cancer
care, with new agents being added as they are developed
(Table 1) [2,14,16]. Low, moderate and high emetogenic
risk chemotherapy are commonly abbreviated as LEC,
MEC and HEC, respectively.
The above classifications are primarily applicable to
single-day chemotherapy cycles. However, the assessment of emetogenicity has become complicated by the
increasing use of multi-day chemotherapy regimens—in
part triggered by a rise in the use of oral chemotherapy
agents, which tend to be used in extended regimens [14].
Antiemetic treatment decisions for multi-day regimens
are complicated by the overlap of acute and delayed emesis after the first day of chemotherapy [2]. In addition,
some agents only become consistently emetogenic after
a week or more of continuous administration [14]. This
area is relatively underrepresented in the literature and,
crucially, the established emetogenicity scales have not
been validated against multi-day regimens. A practical
method for assessing the emetogenic risk of multi-day
regimens was proposed as part of a recent evaluation of
multi-day antiemetic therapy [19]. This study adopted
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Clinical Review
an emetogenicity classification for 3- to 5-day chemotherapy regimens based on a modification of the Hesketh scale [19]. Although not formally validated, this
approach offers a pragmatic option for use in routine
practice.
Risk Factors
Beyond the inherent emetogenic risk of each chemotherapy regimen, a number of factors affect the risk of
CINV in individual patients. In particular, women have
an elevated risk of experiencing CINV as do younger
patients and those who don’t drink much alcohol.
A history of morning sickness or previous CINV can
also increase a patient’s individual risk of CINV [2,5,14].
These risk factors are well established, and there have
been relatively few further studies in recent years. Leading treatment guidelines recommend that the choice
of antiemetic prophylaxis is primarily guided by the
emetogenicity of the chemotherapy regimen, rather than
patient-related risk factors [5]. However, some guidelines recommend that these factors should be taken into
account in individual treatment decisions [2,20],
although more research is necessary to establish
the effect of such an approach on overall treatment
outcomes [5].
Table 1. Classification of the emetogenic potential of
antineoplastic Agents
Risk
Classification
High emetic risk
Definition
Examples
90% or more of patients experience
acute emesis
Cisplatin (≥ 50 mg/m2)
Cyclophosphamide (≥ 1500 mg/m2)
Carmustine
Procarbazine (PO)
Moderate emetic risk
30% to 90% of patients experience
acute emesis
Carboplatin
Ifosfamide
Cyclophosphamide (< 1500 mg/m2)
Doxorubicin
Vinorelbine (PO)
Low emetic risk
10% to 30% of patients experience
acute emesis
Paclitaxel
Etoposide
5-Fluorouracil
Trastuzumab
Thalidomide (PO)
Minimal emetic risk
Fewer than 10% of
patients experience
acute emesis
Bleomycin
Vinorelbine (IV)
Sorafenib (PO)
Based on data from references 2, 14, and 16.
PROPHYLAXIS AND TREATMENT OPTIONS
Neurophysiology
Evidence accumulating in recent years has shown that
the activation of neurotransmitters via peripheral and
central pathways highly influences the development of
CINV [21]. As a result, treatment of CINV focuses on
the modulation of neurotransmitter and receptor systems
[21]. While numerous neurotransmitters may contribute
to the vomiting response, two of the most clinically
important are 5-HT and substance P. The activation of
these influences the development of CINV at different
phases (acute and delayed, respectively) and may therefore be used to guide treatment decisions or influence
drug selection (Table 2) [3].
Historical Perspectives
Antiemetic prophylaxis has been improving continuously
over the past decades. In the past, patients receiving cisplatin would frequently be admitted and heavily sedated
with lorazepam; in contrast, with modern antiemetics
and a shift towards less highly emetogenic chemotherapies (eg, carboplatin rather than cisplatin), many fewer
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patients require admission and antiemetic outcomes have
improved dramatically.
Corticosteroids were first found to have antiemetic
properties more than 30 years ago [22]. As research
gradually revealed more about the mechanisms and signaling systems involved in CINV, a growing number of
therapeutic targets were identified. An initial focus on
the dopamine system pointed to the use of phenothiazines and butyrophenones.
Subsequently, studies of the 5-HT3 receptor in particular proved to be a key advance, and the introduction of
5-HT3 antagonists in the 1990s is often heralded as one
of the most significant advances in the treatment of CINV
[5]. The emergence of the NK-1 receptor antagonist aprepitant in 2003, followed by development of novel delivery
mechanisms and combination regimens for 5-HT3 antagonists, represent key recent developments in this field.
Agents and Evidence
Given the involvement of several neural systems in the
pathophysiology of CINV, it is logical to consider targetVol. 20, No. 8 August 2013 JCOM 379
CINV
Table 2. Roles of 5-HT and Substance P in CINV
Phase of CINV
Affected
Neurotransmitter
Role in CINV
5-HT
5-HT (serotonin) is released from enterocromaffin cells following gastrointestinal damage 5-HT activates the peripheral pathway and binds to 5-HT3 receptors
on the vagus nerve of the GI tract, stimulating emesis Acute phase Substance P
Release of substance P (present in large amounts in the CTZ and
area postrema of the brain) causes activation of the central pathway
Substance P binds to NK-1 receptors in the brain and induces vomiting
Delayed phase CTZ = chemoreceptor trigger zone. Content from references 3 and 30.
ing any or all of these systems for prevention of nausea
and vomiting. Consequently, a wide array of antiemetic
agents from several different classes are in common
use (Table 3).
Consistent with the unmet needs in this area, CINV
remains an active subject of research. There is a plethora
of published and ongoing studies examining the efficacy of the key agents, and numerous comprehensive
reviews are available [3,10,23]. Treatment guidelines
(see below) are based on thorough and up-to-date systematic reviews and so provide an ideal starting point
for understanding the evidence in this area. Moreover,
a 2010 Cochrane review examined the comparative evidence between 5-HT3 antagonists for highly emetogenic chemotherapy, reviewing 16 randomized controlled
trials involving a total of 7808 participants [24]. The
authors found little evidence for efficacy differences between first-generation 5-HT3 antagonists. Interestingly,
the authors highlighted the results of a head-to-head
comparison between palonosetron and oral granisetron,
which suggested that the second-generation agent shows
superior efficacy in the delayed phase [24]. Further
Cochrane reviews focusing on NK-1 antagonists and
cannabinoids are currently in progress [25,26], and the
results are awaited with interest.
Beyond specific agents, consideration may be given
to alternative delivery formulations. More drugs are
becoming available in forms other than IV, including
more oral forms and a broadening array of transmucosal
and transdermal delivery methods. In the case of antiemetics, the growing choice of delivery options offers
improved flexibility to meet the needs of each individual
patient. For example, the transdermal formulation of
granisetron adds an extra option for sustaining therapeu380 JCOM August 2013 Vol. 20, No. 8
tic drug levels over many days in patients receiving multiday chemotherapy, and as an alternative to IV therapy for
patients unable to swallow [2,19].
Guidelines
Current treatment approaches to CINV are predominantly guided by recommendations from the American
Society of Clinical Oncology (ASCO), the Multinational Association of Supportive Care in Cancer
(MASCC), and the National Comprehensive Cancer
Network (NCCN) [2,14,16], providing robust and
evidence-based guidance drawn from systematic reviews
and expert consensus. The recommendations advocate
approaching CINV based primarily on the emetogenic
risk of chemotherapy. For MEC and HEC regimens,
5-HT3 antagonists and NK-1 antagonists represent
the core treatments, while other agents such as phenothiazines, metoclopramide, cannabinoids and steroids
offer effective options for LEC and as adjuncts in more
emetogenic regimens [2,14,16].
Research has shown that following treatment guidelines results in significantly improved emetic control,
compared to antiemetic regimens inconsistent with
guidelines: approximately 60% of patients experienced
complete control of CINV when following guidelines,
compared to 50% of those patients using other regimens
(P = 0.008) [27]. However, there are numerous anecdotal concerns about both the awareness and implementation of these guidelines by clinical staff [4,23]. If this
is indeed the case—that there is a lag in understanding
or use of the latest agents and protocols—this could
potentially lead to inequalities of care and suboptimal
treatment outcomes, and hence provide some explanation of the lingering unmet need.
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Clinical Review
Table 3. Agents Used for Prophylaxis and Treatment of CINV
Drug
Formulations
Notes
Oral, IV
May be used alone for LEC regimens; most commonly used in combination
regimens for MEC and HEC, where it increases the complete response rate
by approximately 15–20% [31]
Glucocorticoids
Dexamethasone
First-generation 5-HT3 antagonists
Dolasetron
Oral, IV
IV formulation no longer indicated for CINV due to risk of torsade de pointes;
risk lower with oral formulation, but caution is needed [32]
Granisetron
Oral, IV, transdermal
Transdermal formulation offers alternative for patients who cannot swallow [19]
Ondansetron
Oral, IV, oro-dispersible
Oro-dispersible formulation may be helpful for patients with dysphagia or anorexia; risk of QT prolongation [33]
Second-generation 5-HT3 antagonists
Palonosetron
Oral, IV
High affinity for 5-HT3 receptor and 40 hour half-life [2]; superior to other 5-HT3
antagonists for MEC and HEC [24]
Ramosetron
Oral, IV
Similar efficacy to granisetron with longer duration of action (half-life 5.78 ± 1.18
hours) [34]
Dronabinol
Oral
May be useful adjunctive therapy in refractory CINV; clinical utility may be limited by side effects [10]
Nabilone
Oral
Semi-synthetic cannabinoid; no clear advantage over dronabinol [35]
Cannabinoids
NK-1 receptor antagonists
Aprepitant
Oral
Administered in combination with 5-HT3 antagonists and dexamethasone to prevent both acute and delayed cisplatin-induced emesis [2]
Fosaprepitant
IV
Single-day IV regimen bioequivalent to the 3-day aprepitant (oral) regimen [36]
Oral
NCCN guidelines: not recommended as single agent but a useful adjunct to
reduce anxiety [2]
Benzodiazepines
Lorazepam
Dopamine receptor antagonists and phenothiazines
Metoclopramide
Oral, solution, IV
Typically used for LEC, as adjunct in MEC and HEC, and for breakthrough nausea and vomiting; patients should be monitored for dystonic reactions [2]
Prochlorperazine
Oral, IV, suppository
Typically used for LEC, as adjunct in MEC and HEC, and for breakthrough nausea and vomiting; patients should be monitored for dystonic reactions [2]
Promethazine
Oral, syrup, suppository, IV
Typically used for LEC, as adjunct in MEC and HEC, and for breakthrough nausea and vomiting [2]
Olanzapine
Oral
Evidence for efficacy when given in combination with dexamethasone and palonosetron [37]
Gabapentin
Oral
Addition to ondansetron + dexamethasone regimen significantly increases complete response in patients receiving MEC or HEC [38]
Other
HEC = highly emetogenic chemotherapy; LEC = low emetogenic chemotherapy; MEC = moderately emetogenic chemotherapy.
IMPROVING OUTCOMES: TOWARDS
INTEGRATED STRATEGIES
Despite the availability of a wide range of effective treatment options, CINV remains an important clinical problem.
Given that a variety of effective antiemetics with different
modes of action are available, the emphasis must be on the
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appropriate use of these drugs. First and foremost, this means
appropriate selection of agents. Nonetheless, following published guidance does not represent a panacea, as evidence
indicates that nausea and vomiting remains problematic in
some patients, even when guidelines are being followed [28].
Consequently, more sophisticated strategies are needed.
Vol. 20, No. 8 August 2013 JCOM 381
CINV
With the increased availability and use of non-IV
formulations of antiemetics, consideration may be given
to whether patients are taking their medication correctly,
and whether an alternative formulation may better meet
their needs. Taking the patient perspective further, we
can look for opportunities to encourage patient involvement in the treatment process. One such opportunity
is with adjunctive antiemetics. Providing patients with
supplemental antiemetics, along with careful education
on how to use them, puts the patient in control and
allows them to make the most of opportunities to improve symptom control. This strategy must include a
strong educational aspect to ensure the adjuncts are used
safely and effectively.
In fact, the broader benefits of patient education in this
field could be substantial. This process will naturally begin
with the treating physician but also opens up an important
role for nurses and pharmacists. Oncology nurses and midlevel nurse practitioners are well placed to discuss diverse
aspects of symptom and outcome management with patients, so expanding the educational side of this role could
deliver important benefits in CINV control.
In addition to patient education, oncology nurses and
oncology nurse practitioners are also ideally positioned
to play a triage role for CINV. As established above,
many cases of uncontrolled nausea and vomiting go
unreported, particularly in the delayed phase. Hilarius
and colleagues have suggested that clinic- and homebased symptom monitoring via recording emetic episodes
and nausea assessments in a daily diary could help healthcare professionals monitor delayed CINV [9]. Other
methods of monitoring, such as follow-up phone calls,
may help to increase the accuracy of symptom records
between clinic appointments [29]. By actively discussing and monitoring CINV and acting as an accessible
contact for chemotherapy patients, oncology nurses and
nurse practitioners may be able to increase the visibility
of emerging issues for the treating physician and thereby
assist in optimizing therapy.
Such expanding roles for nurses and nurse practitioners working alongside the oncologist throughout the
treatment process highlight the potential for an integrated team approach to CINV, drawing on multiple disciplines in a holistic strategy to target supportive care. Such
a “supportive care team” could incorporate oncologists
and nursing staff alongside pharmacists, dietitians, social
workers, and several other disciplines. Indeed, the team
could almost incorporate any number of participants,
382 JCOM August 2013 Vol. 20, No. 8
depending on the needs of the patient and the resources
available in a given setting. In this way, the team could
work to address issues across the breadth of supportive
care, and be individualized to the needs of each patient.
Priority issues such as CINV can then receive the attention needed to ensure optimized patient outcomes,
within a structure designed to understand and manage
patients’ needs.
CONCLUSION
Despite dramatic improvements over recent decades,
CINV remains a key challenge in caring for cancer
patients, and control remains suboptimal. With a wide
range of effective agents available, attention must shift
to strategies that ensure optimal use of these agents.
Evidence-based guidelines have been demonstrated to
improve outcomes, yet concerns remain that these guidelines are not fully adopted.
Integrated approaches to supportive care and CINV
represent promising options for improving chemotherapy
outcomes. Building cross-disciplinary expertise in a supportive care team is one such approach. A simple, accessible system spanning the full breadth of supportive care
offers an opportunity to individualize care to the needs
of the patient, within the constraints of each care setting.
For CINV, such teams would improve the visibility of
uncontrolled nausea and vomiting while emphasizing and
facilitating optimized, evidence-based use of antiemetics.
Acknowledgment: Assistance with medical writing and preparation of this article was provided by Ian Watson of Acumen
Healthcare Communications Ltd, supported by ProStrakan
Group Plc.
Corresponding author: Ralph V. Boccia, 6410 Rockledge Dr.,
Suite 660, Bethesda, MD 20817, [email protected].
Funding/support: Preparation of this article was supported
by ProStrakan Group Plc.
Financial disclosures: Dr. Boccia has received research support from ProStrakan Pharmaceuticals.
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