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Chemotherapy-Induced Nausea and Vomiting:

The Importance of Acute Antiemetic Control
FREDERICK M. SCHNELL
Central Georgia Hematology and Oncology Associates, Macon, Georgia, USA
Key Words. Chemotherapy Nausea Vomiting 5-HT3-receptor antagonists

A BSTRACT
Nausea and vomiting are two of the most feared side
effects of cancer chemotherapy and radiotherapy.
Chemotherapy-induced nausea and vomiting can be
broadly categorized as acute (occurring within 24 hours
of therapy), delayed (persisting for 6-7 days after therapy), or anticipatory (occurring prior to chemotherapy
administration). Breakthrough and refractory nausea
and vomiting describe the symptoms of uncontrolled
emesis. Evidence suggests that good control of nausea
and vomiting during the acute period correlates with
the control of delayed emesis. Conversely, protection
failure during the first 24 hours has a high predictive
value for delayed emesis in the same cycle.
The 5-HT3-receptor antagonists, regarded as the
gold standard in antiemetic therapy, are the first-line

treatment for moderately and highly emetogenic

chemotherapy and radiotherapy regimens in adults and
children. Evidence suggests that the 5-HT3-receptor
antagonists administered in combination with corticosteroids afford the best protection from symptoms of
acute emesis and, by extrapolation, the most effective
prevention of delayed emesis.
Antiemetic therapeutic guidelines stress that the
goal of therapy is to prevent cytostatic-induced nausea
and vomiting. Therefore, the prophylactic use of the
most effective antiemetic regimentaking into consideration the emetogenicity of the chemotherapy and individual patient characteristicsmust be adhered to in
order to prevent acute, delayed, and anticipatory nausea
and vomiting. The Oncologist 2003;8:187-198

INTRODUCTION
Chemotherapy-induced nausea and vomiting (CINV)
are two of the greatest fears of patients with cancer [1-4].
Inadequately controlled CINV and radiation-induced
nausea and vomiting (RINV) can precipitate a number of
medical complications that may prove life threatening,
including dehydration and electrolyte imbalance, or cause
physical damage, including Mallory-Weiss tears of the
esophagus. These complications may lead to extended hospitalization, with the associated burden on nursing time and
pharmacy resources and overall cost implications. The distressing symptoms of nausea and vomiting have a considerable impact on all aspects of the patients qualities of
life, as well as those of their family and caregivers. The
distress resulting from these symptoms can escalate over

time [5, 6] and can potentially lead to a patients refusal to

continue with the most effective antitumor therapy [1, 7, 8].
Indeed, failure to control these side effects can lead to 25%50% of patients delaying or refusing possible lifesaving
antineoplastic therapy [9].
Nausea and vomiting associated with chemotherapy
can be classified as acute, delayed, or anticipatory. In addition, two further categories exist for uncontrolled symptomsbreakthrough and refractory nausea and vomiting.
Acute nausea and vomiting are defined as occurring within
24 hours after chemotherapy and can be further subdivided
into acute (within 12 hours) and late-acute (12-24 hours).
Delayed nausea and vomiting are usually defined as commencing more than 24 hours after administration of
chemotherapy and may persist for 6-7 days [1, 10]. They

Correspondence: Frederick M. Schnell, M.D., F.A.C.P., Central Georgia Hematology and Oncology Associates, 682 Hemlock
Street, Suite 100, Macon, Georgia 31201, USA. Telephone: 478-743-7068; Fax: 478-741-1354; e-mail: fmschnell@aol.com
Received September 3, 2002; accepted for publication December 20, 2002. AlphaMed Press 1083-7159/2003/$12.00/0

The Oncologist 2003;8:187-198 www.TheOncologist.com

Schnell

188

commonly occur following the administration of cisplatin,

carboplatin, cyclophosphamide, or doxorubicin [11]. Some
reports also have suggested that delayed symptoms may
begin sooner than 24 hours, perhaps as soon as 16 hours,
postchemotherapy [12, 13]. Anticipatory nausea and vomiting occur before, during, or after (but before acute
chemotherapy symptoms would be expected to occur) the
administration of a subsequent course of treatment if previous emetic control has been poor [10, 11]. They are conditioned responses linked to visual, gustatory, olfactory, and
environmental factors associated with previously administered chemotherapy [1]. Breakthrough nausea and vomiting
refer to symptoms that occur despite antiemetic prophylaxis
and/or necessitate the use of rescue medication. Refractory
nausea and vomiting refer to symptoms that occur during
subsequent treatment cycles when control was incomplete
in earlier cycles [14].
This review focuses on the relationship between acute
antiemetic control and the occurrence of delayed-onset and
anticipatory nausea and vomiting. It highlights data supporting the concept that good acute control, with appropriate doses of prophylactic antiemetics with proven efficacy,
has a positive impact on the incidence and control of delayed
and anticipatory nausea and vomiting. The therapeutic

benefits of the 5-HT3-receptor antagonists are discussed in

this context.
RISK FACTORS FOR THE DEVELOPMENT OF ACUTE
NAUSEA AND VOMITING
The incidence of acute emesis is determined by the emetogenic potential of the administered chemotherapy, patient
variables, and the dosage and efficacy of the prescribed
antiemetic regimen.
The emetogenic potential of a chemotherapeutic regimen
depends on a number of factors, including the chosen cytotoxic agent(s), the dose given, and the administration schedule (Table 1) [7, 15, 16]. Cisplatin is one of the most highly
emetogenic agents, with doses of 50 mg/m2 or more inducing
nausea and vomiting within 24 hours in more than 90% of
patients not administered antiemetic prophylaxis. Even in
those patients receiving appropriate prophylaxis during multiple-cycle chemotherapy, the risk of vomiting associated with
cisplatin is 20% greater than with non-cisplatin-containing
regimens [17]. Agents with moderately high emetogenic
potentials include methotrexate, doxorubicin, cyclophosphamide, and carboplatin, while vinblastine and bleomycin
are considered to have low emetogenicity as monotherapy
products [7]. The emetogenicity of radiotherapy is mainly

Table 1. Relative emetogenic potential of antineoplastic drugs

Emetogenic potential (% of patients)
High (>90%)

Agent
Cisplatin
Cyclophosphamide

Dosage

Onset/duration of response (hours)

2

>50 mg/m

1.5-56

>1,000 mg/m2

9-28

Dacarbazine

4-24

Mechlorethamine
Moderately high (60%-90%)

Cisplatin
Cyclophosphamide
Methotrexate

0.5-24
<50 mg/m2

1.5-56

750-1,000 mg/m

9-28

>1,000 mg/m2

4-12

>60 mg/m2

3.5-34

<750 mg/m2

9-28

Carboplatin
Doxorubicin
Moderate (30%-60%)

Moderately low (10%-30%)

Cyclophosphamide
Methotrexate

250-1,000 mg/m

4-12

Doxorubicin

<60 mg/m2

3.5-34

Methotrexate

<250 mg/m2

4-12

Fluorouracil
Etoposide
Low (<10%)

6-46

3-10
3.5-34

Hydroxyurea

8-48

Vinblastine

3.5-34

Bleomycin

3.5-24

Tamoxifen

12-36

Chlorambucil

48-56

Adapted with permission from Clin J Oncol Nurs 1999;3:113-119 [7]. Based on information from Bilgrami and Fallon [15] and Hesketh et al. [16].

CINV: Acute Antiemetic Control

189

dependent upon the treatment field. For example, almost

100% of patients undergoing total body irradiation (TBI)
experience symptoms of emesis, while radiation of the cranium only is considered low risk (about 10%-30% of
patients experience emesis) [11]. The dose of radiation
administered per fraction and the pattern of fractionation are
also risk factors for RINV [11]. For example, a patients risk
of developing RINV is greater if the radiation is delivered
as a single high dose than if it is fractionated [18].
Fractionated irradiation can cause considerable distress to
the patient, since treatment can comprise up to 40 sessions
given over a period of 6-8 weeks [18]. Chemotherapeutic
agents also differ in the time-to-onset of symptoms and
duration of the emetic response. For example, cyclophosphamide has a latency period of about 10 hours before the
onset of symptoms, which then continue for up to 3 days
[19], while mechlorethamine can stimulate emesis within
30 minutes of administration [7].
Antiemetic therapeutic efficacy is also influenced by a
number of patient characteristics, and each individual
should be treated according to his or her unique risk factor
profile (Table 2) [7, 13, 20]. The risk associated with the
presence of multiple risk factors is likely to be cumulative.
Indeed, in an investigation of over 800 chemotherapy-nave
patients, the incidence of postchemotherapy nausea was
20% in patients having no risk factors and 76% in those
with four risk factors [20]. Moreover, a significant interaction between age and gender has been shown, with younger
women being at greatest risk [21].
Pharmacogeneticsan area of research that makes
use of genetic variations to optimize drug discovery and
development and patient treatmentwill inevitably
impact on future drug selection in certain groups of
patients requiring therapy [22]. Recently, a genetic polymorphism has been identified that affects patients
responses to antiemetic therapy following moderate to
highly emetogenic chemotherapy [23]. The 5-HT3-receptor antagonists are metabolized by the cytochrome P450

(CYP) enzymes, and patients who have been identified as

ultrarapid metabolizers of the isoenzyme CYP2D6 have a
significantly higher frequency of vomiting within the first 24
hours after chemotherapy following administration of
ondansetron or tropisetron (which is licensed outside of the
U.S.). The results of this small study suggest that effective
acute control may be compromised in patients with this
genetic polymorphism who are offered these antiemetics as
supportive care agents since both 5-HT3-receptor antagonists
are metabolized by CYP2D6; tropisetron is metabolized
principally by CYP2D6, whereas ondansetron is also partially metabolized by CYP3A, CYP1A2, and, to a small
degree, CYP1A1 [24]. This is in contrast with granisetron,
which is metabolized exclusively by the CYP3A subfamily
[24], and may thus be the antiemetic of choice in patients
suspected of being ultrarapid metabolizers of CYP2D6.
IMPACT OF ACUTE CONTROL ON DELAYED AND
ANTICIPATORY NAUSEA AND VOMITING
Evidence suggests that good control of acute nausea
and vomiting, particularly during the initial treatment
received by chemotherapy-nave patients, correlates with
the control of delayed and, by extrapolation, anticipatory
symptoms as well as acute- and delayed-onset emesis
associated with subsequent cycles of treatment [25-27].
Correlation Between Acute and Delayed Control of CINV
Although the neuropharmacologic mechanism of
delayed CINV is not well understood, these symptoms occur
more frequently with highly emetogenic chemotherapy and
are more difficult to treat than acute nausea and vomiting
[28, 29]. Because delayed symptoms are less responsive to
treatment than prevention, optimal prophylactic control is
imperative to minimize their occurrence.
Patients who do not vomit in the first 24 hours posttreatment have shown high rates of complete protection
from delayed emesis. Conversely, failure during the acute
period has a high negative predictive value for delayed

Table 2. Risk factors associated with the development of chemotherapy-induced nausea and vomiting
Risk factor

Change in risk

Gender

Greater risk in females

Age

Lower incidence at <6 or >50 years

Alcohol consumption

Lower incidence in individuals consuming >10 alcohol units/week

Motion sickness

Prior history leads to greater risk

Pregnancy-induced emesis

Prior history leads to greater risk

Anxiety

High anxiety levels correlated with greater risk

Previous cycles of chemotherapy

Poorly controlled nausea and vomiting in previous cycles increases likelihood of CINV and anticipatory
nausea and vomiting

Schnell

that physicians take a full medical history to identify

patients at greatest risk of developing nausea and vomiting
and ensure that the most effective currently available
antiemetic agents are administered prophylactically at optimum doses to control symptoms during the acute phase.
Nevertheless, it must be stressed that good acute control
must be coupled with the administration of regular
antiemetic medication throughout the posttreatment period
to maximize the control of delayed CINV.
Protection Against Anticipatory Nausea and Vomiting
Anticipatory nausea and vomiting are conditioned
responses and, therefore, typically only occur after a previous negative experience with chemotherapy [11]. Although
individual risk profiles (e.g., a history of motion sickness,
anxious personalities; Table 2) are indirect predictors for
the development of anticipatory nausea and vomiting, the
most important risk factor is the occurrence of acute or
delayed symptoms with prior chemotherapy [9, 11, 33]. A
conditioning response may ensue, such that these symptoms then occur spontaneously hours or even days before
the next series of treatments [34]. Therefore, aggressive
prophylaxis against both acute and delayed symptoms
particularly during the first cycle of chemotherapyconfers the most effective prevention against anticipatory
CINV [11, 13].
OPTIMAL CONTROL OF THE ACUTE PHASE
The aim of antiemetic treatment is the total prevention
of nausea and vomiting for each individual, thereby conferring the best patient outcome [11]. Total control (i.e., no
nausea, no vomiting or retching, and no use of antiemetic
rescue medication) during the postchemotherapy period

No retching/vomiting

100

No nausea

80
Patients (%)

emesis in the same cycle [12]. Furthermore, patients who

experience delayed symptoms during their initial cycle of
chemotherapy are more likely to suffer recurrent delayed
symptoms during subsequent cycles [13] as well as reduced
acute antiemetic protection in the next cycle [30]. Thus, any
patient characteristic that predisposes an individual to acute
symptoms (such as female sex, low prior alcohol intake
history, and emesis with prior cycles of chemotherapy)
should also be considered as a predictive factor for delayed
nausea and vomiting [11].
Of these predictors, poor control of acute CINV (often
defined as three or more vomiting episodes associated with a
particular treatment) constitutes an important risk factor for
the occurrence of delayed symptoms [31]. For example,
Mantovani et al. observed poor control of acute emesis to
predict for symptoms of delayed emesis following cisplatin
therapy, the incidence and severity of which were greatest
during the period from 48-72 hours following treatment [12].
In that study, good control of delayed emesis was achieved in
patients who had complete protection from acute symptoms
(75% and 72.2%, respectively). Similarly, in a study of 267
evaluable patients who received cisplatin (50 mg/m2),
antiemetic prophylaxis resulted in the control of vomiting in
79% of patients with comparable control rates being maintained through to day 5 (range, 84%-86%; Fig. 1) [27]. The
degree of nausea control achieved on day 1 (77%) was also
comparable with the rates reported on days 2 to 5 (range,
69%-77%; Fig. 1). A further study of 532 patients receiving
granisetron plus dexamethasone as antiemetic prophylaxis
for cisplatin chemotherapy found that a comparable percentage of patients who were complete responders (defined as no
vomiting, no worse than mild nausea, no use of rescue medication, and no withdrawal from the study over the 3-day
treatment period) on the day of chemotherapy (day 0, 79%)
maintained a complete response over the following 3 days
(range, 75%-81%) [8]. Rates of total control (i.e., absolute
absence from nausea and vomiting, no use of rescue medication, and no study withdrawal) over the study period were
also comparable (day 0, 72%; days 1-3, 65%-83%).
Delayed CINV seems to be less prevalent in children
than in adults [32], which may be reflected by the lower
incidence of chemotherapy-induced emesis in children
under the age of 6 years [7] (Table 2). Nevertheless, platinum-based and cyclophosphamide chemotherapeutic regimens, which are accompanied by vomiting during the acute
phase, are associated with a significantly higher incidence
of delayed vomiting [32].
These findings confirm the paramount importance of
achieving effective control of acute CINV in order to
reduce the development of delayed symptoms [4], which
presents physicians with a clinical challenge. It is important

190

60
40
20
0
Day 1

Day 2

Day 3

Day 4

Figure 1. Rates of complete protection against retching/vomiting

and nausea from days 1-5 following the administration of cisplatin
(50 mg/m2). Antiemetic prophylaxis comprised three doses of intravenous ondansetron, 0.15 mg/kg, plus intravenous dexamethasone, 20
mg. Reprinted with permission from Oncology 1993;50:163-167 [27].

191

will maximize patients quality of life, including their ability to sustain their normal daily activities after such treatment, thereby reducing associated symptom management
costs. Thus, optimum control will be associated with considerable socio- and pharmacoeconomic, as well as
clinical, benefits.
As discussed above, effective acute prophylaxisin
conjunction with the administration of regular and adequate
prophylaxis post-treatmentis an important determinant of
the control of both delayed and anticipatory CINV. Hence,
maximizing the number of patients who experience total
control of nausea and vomiting during the acute phase of
the first cycle of treatment is an important goal of
antiemetic therapy [7]. Effective acute prophylaxis is
achieved by tailoring antiemetic therapy to the individual at
the outset of cancer treatment.
The Role of 5-HT3-Receptor Antagonists
The Accepted Gold Standard
Since the mid-1980s, major progress has occurred in
antiemetic drug development. Prior to that time, high doses
of metoclopramide were used to combat cisplatin-induced
nausea and vomiting. However, while these partially suppressed symptoms, as many as 30%-60% of patients continued to suffer nausea and vomiting, and extrapyramidal
effects associated with dopamine (D2) antagonism occurred
in up to 5% of patients [35]. A greater understanding of the
pathophysiology of emesis disclosed the importance of serotonin (5-HT) in the mediation of the emetic response.
Release of serotonin from enterochromaffin cells in the small
intestinal mucosa contributes to the acute nausea and vomiting associated with chemotherapy. Serotonin activates receptors on vagal afferent fibers in the intestinal mucosa, which
relay sensory information to discrete brain areas involved in
the genesis of nausea and vomiting [36]. However, the precise mechanism underlying the development of CINV
remains unclear and is likely to involve additional pathways
to those mediated by serotonin or dopamine [28].
The 5-HT3-receptor antagonists specifically block the
binding of serotonin to the receptors on the vagal nerves that
trigger the emetic response [7]. This specificity obviates the
severe and distressing extrapyramidal side effects sometimes
associated with conventional antiemetics [17]. The introduction of the 5-HT3-receptor antagonists has represented a significant clinical advance in the prevention of CINV,
particularly for patients receiving highly emetogenic cisplatin-containing chemotherapy, in whom the 5-HT3-receptor
antagonists generally produce superior efficacy to high-dose
metoclopramide [1]. Three of these agents are licensed for use
in the U.S.: granisetron, ondansetron, and dolasetron. A

CINV: Acute Antiemetic Control

further agent in this class, tropisetron, is available in Europe
and selected other countries. All three agents licensed for use
in the U.S. are available in both injectable and oral formulations; however, only granisetron and ondansetron are indicated for use with highly emetogenic chemotherapy by the
oral route. Data from animal studies have shown that the oral
formulation reaches the gut directly, is absorbed across the
proximal gut mucosa, and is immediately available to bind
with 5-HT3 receptors on the vagal afferent neurons [37, 38].
Oral antiemetics can be more convenient for patients and may
allow reductions in nursing time, in contrast with intravenous
administration of the same agents [39].
A Comparable Pharmacologic Profile?
Although the chemical structures of all drugs in this
class are similar, the individual 5-HT3-receptor antagonists
exhibit notable pharmacologic differences in their selectivity, potency, dose-response profiles, and half-lives [1, 40,
41] that may affect their activities as antiemetic agents in
certain individuals. For example, pharmacologic potencies
of these agents differ; the rank order of the U.S.-licensed
agents is granisetron > ondansetron > dolasetron. Although
both granisetron and ondansetron exhibit high binding
affinities for the 5-HT3 receptor (pKi values, 8.42 and 8.07,
respectively), granisetron is specific for this receptor,
whereas ondansetron also possesses weak affinity for 5HT1B, 5-HT1C, 1-adrenergic, and -opioid receptors [42].
The affinities ondansetron has for receptors other than the
target 5-HT3 receptor may confound antiemetic therapy,
potentially producing more adverse drug reactions in
patients than a drug that does not possess affinities for other
receptors (e.g., granisetron). In addition, dolasetron and
granisetron possess significantly longer elimination halflives than ondansetron, that is, the time a drug is present
and active in the body. The shorter elimination half-life of
ondansetron may account for the dosing variability associated with this drug [1]. For example, when used as monotherapy, to produce satisfactory control of emesis in
patients undergoing chemotherapy, it is necessary to
administer ondansetron as a single high dose (32 mg i.v.) or
as part of a multiple dosing regimen (0.15 mg/kg three
times daily) [43]. This is in contrast with granisetron, which
is effective as a single-dose monotherapy agent (10 g/kg
i.v. or 2 mg orally once daily) [44]. Of interest, the duration
of action of granisetron has been shown to be at least 24
hours, considerably longer than that predicted by its halflife [45], and is a possible consequence of its noncompetitive antagonism of the 5-HT3 receptor [46]. However, while
such pharmacologic differences may be expected to translate into clinical relevance, the full significance of these
variations remains thus far equivocal [1, 47]. Nevertheless,

Schnell
these differences may differentiate individuals responses to
their given antiemetic therapies, impacting on acute control
of nausea and vomiting and the overall success of treatment.
Optimizing Efficacy
Comparative trials with high-dose metoclopramide
have demonstrated that dolasetron, ondansetron, and
granisetron are more effective in preventing acute emesis,
are better tolerated, and are preferred by more patients [1,
19, 48-50]. 5-HT3-receptor antagonists have become the
agents of choice in preventing acute CINV following both
moderately and highly emetogenic chemotherapy [11, 51].
Complete response and total control rates seen with specific
drugs range from 60%-80% for moderately emetogenic
chemotherapy [4, 52-54], 40%-60% for cisplatin-containing therapy [4, 33, 55, 56], and 25%-60% for high-dose
cisplatin regimens [33, 35, 47, 57, 58].
The efficacies of the 5-HT3-receptor antagonists are
dependent on their appropriate use, including the administration of adequate doses. However, due to cost considerations,
many of these agents are often used at lower than optimal
doses. In the U.S., the approved dose of intravenous
ondansetron is 32 mg; however, ondansetron is frequently
given at doses as low as 8 mg when administered as part of a
combination treatment approach for moderately or highly
emetogenic chemotherapy [59-62]. The impact of such a
practice on symptom control may jeopardize effective patient
management. In contrast, oral dolasetron is approved in the
U.S. for use with moderately emetogenic chemotherapy at a
dose of 100 mg administered within 1 hour before chemotherapy [63]. However, a dose-related response for oral
dolasetron has been shown to occur at doses between 25 and
200 mg [64, 65]. Indeed, a significant linear dose-response
relationship was observed in 399 cancer patients receiving
moderately emetogenic chemotherapy over the entire
dolasetron dose range of 25-200 mg (p < 0.001), with complete response rates of 60.5% and 76.3% achieved with the
100 mg and 200 mg doses, respectively [64].
Consideration of the consequences of potentially worse
acute control, with its associated adverse clinical, humanistic,
and economic effects, is therefore essential before administering lower-than-indicated doses of any approved agent.
Administration of lower doses of agents with lower potency
and/or shorter half-lives in those patients receiving carboplatin
or cyclophosphamide agents (in whom nausea and vomiting
typically peak about 12-18 hours after administration) may be
particularly detrimental [7].
Bone Marrow Transplantation
Conditioning treatments for patients undergoing bone
marrow transplantation (BMT)TBI and high-dose

192

chemotherapyare both highly emetogenic procedures.

Cancer patients undergoing these procedures often suffer
from acute nausea and vomiting, which can extend for prolonged periods of days or weeks after high-dose chemotherapy [66]. It is especially imperative that acute nausea and
vomiting are adequately controlled to minimize the occurrence of delayed emesis in these patients. 5-HT3-receptor
antagonists have been shown to be highly effective in controlling emesis after conditioning treatments [67-70] and are
the first-line treatment for both adults and pediatric patients
undergoing such therapies [11, 13]. Granisetron was found
to be significantly more effective for prophylaxis of emesis
induced by conditioning chemotherapy prior to BMT than
older, conventional antiemetic therapies [71]. Ninety-four
percent of patients who were administered granisetron experienced complete control of acute emesis, while only 7.6%
of patients treated with conventional antiemetics had the
same degree of control. As a consequence, granisetron was
more effective at preventing delayed nausea and vomiting
than the standard antiemetics (control of emesis on days 5-6
for patients receiving granisetron or standard antiemetics
was 66.7% and 20.0%, respectively) [71].
Potential for Corticosteroid Combination
All current evidence suggests that prophylactic administration of the 5-HT3-receptor antagonists affords the best protection from acute CINV and, by extrapolation, the most
effective prevention of delayed and anticipatory symptoms.
However, despite their proven efficacies, a significant proportion of patients still experience symptoms of CINV during
the first 24 hours, depending on the chemotherapy regimen
administered [29].
The synergistic effect of conventional antiemetics in
combination with corticosteroids is well established, and,
prior to the introduction of the 5-HT3-receptor antagonists,
combination antiemetic therapy, such as metoclopramide
plus dexamethasone and diphenhydramine or lorazepam,
was generally regarded as the most effective treatment in
this setting. The addition of corticosteroids to 5-HT3-receptor antagonists has also been shown to be significantly more
effective than the combination of a steroid with conventional antiemetics. For example, complete protection from
retching and vomiting was achieved in 79% of patients who
received a 5-HT3-receptor antagonist plus steroid, compared with 59% of patients who received a steroid as part of
a non-setron antiemetic regimen (p < 0.002) [26, 27].
Similarly, in a comparative trial of 357 patients receiving
cisplatin therapy, total control (defined as no vomiting, no
nausea, and no use of rescue medication) occurred in 65%
of patients receiving oral granisetron, 1 mg twice daily plus
intravenous dexamethasone, compared with only 45% of

CINV: Acute Antiemetic Control

193

metoclopramide plus dexamethasone-treated patients

(p = 0.007) [29].
In directly comparative, single-agent studies of 5-HT3receptor antagonists that permitted concomitant corticosteroid use [39, 52], the addition of the steroid improved
total control rates by 9.8%-13.4% at 24 hours and by 4.7%8.7% at 48 hours postchemotherapy. Results from a study
investigating optimum corticosteroid doses suggest that a
dexamethasone dose of 20 mg be used as standard prophylaxis in combination with 5-HT3-receptor antagonists [72]
(Table 3). As previously noted, patients most at risk for
CINV are younger, female patients and patients who have
received either high doses of cisplatin or additional emetogenic chemotherapy. The benefit of adding dexamethasone
to a 5-HT3-receptor antagonist antiemetic in these higher
risk groups suggests that women and younger patients may
attain a particular advantage from this combination regimen
[29]. Pediatric patients have also been shown to benefit
from the addition of a corticosteroid to a 5-HT3-receptor
antagonist. Sixty-one percent of children aged 3-18 years
receiving ondansetron, 0.15 mg/kg i.v. three times daily,
supplemented with dexamethasone, 8 mg/m2 i.v. plus 16
mg/m2 in divided doses, experienced a complete emetic
response, compared with only 23% of patients administered
ondansetron alone [73]. Similarly, a number of studies have
shown that corticosteroids can enhance the safety and efficacy of antiemetic regimens in BMT patients [66]. The regular administration of a steroid, as the minimum treatment
regimen, throughout the posttreatment period is also recommended to protect against the occurrence of delayed
emesis [11, 13].
Multiple-Cycle Chemotherapy
An important aspect of prophylactic antiemetic therapy is
control of nausea and vomiting over repeated cycles of
chemotherapy. A decline in antiemetic effect has been shown
during successive treatment cycles with standard antiemetic
regimens, including high-dose metoclopramide plus dexamethasone or methylprednisolone [74] and combination prophylaxis with methylprednisolone, thiethylperazine, and

amitriptyline [75]. In contrast, combination therapy with a 5HT3-receptor antagonist plus dexamethasone has been shown
to be effective in the majority of patients over successive
courses of carboplatin-based chemotherapy [76]. Unlike
metoclopramide, antiemetic efficacy of ondansetron plus dexamethasone was retained in patients who completed second
and third cycles of cisplatin chemotherapy [27]. In addition,
the antiemetic efficacy of granisetron has been shown to be
maintained for up to eight repeated chemotherapy cycles
[9, 77]. Good control of acute nausea and vomiting during
first-cycle chemotherapy is thus crucial, as emesis in prior
chemotherapy cycles is a predictor for emesis in subsequent
cycles (Table 2) [7, 13].
Breakthrough Emesis and Treatment Failure
Patients who fail on antiemetics during initial chemotherapy cycles (i.e., those experiencing three or more vomiting
episodes) are at high risk of experiencing all types of nausea
and vomiting during subsequent treatments. It is of extreme
importance that a critical reevaluation of the antiemetic regimen is performed and control is maximized in subsequent
cycles by administration of proven antiemetic agents that
afford the best acute control of nausea and vomiting, thereby
limiting future breakthrough emesis.
In an evaluation of granisetron in patients refractory to
previous antiemetics, some of whom had received ondansetron, a complete response was achieved in 53%-60% of
patients in cycles 1-6, with the proportion of complete responders remaining constant throughout successive treatment
cycles (Fig. 2) [17]. However, patients receiving doses of cisplatin in excess of 50 mg/m2 had lower complete response
rates (25.0%-57.1%) than those receiving other cytostatic
agents (59.3%-67.9%). Furthermore, in a small, randomized,
double-blind study of patients failing ondansetron plus dexamethasone during the first 24 hours following highly emetogenic chemotherapy, granisetron plus dexamethasone was
compared with continued ondansetron treatment [78, 79]. Of
the 40 eligible patients, significant benefit was achieved by
switching patients to granisetron after failure with ondansetron
(p = 0.005) (Fig. 3). The authors stated that this effect is

Table 3. 5-HT3-receptor antagonists plus varying dexamethasone doses in a randomized trial with 531 patients
Dexamethasone dose

Complete control: vomiting

Complete control: nausea

4 mg

69%*

61%

8 mg

69%*

61%

12 mg

78%*

66%

20 mg

83%*

71%

*p < 0.01 compared with dexamethasone, 4 mg and 8 mg.

Reprinted with permission from J Clin Oncol 1998;16:2937-2942 [72].

Schnell

194

Ondansetron (n = 21)

100

Granisetron (n = 19)

80

n = 512

n = 333

n = 227 n = 149

n = 102

n = 48

40

60

Patients (%)

Patients (%)

60

66.7

70

80

47.4

50

36.8

40
28.6

30

15.8

20

20

10

4.8

0
1

3
4
Cycle of treatment

Figure 2. Proportion of patients showing a complete response following administration of antiemetic prophylaxis with granisetron
prior to administration of chemotherapy. Data from later cycles
were not analyzed due to low patient numbers. Reprinted with
permission from Anticancer Drugs 1998;9:381-385 [17].

unlikely to be explained by efficacy differences in the administered doses. Thus, treatment failure with one 5-HT3-receptor
antagonist does not predict subsequent failure with all setrons,
or at least not in patients who receive granisetron following
treatment failure with ondansetron.
Therapeutic Recommendations
The importance of the prophylactic administration of
antiemetics is recognized by various evidenced-based U.S.
guidelines, including those compiled by the American Society
of Clinical Oncology (ASCO), the American Society of
Health-System Pharmacists (ASHP), and the Multinational
Association of Supportive Care in Cancer (MASCC). All
these guidelines recommend antiemetic prophylaxis with a 5HT3-receptor antagonist in combination with a steroid in
patients receiving moderately to highly emetogenic
chemotherapy or radiotherapy. These guidelines emphasize
that prevention of delayed and anticipatory nausea and vomiting is predominantly dependent on ensuring optimum acute
symptom control. In all patients receiving cisplatin, a corticosteroid plus a 5-HT3-receptor antagonist is recommended
for the prevention of delayed and anticipatory CINV. In
patients receiving high-risk, non-cisplatin regimens, a prophylactic corticosteroid with or without either a 5-HT3-receptor antagonist or metoclopramide is suggested [11, 51].
Overall, the prophylactic use of the most effective antiemetic
regimen appropriate to the chemotherapy employed is suggested to prevent acute, delayed, and anticipatory nausea and
vomiting. Such regimens must be used with the initial
chemotherapy in order to prevent the occurrence of symptoms, rather than waiting to assess the patients emetic
response with less effective treatment.
Treatment should be individualized by considering the
important individual patient risk factors. In the outpatient

Complete
protection

Partial
protection

Failure

Figure 3. Effect of switching antiemetic treatment to granisetron

after failure with ondansetron, compared with continuous
ondansetron treatment [78, 79].

setting, patients must be encouraged to continue with prophylactic antiemetics. This is highlighted following a recent
survey that suggested that nurses and physicians often underestimate the occurrence of nausea and vomiting in cancer
patients [80]. This may be due to underreporting of these
symptoms by patients while they are in hospital or because of
delayed symptoms that patients experience once discharged
from hospital without provision of adequate antiemetic prophylaxis. All patients at risk of delayed emesis require sustained prophylaxis throughout the posttreatment period. The
prescription of antiemetics during the delayed phase should
be accompanied by patient counsel emphasizing the importance of prevention over treatment and thus the need for regular self-administration. Effective preventative measures
serve to enhance patients quality of life and lead to
improved patient compliance with subsequent chemotherapy
cycles. Administration of appropriate antiemetic prophylaxis
should be accompanied by close monitoring of the success of
therapy. The success of symptomatic control should not be
assumed and must be established by direct communication
with, and assessment by, the patient.
DISCUSSION
Prevention of nausea and vomiting induced by cytotoxic agents is critical in the management of the patient
with cancer. The 5-HT3-receptor antagonists are currently
perceived as the gold standard antiemetic treatment, providing effective control of acute nausea and vomiting,
while offering a substantial tolerability benefit over older
conventional antiemetics. Three agents are currently
licensed in the U.S.: ondansetron, granisetron, and
dolasetron. All are available as oral and i.v. formulations,
but only oral granisetron and ondansetron are currently
indicated for use with highly emetogenic agents. Efficacy
of the 5-HT3-receptor antagonists is further increased with
the concurrent use of corticosteroids, and U.S. guidelines

195

now recommend the concomitant use of these agents in

moderately/highly emetogenic settings [11, 13].
Successful prevention and control of acute CINV considerably reduces the risk of delayed symptoms in the
same cycle, which are inherently more difficult to treat.
The challenge of treating delayed symptoms may be due
in part to the underlying physiological mechanism, which
has not been fully elucidated and is likely to involve transmitters other than serotonin. Indeed, recent clinical trials
have examined the antiemetic effect of neurokinin-1
(NK1)-receptor antagonists in cancer patients undergoing
highly emetogenic chemotherapy, suggesting a partial
involvement of substance P [81]. During the delayed
phase, an NK1-receptor antagonist in combination with
granisetron and dexamethasone provided significantly
better control of emesis than placebo during days 2-5.
This combination was also more effective during the acute
phase than granisetron plus dexamethasone alone, though
the NK1-receptor antagonist plus dexamethasone combination without granisetron was significantly less effective
than the triple combination. This suggests that, during the
acute phase, 5-HT and substance P may be acting together
to produce emesis and that antagonists for both transmitters are necessary to confer good overall protection from
emesis. However, no NK1-receptor antagonists are currently licensed, and until they are commercially available, health care professionals should use the best
available and most suitable agents during the acute and
delayed phases. This choice should accommodate patient

CINV: Acute Antiemetic Control

factors as well as pharmacologic consideration of the
5-HT3-receptor antagonists.
Effective control of CINV during a patients initial
treatment reduces the incidence of symptoms, including
anticipatory CINV, associated with subsequent cycles. As a
result, patients are more likely to retain their quality of life,
have a more positive attitude toward chemotherapy, and opt
to continue receiving treatment over multiple cycles as a
consequence. In addition, pharmacoeconomic benefits are
also attained, with reduced hospital stays per patient leading to lower hospital costs and lower resource consumption
[13]. Thus, complete protection against nausea and vomiting during the acute phase of the first cycle of treatment is
imperative during antiemetic therapy. However, there is the
risk that not all patients will respond to antiemetic therapy.
In conclusion, in controlling CINV, the strategy should
always focus on prevention rather than treatment. Health care
professionals can optimize their patients outcomes by ensuring that therapy is tailored according to each patients individual risk profile. Consideration of the chemotherapeutic
regimen and patient characteristics must be coupled with the
provision of antiemetic therapy with proven efficacy at fully
effective doses. In this way, effective acute control with its
attendant advantages can be maximized during a patients initial treatment, in adherence with the right first time ethic.
ACKNOWLEDGMENT
This manuscript was supported by Roche. F.M.S. has
received honoraria and is a consultant for Roche.

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