Critical Reviews in Oncology/Hematology 61 (2007) 162175

Comparative activity of antiemetic drugs

Karin Jordan a, , Hans J. Schmoll a , Matti S. Aapro b
a

Department of Internal Medicine IV, Haematology/Oncology, Martin-Luther-University Halle/Wittenberg,

Ernst-Grube-Str. 40, 06120 Halle/Saale, Germany
b Institut Multidisciplinaire dOncologie, Clinique de Genolier S.A., CH-1272 Genolier, Switzerland
Accepted 25 August 2006

Contents
1.
2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Antiemetic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. 5-HT3 -receptor-antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.1. Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.2. Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.3. Dose recommendation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.4. Side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.5. Genetic polymorphism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.6. Comparative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. Steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.1. Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.2. Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.3. Dose recommendation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.4. Side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.5. Comparative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3. Neurokinin-1-receptor-antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.1. Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.2. Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.3. Dose recommendation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.4. Side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.5. Comparative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4. Substituted benzamides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.1. Metoclopramide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.2. Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.3. Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.4. Dose recommendation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.5. Side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.6. Metopimazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.7. Comparative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5. Neuroleptics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.1. Phenothiazines/butyrophenones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.2. Atypical neuroleptics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.3. Comparative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.6. Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.6.1. Lorazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Corresponding author. Tel.: +49 345 557 2924; fax: +49 345 557 2950.
E-mail address: Karin.Jordan@medizin.uni-halle.de (K. Jordan).

1040-8428/$ see front matter 2006 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.critrevonc.2006.08.003

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3.

2.6.2. Midazolam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.6.3. Comparative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.7. Cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.7.1. Comparative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.8. Antihistamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.8.1. Comparative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.9. Herbs as antiemetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.9.1. Ginger (Zingiber ofcinale Roscoe) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.9.2. Peppermint (Mentha x piperita Lamiaceae) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.9.3. Comparative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract
Nausea and vomiting continues to be an important problem for cancer patients receiving chemotherapy. Chemotherapy-induced nausea and
vomiting (CINV) are classified as acute, occurring within the first 24 h, or delayed, occurring after the first 24 h. A number of antiemetic agents
are available for the management of nausea and vomiting, including 5-HT3 -receptor-antagonists, corticosteroids, NK-1-receptor-antagonists,
dopamine-receptor antagonists, benzodiazepines, neuroleptics and cannabinoids. With modern antiemetic therapy, vomiting can be prevented
in 7080% of patients, whereas the control of nausea remains suboptimal. The development of acute emesis is known to depend on serotonin.
The pathophysiology of delayed emesis is less well understood, and multiple mechanisms may contribute, including substance P. Here, the most
recent developments in the antiemetic therapy, including new antiemetic drugs and the latest guidelines for antiemetic prophylaxis, are reviewed.
2006 Elsevier Ireland Ltd. All rights reserved.
Keywords: Antiemetic drugs; Antiemetic therapy; MASCC guidelines; ASCO guidelines; 5-HT3 -receptor-antagonists; Steroids; Neurokinin-1-receptorantagonists; Chemotherapy-induced nausea and vomiting (CINV)

1. Introduction
The goal of each antiemetic therapy is to abolish nausea and vomiting. Twenty years ago, nausea and vomiting
were common adverse events of certain types of chemotherapy and forced up to 20% of patients to postpone or refuse
potentially curative treatment [1]. Clinical and basic research
over the past 25 years has lead to steady improvements in
the control of chemotherapy-induced nausea and vomiting
(CINV). The development of the 5-HT3 -receptor-antagonists
(5-HT3 -RAs) has been one of the most significant advances
in chemotherapy of cancer patients. While being effective in
acute CINV, 5-HT3 -RAs fail to completely protect against
delayed CINV. Palonosetron, a new 5-HT3 -RA, has recently
been introduced into clinical practice. The actual role of this
new agent has to be established in the daily practice.
Corticosteroids are often underestimated although they
show when combined with other antiemetic agents good
antiemetic efficacy in the prevention of acute and delayed
CINV. Another group of antiemetics, the neurokinin receptorantagonists, has recently been developed, and the first drug
in this class, aprepitant, has been approved. Studies have
shown that patients benefit from the use of this drug in combination with standard antiemetic therapy, both in the acute
and delayed setting of highly and moderately emetogenic
chemotherapy.
CINV may be classified into three categories: acute onset,
occurring within 24 h of initial administration of chemother-

apy; delayed onset, occurring 24 h to several days after initial

treatment; and anticipatory nausea and vomiting, observed in
patients whose emetic episodes are triggered by taste, odour
sight, thoughts, or anxiety secondary to a history of poor
response to antiemetic agents or by inadequate antiemetic
prophylaxis in the previous cycle of chemotherapy [2,3]
(Table 1).
The emetogenic potential of the chemotherapeutic agents
used is the main risk factor for the degree of CINV. In regard
to its emetogenic potential, the chemotherapeutic agents are
classified into four emetic risk groups: high, moderate, low
and minimal [46]. Other patient risk factors including young
age, female gender, a history of low alcohol intake, experience of emesis during pregnancy, impaired quality of life and
Table 1
Three categories of chemotherapy-induced nausea and vomiting (CINV)
Acute nausea and vomiting
- within the first 24 h after chemotherapy
- mainly by serotonin (5 HT) release from the enterochromaffin cells
Delayed nausea and vomiting
- after 24 h to 5 days after chemotherapy
- various mechanisms: mainly substance P mediated, disruption of
the blood brain barrier, disruption of the gastrointestinal motility,
adrenal hormones [3]
Anticipatory nausea and vomiting
- Occurrence is possible after 1 cycle of chemotherapy [2]
- Involves the element of classic conditioning

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K. Jordan et al. / Critical Reviews in Oncology/Hematology 61 (2007) 162175

previous experience of chemotherapy are known to increase

the risk of nausea and vomiting after chemotherapy [4,7].
This article will review the most recent developments
in antiemetic therapy, including the neurokinin-1-receptorantagonist aprepitant, the new 5-HT3 -RA, palonosetron and
olanzapine an atypical antipsychotic drug.
2. Antiemetic agents
With modern antiemetics, vomiting can completely be
prevented in up to 7080% of patients [8,9]. Combination
antiemetic regimens have become the standard of care for
the control of CINV.
2.1. 5-HT3 -receptor-antagonists
The introduction of 5-HT3 -RAs has dramatically improved the management of chemotherapy- and radiotherapyinduced emesis. The wide experience acquired with these
drugs in daily clinical practice since the early 1990s
has confirmed the remarkable safety profile. Five 5-HT3 RAs, ondansetron, granisetron, tropisetron, dolasetron and
palonosetron, are currently available in Europe and the United
States.
2.1.1. Mechanism of action
Serotonin is the main neurotransmitter responsible for
emesis after chemotherapy. The 5-HT3 receptors are located
in three sites: gastrointestinal tract, chemoreceptor trigger
zone located in the area postrema and nucleus tractus solitarius of the vomiting centre. The chemoreceptor trigger zone
is a circumventricular organ located at the caudal end of the
fourth ventricle. This structure lacks an effective bloodbrain
barrier, and will detect emetic agents in both the systemic
circulation and the cerebrospinal fluid. The vomiting centre
is located in the brainstem medullary structures. It receives
major inputs from the chemoreceptor trigger zone, and a vagal
and sympathetic input from the gut.
Following exposure to radiation or cytotoxic drugs, serotonin (5-HT) is released from enterochromaffine cells in the
small intestinal mucosa, which are adjacent to the vagal afferent neurones on which 5-HT3 receptors are located [10]. The
released serotonin activates vagal afferent neurones via the
5-HT3 receptors which lead ultimately to a severe emetic
response mediated via the chemoreceptor trigger zone within
the area postrema [11].
2.1.2. Clinical studies
2.1.2.1. 5-HT3 -receptor-antagonists in acute CINV. Ondansetron, the first 5-HT3 -RAs developed, became available in
the United States in 1991 and was followed by granisetron
in 1994. Since then, numerous trials have been published in
the field to evaluate the role of 5-HT3 -RAs in the prevention
of acute CINV. All studies demonstrated that 5-HT3 -RAs are
advantageous in comparison to other antiemetics (e.g., metoclopramide, dexamethasone and aprepitant) in the prevention

of acute CINV in both highly and moderately emetogenic

chemotherapies [7,1214].
2.1.2.2. 5-HT3 -receptor-antagonists in delayed emesis.
Highly emetogenic chemotherapy: 5-HT3 -RAs are not universally accepted as standard therapy in preventive treatment
of delayed CINV in patients receiving highly emetogenic
chemotherapy [1517]. Metoclopramide has been shown to
be as efficacious as 5-HT3 -RAs when combined with dexamethasone in the prevention of delayed CINV [18,19]. This
is supported by a study looking into serotonin metabolism.
Wilder-Smith measured urinary 5-hydoxyindoleacetic acid
(5-HIAA) excretion during the 48 h following high dose cisplatin (80 mg/m2 ). They found a significant urinary 5-HIAA
peak after 6 h after the induction of chemotherapy, with no
peaks thereafter, suggesting that the delayed period nausea
and vomiting is not associated with the release of serotonin
[20]. Of course, also due to the fact that the combination of
aprepitant and dexamethasone in the delayed phase showed
a high rate of protection is important for the assessment of
5-HT3 -RAs in the delayed phase [8,9]. Although not fully
published at the accrual of the new guidelines the study of
Schmoll et al. compared an aprepitant regimen with a control
regimen of ondansetron + dexamethasone given for 4 days
[21]. Aprepitant and dexamethasone were superior to the control regimen (ondansetron and dexamethasone) in preventing
CINV in the delayed phase. Based on all these findings,
the Multinational Association for Supportive Care in Cancer (MASCC) and ASCO guidelines no longer recommend
5-HT3 -RAs for the prevention of delayed CINV in highly
emetogenic chemotherapy [12].
Moderately emetogenic chemotherapy: The role of 5HT3 -RAs in moderately emetogenic chemotherapy remains
controversial. In a recently published meta-analysis, it could
be demonstrated that the addition of a 5-HT3 -RA did not
significantly improve control of delayed emesis as compared
with dexamethasone monotherapy [22]. In a study by Kaizer
et al. the complete response rate for delayed emesis in the
ondansetron arm was significantly higher than in the placebo
arm (59.6% versus 41.1%, p = 0.012) [23,24]. However, one
criticism was that the patient baseline characteristics were not
well balanced in both groups. Another multicenter study evaluated the use of dexamethasone alone or in combination with
ondansetron [24]. In terms of providing complete protection
from both delayed vomiting and moderate to severe nausea,
the combination therapy arm and the dexamethasone alone
arm were statistically equivalent. Another big randomised
trial addressed the same issue. The results showed that combination treatment (dexamethasone plus 5-HT3 -RA) was not
better than dexamethasone alone in achieving complete protection from delayed emesis (41% versus 47%, respectively)
[25]. Delayed nausea, however, was significantly less in the
combination arm.
Another recently published study compared two different
5-HT3 -RAs palonosetron and ondansetron [26]. No steroids
were permitted during the study period. A single i.v. dose

K. Jordan et al. / Critical Reviews in Oncology/Hematology 61 (2007) 162175

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Table 2
Pharmacokinetic parameters of 5-HT3 -receptor-antagonists
Half-life (h)
Receptor binding constant, pKi

Ondansetron

Granisetron

Tropisetron

Dolasetron

Palonosetron

4.0
8.1

9.0
8.4

8.0
8.8

7.5
7.6

40
10.5

of palonosetron (0.25 or 0.75 mg) or ondansetron (32 mg)

were administered on day 1. Complete response rates (no
emesis, no rescue medication) in the delayed phase were significantly better in the 0.25 mg palonosetron arm than in the
ondansetron arm (74% versus 51%). The authors suggested
that the efficacy of palonosetron in the prevention of delayed
emesis is due to its high 5-HT3 receptor binding affinity and
long plasma elimination half-life. In another study single
doses of palonosetron (0.25 and 0.75 mg i.v.) were compared to a single dose of dolasetron 100 mg i.v. as the third
arm [27]. Due to a late amendment allowing corticosteroids,
5% of patients received these additional agents. Palonosetron
showed a markedly improved complete response rate in the
delayed period (54.0% versus 38.7%). Further studies have
to evaluate the role of this new 5-HT3 -RA palonosetron in
combination with steroids.
Due to these findings, the MASCC and ASCO guidelines recommend that dexamethasone should be the agent
of choice and 5-HT3 -RAs can be used as an alternative agent
in the prevention of delayed nausea and vomiting in moderate emetogenic chemotherapy [6,28]. Recommendations
in patients receiving an anthracycline + cyclophosphamidebased chemotherapy are different and discussed below.
2.1.2.3. Comparative efcacy of the available 5-HT3 receptor-antagonists. All currently marketed 5-HT3 -RAs
are efficacious in preventing acute CINV [7,12,29,30]. None
of the systematic reviews done so far (no inclusion of
palonosetron) have clearly demonstrated superiority of one
agent over another. These studies included a comparison of
granisetron, ondansetron, tropisetron and dolasetron, using
all studies as references rather than head-to-head trials
[31], and meta-analyses of randomised trials comparing
granisetron with ondansetron [32], granisetron or tropisetron
with ondansetron [33]. A recently performed meta-analysis
of more than 40 cisplatin and non-cisplatin based studies
showed an equivalence of ondansetron and granisetron, a significant advantage for granisetron over tropisetron, and no
clear advantage of ondansetron over tropisetron [34,35]. In
a subanalysis of granisetron and ondansetron, it was demonstrated that in non-cisplatin-based studies, ondansetron, 8 mg
i.v., appears to be inferior to granisetron, 3 mg i.v., although
this observation comes from an analysis of small studies
that were underpowered. No comparisons were made with
the commonly used dose of 1 mg i.v. granisetron due to
a lack of studies comparing this dose with ondansetron.
Despite the statistically significant differences among the
5-HT3 -RAs, it is difficult to know if these differences are
clinically relevant. Palonosetron was not included in this
meta-analysis because only two studies were fully pub-

lished so far at that time [26,27]. In the three available

randomised studies, palonosetron has proven to be at least
as effective as the presently available 5-HT3 -RAs in the prevention of acute emesis after both highly and moderately
emetogenic chemotherapy. In the setting of highly emetogenic chemotherapy, palonosetron was as effective as a single
dose of ondansetron for the prevention of delayed emesis as lately published by Aapro et al. [36]. In the setting
of moderately emetogenic chemotherapy, a single dose of
palonosetron 0.25 mg provided significant better control than
either ondansetron 32 mg (Pal. versus Ond.: 81.0% versus
68.8%) or dolasetron 100 mg. (Pal. versus Dol.: 63.0% versus 52.9%) [26,27]. However, results referring to the delayed
phase have to be interpreted with caution because dolasetron
and ondansetron only were given on day 1 although it is
known that the half-life and receptor binding is different
among the three 5-HT3 -RAs (Table 2). Further studies are
necessary when the comparator 5-HT3 -RA has to be administered at least for 3 days.
In light of the new MASCC and ASCO guidelines, it
has been suggested that, given at biologically equivalent
doses, ondansetron, granisetron, dolasetron, tropisetron and
palonosetron are equally efficacious, equally safe, and appear
to be interchangeable [6,12].
2.1.3. Dose recommendation
When administering 5-HT3 -RAs, several points should be
taken into consideration [7,12,37]:
The lowest fully effective dose for each agent should be
used (Table 3); higher doses do not enhance any aspect of
activity because of the receptor saturation.
Oral and intravenous route are equally effective.
No schedule is better than a single dose daily given before
chemotherapy.
Table 3
Dosages of 5-HT3 -RAs
Drug

Route

Recommended dose per day

Ondansetron

p.o.
i.v.

1224 mg
8 mg (0.15 mg/kg)

Granisetron

p.o.
i.v.

2 mg
1 mg (0.01 mg/kg)

Tropisetron

p.o.
i.v.

5 mg

Dolasetron

p.o.
i.v.

100 mg
100 mg (1.8 mg/kg)

Palonosetron

i.v.

0.25 mg

Adapted from refs. [7,12,30,37].

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K. Jordan et al. / Critical Reviews in Oncology/Hematology 61 (2007) 162175

Table 4
Cytochrome P450 (CYP) enzymes involved in the metabolism of 5-HT3 RAs
5-HT3 -receptorantagonists

Enzyme system

Granisetron
Ondansetron
Dolasetron
Tropisetron
Palonosetron

CYP3A4/5
CYP1A1, CYP1A2, CYP2D6, CYP3A/4/5
CYP2D6, CYP3A/4/5
CYP2D6, CYP3A/4/5
CYP2D6, CYP1A2, CYP3A

analysis suggests some differences between the 5-HT3 -RAs,

but it is not clear yet if these findings translate into clinical
practice.
2.2. Steroids

2.1.4. Side effects

The adverse effects of 5-HT3 -RAs are generally mild,
with headache, constipation, diarrhea and asthenia mainly
described [38]. Small, transient, reversible changes in electrocardiographic parameters have been shown to occur with
all available 5-HT3 -RAs. However, after more than 13 years
of commercial use, clinically relevant cardiovascular effects
have not been reported [39].
2.1.5. Genetic polymorphism
The cytochrome P450 enzyme system participates in
the metabolism of all five 5-HT3 -RAs, but plays a significant role only in the metabolism of tropisetron [40]. As
shown in Table 4, ondansetron and palonosetron utilizes the
widest spectrum of isoenzymes. Palonosetron is metabolised
mainly by CYP2D6 and to a lesser extent by CYP3A and
CYP1A2. However, a study on poor and extensive metabolisers of CYP2D6 has not shown any modification of the
AUC of palonosetron in these subjects [41]. Tropisetron and
dolasetron are predominately metabolised by CYP2D6 [42].
Tropisetron undergoes metabolism by the cytochrome P450
2D6 isoenzyme system, which shows phenotypic population
of poor and extensive metabolisers. This means that the T 1/2
of tropisetron is 7.3 h in most patients, but is prolonged to 30 h
in poor metabolisers and shortened in ultrafast metabolisers (1 out of 12 caucasians) [43,44]. Studies in patients and
healthy volunteers have demonstrated these differences in the
clinical responses and pharmacokinetics of ondansetron and
tropisetron are due to genetic polymorphisms of CYP2D6
[40,44]. Genetically defined ultra-rapid metabolisers were
found to have higher scores of nausea and vomiting, compared with poor metabolisers who had the lowest scores.
2.1.6. Comparative assessment
Without doubt 5-HT3 -RAs are the most important agents
in the prevention of CINV. Whereas they have excellent
activity in the prevention of acute CINV, they show little
activity in the prevention of delayed CINV. However, some
patient might benefit from the additional usage of setrons in
the delayed setting. Palonosetron, a new 5-HT3 -RA, demonstrated antiemetic activity in the delayed period. However,
further investigation with different study designs are necessary to explore the actual role of palonosetron.
In accordance to the new guidelines, the 5-HT3 -RAs
appear to be interchangeable. A recently performed meta-

Steroids are an integral component of almost each

antiemetic therapy [12,30,45]. When used in combination
with other antiemetics, steroids appear to exert a booster
effect in raising the emetic threshold. No study supports the
superiority of one corticosteroid over another in terms of
efficacy [7].
2.2.1. Mechanism of action
The mechanism by which steroids exert their antiemetic
activity are not fully understood, but they may affect
prostaglandin activity in the brain, modify the bloodcerebrospinal fluid barrier and inhibit cortical input to the vomiting
centre [46]. Further, the anti-inflammatory effect of steroids
may act as an antiemetic by either preventing the release of
serotonin in the gut or by interfering with the activation of
5-HT3 receptors in the gastrointestinal tract [47].
2.2.2. Clinical studies
2.2.2.1. Steroids before the introduction of 5-HT3 -receptorantagonists. First results about the efficacy of steroids were
demonstrated in patients refractory to standard antiemetic
therapy in 1980. In a study by Silvey et al. in 1988, a reduction of 75% in the incidence of nausea and 82% in vomiting
was observed of 55 patients treated with different kinds of
chemotherapies [48]. These initial observations led to the
further evaluation of corticosteroids in randomised trials.
Antiemetic benefit was evident when a single dose of dexamethasone administered before chemotherapy significantly
improved the control of nausea and vomiting compared with
placebo or compared with traditional antiemetics at this time
[4951].
2.2.2.2. Steroids after the introduction of 5-HT3 -receptorantagonists. Acute CINV: The efficacy of the combination
of dexamethasone and 5-HT3 -receptor-antagonist has been
evaluated in numerous randomised clinical trials. When
dexamethasone is administered in the first 24 h after
chemotherapy, complete response rates between 80 and 90%
are achieved in patients receiving moderately emetogenic
chemotherapy [52,53], and between 60 and 70% in most
studies with cisplatin [54,55].
Delayed CINV: Dexamethasone plays a major role in the
prevention of delayed CINV although it is not approved as
an antiemetic. Available data from a meta-analysis showed
superiority of dexamethasone over a 5-HT3 -RA in protection
against delayed CINV [56]. Dexamethasone has also shown
its antiemetic efficacy over other agents (metoclopramide,
neuroleptics and benzodiazepines) for preventing delayed
nausea and vomiting in both non-cisplatin and cisplatin based
chemotherapy [16,18,24].

K. Jordan et al. / Critical Reviews in Oncology/Hematology 61 (2007) 162175

2.2.2.3. Steroids after the introduction of NK-1-receptorantagonists. In the two approval studies of aprepitant,
dexamethasone was used in combination for both acute and
delayed CINV [8,9]. Due to inhibition of CYP3A4 through
aprepitant, dexamethasone was given in a reduced dose. In
the study by Warr et al., in patients receiving moderate/highly
anthracycline-cyclophosphamide-based chemotherapy, dexamethasone was used for the prevention of acute but not for
delayed CINV in both study arms [57]. Use of aprepitant as
a mono therapy in the prevention of delayed emesis achieved
a complete response rate of 55%. In the ondansetron, singleagent arm complete response was 49%. It is assumable that
the combination of both dexamethasone and aprepitant in the
delayed phase would have enhanced the antiemetic efficacy
rate. Further studies are warranted.
2.2.2.4. Important studies to nd the optimal dose of corticosteroids. A large randomised study in patients receiving
highly emetogenic chemotherapy demonstrated that dexamethasone, given as a single 20 mg dose with a 5-HT3 -RA,
gave the best results in preventing both nausea and vomiting.
The 20 mg dose was the highest tested and was compared
with 4, 8 and 12 mg doses. No increase of side effects was
seen at 20 mg of dexamethasone compared with the lower
doses [58].
The latest publication finding the best dose of dexamethasone in moderate emetogenic chemotherapy was published
by the Italian Group for Antiemetic Research [45]. Three different doses of (A) 8 mg, (B) 24 mg or (C) 8 mg followed by
4 mg dexamethasone every 6 h for 24 h were administered
together with a 5-HT3 -RA. All patients received from days 2
to 5 oral dexamethasone 4 mg bid. Complete protection (no
emetic episodes) was similar in all three treatment groups in
the acute (A: 89%; B: 84%; C: 85%) and delayed period (A:
80%; B: 81%; C: 81%). The authors concluded that dexamethasone 8 mg as a single dose prior to chemotherapy should
be the preferred dose to prevent acute emesis induced by
moderate emetogenic chemotherapy.
2.2.3. Dose recommendation
For prevention of acute CINV, 20 mg (12 mg when
coadministered with aprepitant) in highly emetogenic
chemotherapy and a single dose of 8 mg dexamethasone in
moderately emetogenic chemotherapy should be the dose of
choice (Table 5) [45,58] and has been recommended by the
MASCC and ASCO guidelines [6,12,13].
Table 5
Steroids
Drug

Route

Recommended dose per

day (mg), moderate/high

Dexamethasone

p.o.
i.v.

8/12

Methylprednisolone

p.o.
i.v

40125/40125

167

2.2.4. Side effects

Steroids are considered to be safe antiemetics. Side effects
are usually dependent on dose and duration of therapy. In a
recently published study, in patients receiving dexamethasone in the prophylaxis of delayed CINV patients reported
moderate-severe problems with insomnia (45%), indigestion/epigastric discomfort (27%), agitation (27%), increased
appetite (19%), weight gain (16%) and acne (15%) in the
week following chemotherapy [59]. Concerns that steroids
may interfere with the antitumor effects of chemotherapy
through immunosuppressive mechanisms have not been confirmed in clinical trials [60]. In one study by Kemeny et al.,
the addition of dexamethasone to floxuridine into the hepatic artery in patients with colorectal cancer significantly
improved tolerance and showed a trend toward improved survival [61].
2.2.5. Comparative assessment
Corticosteroids improve the effect of almost any other
antiemetic agent and have also considerable efficacy as single agent. Therefore, corticosteroids are an important agent
for antiemetic prophylaxis and therapy in both acute and
delayed CINV. It is possible that the combination of dexamethasone and aprepitant in the delayed setting will give
the best protection in moderately emetogenic chemotherapy
as was shown for highly emetogenic chemotherapy. Further studies should aim to evaluate this combination in this
setting.
The new guidelines recommend corticosteroids in high,
moderate and low emetogenic chemotherapy for the acute
period. Prophylaxis in patients receiving minimal emetogenic chemotherapy is not warranted by any antiemetic
drug. For the prevention of delayed nausea and vomiting,
corticosteroids are recommended for high and moderate
emetogenic chemotherapy. No prophylaxis of low and minimal emetogenic chemotherapy by any antiemetic drug is
warranted.
2.3. Neurokinin-1-receptor-antagonists
The potential value of the NK-1-receptor-antagonists in
the treatment of chemotherapy-induced vomiting was first
recognised in ferret studies, showing that both acute and
delayed emesis were completely absent. Aprepitant, the
first NK-1-receptor-antagonist represents a new class of
antiemetic agents. Aprepitant has been approved to be used in
acute and delayed emesis resulting from highly emetogenic
chemotherapy (FDA) or cisplatin based chemotherapy (EU)
and moderately emetogenic chemotherapy.
2.3.1. Mechanism of action
Substance P, a neuropeptide (mammalian tachykinin),
mediates its action through neurokinin-1-receptors (NK-1).
These NK-1-receptors are abundant in the chemoreceptortrigger-zone (CTZ), nucleus tractus solitarius (NTS) and
gastrointestinal tract (GI tract) [62].

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K. Jordan et al. / Critical Reviews in Oncology/Hematology 61 (2007) 162175

2.3.2. Clinical studies

2.3.2.1. Highly emetogenic chemotherapy. It has been
shown in several studies that aprepitant augments the
antiemetic activity of the 5-HT3 -receptor-antagonist and dexamethasone to inhibit both, acute and, particularly, delayed
emesis in cisplatin based chemotherapy (Table 6). The
first study was done by Kris et al. [63] evaluating the
NK-1-receptor-antagonist CP-122,721 in 17 cancer patients
receiving cisplatin greater than 80 mg/m2 . The addition of
CP-122,721 to a 5-HT3 -RA and dexamethasone prior to cisplatin improved the control of acute and delayed emesis
remarkably as shown in Table 6.These promising results in
a small number of patients suggested that NK-1-receptorantagonists may be useful in controlling cisplatin-induced
acute and delayed vomiting.
Navari et al. [64] evaluated NK-1-receptor-antagonist in a
three-arm trial with 159 patients. In the first 24 h after cisplatin, 67% of the patients who received granisetron and
dexamethasone alone had a complete control of emesis, and
this improved to 9394% in those patients who also received
the NK-1-receptor-antagonist. Delayed emesis was improved
from 33% in the placebo group to 7882% in the patients who
received the NK-1-receptor-antagonist. Only little difference
was noted in the groups who received either 1 or 5 days the
NK-1-receptor-antagonist. In terms of serious adverse events,
there was no difference in the three treatment groups. Similar results were achieved in the study from Hesketh et al.
[65].
The studies from Van Belle et al. [66], Cocquyt et al. [67]
and Campos et al. [68] demonstrated again the importance of
a 5-HT3 -RA in the prevention of acute emesis which cannot
replaced by an NK-1-receptor-antagonist. Furthermore these
studies confirmed the findings of the improvement of delayed
emesis with the use of an NK-1-receptor-antagonist.
The studies from Hesketh et al. [8] and Poli-Bigelli et al.
[9] formed the basis for the approval of the NK-1-receptorantagonist, aprepitant by the FDA in March 2003. In these
two large randomised, double-blind controlled studies cisplatin nave patients received cisplatin (70 mg/m2 ) and
were randomised to receive ondansetron and dexamethasone
(standard therapy) plus placebo prior chemotherapy and dexamethasone on days 24 or standard therapy plus aprepitant
prior chemotherapy followed by aprepitant and dexamethasone on days 2 and 3. The primary endpoint in both studies
was complete response (no emesis and no use of rescue medication). The complete response of the aprepitant group in both
studies was significantly higher in the acute (8389%) and
delayed period (6875%). In comparison, patients receiving
standard therapy achieved complete response between 68
and 78% in the acute period and between 47 and 56% in the
delayed period.
The studies from Hesketh et al. and Poli-Bigelli et al.
compared the aprepitant regimen with an ondansetron regimen in which ondansetron and dexamethasone were given
on day 1, and dexamethasone alone was given on days 24.
A common clinical used antiemetic regimen is a combination

of a 5-HT3 -RA and a corticosteroid for multiple days. In a

recently published trial the aprepitant regimen was compared
with a multiple-day ondansetron regimen similar to that used
in clinical practice (Table 6) [21]. Complete response rates
were higher in the aprepitant group than in the ondansetron
group in the acute (87.7% versus 79.3%), and delayed phases
(74.1% versus 63.1%) and reached statistical significance.
2.3.2.2. Moderately emetogenic chemotherapy. In the moderate emetogenic setting, one randomised study is published
so far [57]. Primary endpoint was complete response (no
vomiting and no use of rescue medication). The triple combination of ondansetron, dexamethasone and aprepitant used
in the first 24 h followed by aprepitant mono for another 2
days proved to be superior over the 5 days of the whole
study period (51% versus 42%, p = 0.015). However, there
was no significant difference in the delayed period (49% versus 55%, p = 0.064). The control of nausea was similar in both
groups over the entire study period. This study formed the
basis for the approval of aprepitant for moderate emetogenic
chemotherapy.
2.3.3. Dose recommendation
A randomised study established the most favorable risk
profile of aprepitant at doses of 125 mg per os on day 1 and
80 mg per os on days 2 and 3 [69].
2.3.4. Side effects
Adverse effects observed during clinical trials with
aprepitant have included headache, abdominal pain, dizziness, anorexia, hiccups and mild transaminase elevation
[66,69,70]. In general, the incidence of adverse events is similar in patients treated with aprepitant plus a 5-HT3 -RA and
dexamethasone and those treated with just the 5-HT3 -RA and
dexamethasone [8,9].
Aprepitant is eliminated primarily by metabolism of
CYP3A4 and is a substrate and a moderate inhibitor of
CYP3A4 [71]. Therefore, possible interactions between
aprepitant and other drugs have been investigated intensively.
In a study, a two-fold increase in the AUC of dexamethasone
as a sensitive substrate of CYP3A4 could be demonstrated
when combined with aprepitant [72]. In conclusion, the dexamethasone dose should be reduced by approximately 50%
when aprepitant is administered. However, in a study by
Nygren et al, aprepitant had no clinically significant effect on
either the pharmacokinetics or toxicity of standard doses of
docetaxel in cancer patients [73]. The authors concluded that
aprepitant given at clinically recommended doses may only
have a low potential to affect the pharmacokinetics of intravenous chemotherapeutic agents metabolised by CYP3A4.
2.3.5. Comparative assessment
The published studies have demonstrated that the addition of NK-1-receptor-antagonist to the standard antiemetic
therapy (5-HT3 -RA plus dexamethasone) appear to have
significant effect in controlling cisplatin-induced acute as

Table 6
Studies with neurokinin-1-receptor-antagonists, mostly with aprepitant in highly emetogenic chemotherapies
n pts.

Antiemetics day 1
NK-1-RA

Steroid

15a

p-Value
(day 1)

Antiemetics days 23 (4)

CR in %days 25
delayed phase

p-Value
(days 25)

p-Value overall
phase (days 15)

Reference

NK-1-RA

Setron

Steroid

NA

86a
80

NA

NA

[63]

NK
NK

5-HT3 -RA

DEX

100

159

APR
APR

GRAN
GRAN
GRAN

DEX
DEX
DEX

67
94
93

0.001

APR

33
78
82

0.001

0.001

[64]

61

NK

GRAN
GRAN

DEX
DEX

67
86

0.09

NK

37
68

0.0425

0.009

[65]

351

APR
APR*
APR

GRAN
GRAN

DEX
DEX
DEX
DEX

51
75
44
41

0.01

APR
APR
APR

22
41
39
39

0.01

[68]

53

APR

OND

48
37

NS

17
48

0.04

NA

[67]

177

APR
APR

OND

DEX
DEX
DEX

83
36
44

0.001

APR

38
46
59

0.05

NA

[66]

523

APR

OND
OND

DEX
DEX

68
83

0.001

APR

DEX
DEX

47
68

0.001

0.001

[9]

521

APR

OND
OND

DEX
DEX

78
89

0.001

APR

DEX
DEX

56
75

0.001

0.001

[8]

484

APR

OND
OND

DEX
DEX

79
88

0.005

APR

OND

DEX
DEX

63
74

0.004

0.003

[21]

K. Jordan et al. / Critical Reviews in Oncology/Hematology 61 (2007) 162175

17

Setron

CR in %day 1
acute phase

CR, complete response (no vomiting and no use of rescue medication); APR, aprepitant; NA, not available; NS, not significant; NK, neurokinin-1-receptor-antagonist; DEX, dexamethasone; OND, ondansetron;
GRAN, granisetron; 5-HT3 -RA, 5-HT3 -receptor-antagonist.
* An extra dose of aprepitant 400 mg per os given the evening before day 1 of cisplatin administration.
a Response: no emesis.

169

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K. Jordan et al. / Critical Reviews in Oncology/Hematology 61 (2007) 162175

well as delayed emesis. In all studies, the comparative

benefit of the aprepitant regimen was more pronounced in
the delayed phase [21]. In accordance to these findings,
the triple combination of a 5-HT3 -RA plus dexamethasone
and aprepitant is now recommended in patients receiving
highly emetogenic chemotherapy by the Perugia Consensus
Conference (MASCC guidelines) and the updated ASCO
guidelines [6,12]. Also, in the latest study by Schmoll et
al. [21], the addition of aprepitant to dexamethasone in
comparison to ondansetron and dexamethasone, a regimen
similar to one frequently used in clinical practice in the
delayed phase proved to be superior.
In the moderate emetogenic setting, vomiting prevention was improved by 9% (p = 0.015) for the 5-day period
after chemotherapy with the aprepitant regimen. Based on
this study aprepitant is recommended by the updated ASCO
guidelines in patients receiving any chemotherapeutic regimen that includes cyclophosphamide alone or in combination
with an anthracycline. In the updated MASCC guidelines, the
recommended use of aprepitant in the moderate emetogenic
setting is restricted to the AC protocol.
Comparing the complete response rates of the delayed
period in the moderate and high emetogenic setting, there
are surprisingly no major differences. This finding indicates
the importance of a steroid in the delayed period, which was
not administered in the study to patients receiving moderate
emetogenic chemotherapy. Therefore, further studies are necessary to explore the role of aprepitant together with steroids
in the delayed period in patients receiving moderate emetogenic chemotherapy. Furthermore, studies are warranted
to explore specific clinical situations such as multiple day
chemotherapy and high dose chemotherapy.
2.4. Substituted benzamides
2.4.1. Metoclopramide
Before the introduction of 5-HT3 -RAs, metoclopramide,
usually at high doses and in combination with a steroid,
played a primary role in the management of acute CINV.
2.4.2. Mechanism of action
Metoclopramide is a D2-antagonist and is active
peripherally in the gut and centrally in the chemoreceptortrigger-zone. Today, it is recognised that the effect of high
dose metoclopramide in patients receiving cisplatin is due to
antagonism at 5-HT3 receptors [74,75].
2.4.3. Clinical studies
Gralla et al. reported in 1981 the efficacy of high-dose
metoclopramide in patients receiving cisplatin [74]. After the
introduction of 5-HT3 -RAs, metoclopramide was replaced
by 5-HT3 -RAs in the prevention of acute CINV. However,
metoclopramide in combination with corticosteroids still has
proven efficacy in the prevention of delayed CINV [76,77].
In these two studies, the combination therapy was better than the steroid mono therapy. In the Italian group for

antiemetic research study, the combination therapy of steroid

plus metoclopramide versus steroid plus 5-HT3 -RAs in the
delayed phase were equally effective (complete response:
60% versus 62%) [19]. Consequently, metoclopramide was
recommended by the former MASCC and former ASCO
guidelines [7,78]. In the new MASCC and ASCO guidelines
[12,28], metoclopramide is no longer recommended in the
prevention of delayed CINV. Indeed, 5-HT3 -RAs are recommended as an alternative to steroids in the prevention of
delayed CINV due to moderately emetogenic chemotherapy.
The role of metoclopramide in the updated ASCO guidelines is reserved for patients intolerant of or refractory to
5-HT3 -RAs, dexamethasone and aprepitant.
2.4.4. Dose recommendation
Metoclopramide has antiemetic properties both in low
doses as a dopamine antagonist and in high doses a serotonin
antagonist. The usual recommended doses are 2040 mg po
q 46 h (conventional dose) or 23 mg/kg (high dose) as suggested by Gralla et al. [74].
2.4.5. Side effects
The side effects commonly associated with metoclopramide include mild sedation, dystonic reactions (age
related) especially in higher doses, akathisia, diarrhea and
orthostatic hypotension [74]. Dystonic reactions can be dealt
with Biperiden.
2.4.6. Metopimazine
Metopimazine is a phenothiazine derivate with antidopaminergic activity [79]. It exerts its antiemetic effects
via the chemoreceptor trigger zone. The addition of metopimazine to ondansetron or ondansetron plus prednisolone
generally significantly increased the efficacy of the regimens in preventing CINV in patients receiving moderately
or highly emetogenic chemotherapy. The percentage of
patients experiencing no acute emesis with metopimazine
plus ondansetron was 6378% compared with 4750%
for ondansetron monotherapy [8082]. Metopimazine combined with prednisolone was significantly less effective than
granisetron in the acute setting [83].
Adverse effects occasionally reported with metopimazine
include sedation, orthostatic hypotension and anticholinergic
effects. Extrapyramidal symptoms, including dyskinesias,
are very uncommon [79].
2.4.7. Comparative assessment
Since the introduction of the modern antiemetics, metoclopramide is no longer the antiemetic drug of choice. Although
metoclopramide has to be proven as effective as 5-HT3 -RAs
when combined with steroids in the prevention of delayed
CINV, it is not recommended again in the new MASCC
and ASCO guidelines in this setting. In the treatment of
breakthrough CINV the use of metoclopramide might be successful if optimal treatment has been given as prophylaxis
[84]. It was stated that metoclopramide should be reserved

K. Jordan et al. / Critical Reviews in Oncology/Hematology 61 (2007) 162175

for special circumstances, including known intolerance to 5HT3 -RAs or steroids. In conclusion, while metoclopramide
is still included in the NCCN guidelines as an option, metopimazine and metoclopramide are currently not recommended
by ASCO and MASCC.
2.5. Neuroleptics
Dopamine receptor antagonists were the basis of
antiemetic therapy from the 1950s to the early 1980s, but
they have low efficacy as single agent. They can be subdivided
into phenothiazines (e.g., promethazine and metopimazine),
butyrophenones (e.g., haloperidol and droperidol), atypical
neuroleptics and substituted benzamides (e.g., metoclopramide, metopimazine and alizapride).
2.5.1. Phenothiazines/butyrophenones
The role of phenothiazines and butyrophenones is usually limited in the prevention of CINV. However, they still
play a role in the treatment of breakthrough CINV [84]. Side
effects include sedation and extrapyramidal syndromes that
are common among all dopamine-blocking drugs.
2.5.2. Atypical neuroleptics
Olanzapine, an atypical antipsychotic drug has potential
antiemetic properties because of its action at multiple receptor sites implicated in the control of nausea and vomiting
[85]. It has been found to be efficacious and well tolerated in
the treatment of chronic nausea related to opioids for pain
in advanced cancer patients [86]. In a recently published
small phase I study, olanzapine was used in the prevention
of delayed emesis in patients receiving highly or moderately emetogenic chemotherapy [87]. Olanzapine showed an
acceptable toxicity profile in a dose of 5 mg daily 2 days
prior chemotherapy and 10 mg daily from start of chemotherapy until 7 days after finishing chemotherapy. Mean side
effect was a depressed level of consciousness and fatigue.
In a following phase II trial of olanzapine in combination
with granisetron and dexamethasone for the prevention of
chemotherapy-induced nausea and vomiting, the combination therapy proved to be highly effective in controlling
acute and delayed nausea and vomiting in patients receiving highly and moderately emetogenic chemotherapy [88].
In 10 patients receiving highly emetogenic chemotherapy,
complete response (no emesis, no rescue) was achieved in
100% in the first 24 h and in 80% in the days 25. The results
for the moderately emetogenic chemotherapy were similar.
Future studies on the use of olanzapine may not only provide additional options for the control of nausea and emesis
due to chemotherapy but may also provide new information on the pathophysiology of CINV. The latest phase II
study was presented on ASCO 2006 by Navari et al. showing also a high complete response rate over the whole study
period (days 15) when palonosetron and dexamethasone
were combined with olanzapine in patients receiving highly
or moderately emetogenic chemotherapy [89].

171

2.5.3. Comparative assessment

Phenothiazines and butyrophenones have limited
antiemetic properties and are not recommended as firstline antiemetics although they may prove to be helpful in
the treatment of breakthrough emesis. In contrast, olanzapine
seems promising as an enhancer of the antiemetic effect of
other drug when used in combination therapy.
2.6. Benzodiazepines
Benzodiazepines can be a useful addition to antiemetic
regimens in certain circumstances.
2.6.1. Lorazepam
Trials with lorazepam have shown a high degree of patient
acceptance. As such, they serve to reduce anxiety and reduce
the risk of anticipatory nausea. Lorazepam may add a small
degree of objective antiemetic efficacy, although the effect is
limited and the use of lorazepam as a single-agent antiemetic
is not recommended [6]. A double-blind randomised study
showed that its known antianxiety effects can be quite prominent in the chemotherapy administration setting when added
to effective antiemetic combination [2,10].
2.6.2. Midazolam
Midazolam is a short acting benzodiazepine which is used
for example in patients with prolonged postoperative emesis resistant to usual treatment [90]. In a recently published
small phase II study, midazolam was added to granisetron
and dexamethasone in patients with refractory acute CINV
in previous cycles of highly emetogenic chemotherapy [91].
Midazolam was given as a continuous infusion of 0.04 mg/kg
during the administration of chemotherapy. With the introduction of midazolam, 73% of patients had a reduction of at
least one grade of nausea and vomiting in comparison with
the previous cycle of chemotherapy. No details of potential
side effects, such as sedation, were described.
2.6.3. Comparative assessment
Benzodiazepines have shown a high degree of patient
acceptance. They serve to reduce anxiety and reduce the risk
of anticipatory nausea and are therefore recommended as an
optional adjunct to antiemetic regimens. Midazolam may be
a useful option in patients with refractory emesis in spite of
optimal standard antiemetic prophylaxis and treatment. This
should include aprepitant as standard prophylaxis, although
this was not part of the study discussed above.
2.7. Cannabinoids
Trials with cannabinoids were encouraged by anecdotal reports of decreased emesis in younger patients who
used marijuana while receiving chemotherapy. Cannabinoids
(e.g., dronabinol, nabilone) are thought to exert antiemetic
activity at the cannabinoid receptor, likely located in the
brain stem [75]. In a study done by Sallan et al. in 1975,

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K. Jordan et al. / Critical Reviews in Oncology/Hematology 61 (2007) 162175

oral tetrahydrocannabinol showed antiemetic properties and

was significantly better than a placebo in reducing vomiting caused by chemotherapeutic agents [92]. In a systematic
review of the efficacy of oral cannabinoids in the prevention
of nausea and vomiting, it was found that cannabinoids were
slightly better than conventional antiemetics (e.g., metoclopramide, phenothiazines, haloperidol) [93]. However, their
usefulness was generally limited by the high incidence of
toxic effects such as dizziness, dysphoria and hallucinations.
On the other hand, side effects like euphoria and sedation may
potentially be beneficial [94]. Accordingly, dronabinol is recommended for consideration in the treatment of breakthrough
or refractory emesis. Doses in the range of 510 mg/m2 , every
34 h, orally appear to be among the most useful [95,96].
Usually 1 or 2 mg of nabilone twice a day is recommended
[97].
2.7.1. Comparative assessment
The combination of weak antiemetic efficacy with potentially beneficial side effects (sedation, euphoria) make
cannabinoids to a useful adjunct to modern antiemetic therapy in selected patients. However, the associated side effects
of dizziness and dysphoria should not be underestimated.

not at the central nervous system level [99]. Ginger is consumed via oral ingestion of powdered extract capsules in
doses of 500 mg taken up to three times daily. The results of
studies done with ginger in patients receiving chemotherapy
are controversial and do not demonstrate convincing efficacy [100,101]. There is some evidence, however, that ginger
might be beneficial as an adjunctive therapy for intractable
nausea.
2.9.2. Peppermint (Mentha x piperita Lamiaceae)
Peppermint acts as an internal calcium channel-blocking
agent, producing intestinal smooth muscle relaxation. Peppermint has supportive evidence for use in patients with
dyspepsia, irritable bowel syndrome and as an intraluminal
spasmolytic agent during barium enemas endoscopy [102].
Up to now, there is no published study using peppermint as
an adjunctive therapy for patients receiving chemotherapy.
Peppermint seems to lessen this symptom in the treatment of
postoperative nausea [103].
2.9.3. Comparative assessment
Herbs as antiemetics do not show any convincing efficacy
in the treatment of CINV. There is some evidence that ginger
as an adjunctive therapy may lessen nausea.

2.8. Antihistamines
Antihistamines have been administered both as antiemetics and adjunctive agents to prevent dystonic reactions with
dopamine antagonists [98]. Studies with diphenhydramine or
hydroxyzine in the prevention of chemotherapy nausea and
vomiting have not shown that these drugs have antiemetic
activity [7].
In palliative care, the antihistamines have a role in the
treatment of nausea thought to be mediated by the vestibular
system. Side effects of antihistamines include drowsiness,
dry mouth, and blurred vision.
2.8.1. Comparative assessment
Due to a lack of efficacy proven in several studies, antihistamines should not be utilized as an antiemetic agent in the
prevention of CINV. Antihistamines may be a useful drug in
the treatment of nausea and vomiting when these symptoms
are not induced by the chemotherapy itself.
2.9. Herbs as antiemetics
Herbs are used by at least 80% of the worlds population
and are increasingly popular. Some studies showed a potential benefit of ginger and peppermint in postoperative nausea
and vomiting as well as in the management of nausea and
vomiting in pregnancy.
2.9.1. Ginger (Zingiber ofcinale Roscoe)
The detailed mechanism of action is unknown, although
ginger is known to exert its antiemetic effect at the gut and

3. Conclusion
With the introduction of the neurokinin-1-receptorantagonist aprepitant, a further step forward the prevention
of nausea and vomiting has been made. With the triple
combination therapy of a 5-HT3 -RA, neurokinin-1-receptorantagonist and dexamethasone, vomiting can be prevented
in 7080% of patients receiving highly emetogenic therapy.
In the updated MASCC and ASCO guidelines, the triple
combination is recommended in patients receiving highly
emetogenic chemotherapy. In patients receiving moderately
emetogenic chemotherapy that includes cyclophosphamide
alone or in combination with an anthracycline the triple
combination is also recommended by the ASCO guidelines. For patients receiving other chemotherapy of moderate
emetogenic risk, the two drug combination of a 5HT3 -receptor-antagonist and a steroid is advised by the
panel.
The new 5-HT3 -RA palonosetron has a significantly
longer half-life and a higher binding activity in comparison
to the other 5-HT3 -RAs. Palonosetron may offer advantages
over other 5-HT3 -RAs with respect to convenience and
improved control of CINV in the acute and delayed period.
The fully published papers of the combined treatment of
palonosetron, aprepitant and dexamethasone are awaited
with interest. Study results to date are promising, but
the design of one study is controversial in regard to the
ondansetron control arm.
Guidelines no longer recommend metoclopramide in the
prevention of acute or delayed CINV despite the fact that

K. Jordan et al. / Critical Reviews in Oncology/Hematology 61 (2007) 162175

they show similar activity in the prevention of delayed CINV

when compared to the 5-HT3 -RAs.
Olanzapine, an atypical antipsychotic drug, showed
promising antiemetic activity when combined with a 5-HT3 RA and a steroid. Its antiemetic potential needs further
investigation.
Regardless of the major improvements made in controlling
CINV after chemotherapy, the effectiveness of the available
antiemetic prophylaxis on nausea is still limited. More studies
are required to define optimal treatment for chemotherapyinduced nausea.

Reviewers
Steven M. Grunberg, M.D., Professor of Medicine and
Pharmacology, Vermont Cancer Center, University of Vermont, UHC Campus/St. Joseph 3400, Burlington, VT 05405,
USA.
Gaia Piraccini, M.Sc., Manager, Oncology & Cancer Supportive Care, Medical Marketing Services, Medical Affairs,
Helsinn Healthcare SA, via Pian Scairolo 9, CH-6912 Pazzallo, Switzerland.

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Biography
Dr. Karin Jordan received her doctorate in the field
of antiemesis from the University of Halle, Germany. She
received postdoctoral training in the Department of Hematology/Oncology, Director Prof. Schmoll. Dr. Jordan is a
member of several scientific societies and she is actively
involved in the supportive care group within the German
Cancer Society. Current areas of research interest include
supportive care with a special focus on antiemesis.