Support Care Cancer (2005) 13:97–103
DOI 10.1007/s00520-004-0701-7
Jørn Herrstedt
Jim M. Koeller
Fausto Roila
Paul J. Hesketh
David Warr
Cynthia Rittenberg
Mario Dicato
Received: 17 August 2004
Accepted: 26 August 2004
Published online: 23 November 2004
Springer-Verlag 2004
J. Herrstedt ())
Department of Oncology 54 B1,
Copenhagen University Hospital,
DK-2730 Herlev, Denmark
e-mail: [email protected]
Tel.: +45-4488-4785
Fax: +45-4453-3076
J. M. Koeller
University of Texas Health Science Center
at San Antonio,
San Antonio, TX, USA
F. Roila
Policlinico Hospital,
Perugia, Italy
P. J. Hesketh
Caritas St. Elizabeth’s Medical Center
of Boston,
Boston, MA, USA
D. Warr
Princess Margaret Hospital,
University of Toronto,
Canada
C. Rittenberg
Rittenberg Oncology Consulting,
Metairie, LA, USA
M. Dicato
Luxembourg Medical Center,
Luxembourg
REVIEW ARTICLE
Acute emesis:
moderately emetogenic chemotherapy
Abstract This paper is a review of
the recommendations for the prophylaxis of acute emesis induced by
moderately emetogenic chemotherapy as concluded at the Perugia Consensus Conference, which took place
at the end of March 2004. The review
focuses on new studies appearing
since the last consensus conference in
1997. The following issues are addressed: dose and schedule of
antiemetics, different groups of
antiemetics such as corticosteroids,
serotonin (5-HT3)-receptor antagonists, dopamine D2 receptor antagonists, and neurokinin (NK1) receptor
antagonists. Antiemetic prophylaxis
in patients receiving multiple cycles
of moderately emetogenic chemotherapy is also reviewed. Consensus
statements are given, including optimal dose and schedule of 5-HT3-receptor antagonists and of dexamethasone. The new 5-HT3-receptor antagonist, palonosetron, is a reasonable alternative to the well-established agents of this class—ondansetron, granisetron, tropisetron
and dolasetron. It is concluded that
the best prophylaxis in patients receiving moderately emetogenic che-
Background
The majority of antiemetic studies have focused on patients receiving their first course of chemotherapy with
either a cisplatin-based (highly emetogenic) regimen or a
motherapy is still the combination of
one of the 5-HT3-receptor antagonists
and dexamethasone. The results of
studies adding a NK1-receptor antagonist to this combination are
awaited and might change future
recommendations.
Keywords Serotonin antagonists ·
Dexamethasone · Anthracycline ·
Cyclophosphamide · Chemotherapy
cyclophosphamide/anthracycline-based (moderately emetogenic) regimen. Furthermore the observation period in
many of these trials was restricted to the initial 24 h following chemotherapy. This means that guidelines have
high levels of evidence and high grades of recommenda-
98
tion concerning prophylaxis of acute emesis in chemotherapy-naive patients, but lower levels/grades concerning
other aspects of chemotherapy-induced emesis. As for
patients receiving moderate emetogenic chemotherapy
(MEC), we consequently have a number of studies investigating antiemetic prophylaxis during the first course
of cyclophosphamide, methotrexate plus 5-fluorouracil
(CMF) or cyclophosphamide, epirubicin plus 5-fluorouracil (CEF/FEC) or doxorubicin/epirubicin plus cyclophosphamide (AC/EC) chemotherapy. On the contrary,
only a few studies have addressed emesis in patients
treated with carboplatin [5] and even fewer studies in
those receiving ifosfamide and other kinds of MEC. Focusing only on the first course of chemotherapy also creates the potential risk of overestimating the efficacy of
antiemetic prophylaxis in studies compared with the efficacy obtained in daily clinical practice, because patients
typically receive multiple courses of chemotherapy.
Recent studies have indicated that although antiemetic
prophylaxis has been markedly improved by the use of
serotonin (5-HT)3 receptor antagonists, nausea is still the
most feared adverse event to chemotherapy [14]. Still,
47% of patients reported acute nausea and 28% acute
vomiting after their first course of MEC [15] in spite of
optimal evidence-based antiemetic prophylaxis 5-HT3receptor antagonist plus a corticosteroid).
Current practice guidelines for prophylaxis
of acute emesis induced by MEC
The current MASCC [2], ASCO [12], ASHP [3] and
ESMO [9] practice guidelines for prophylaxis of acute
emesis following MEC are summarized in Table 1. The
recommendations are clear-cut and all agree that a 5-HT3receptor antagonist in combination with a corticosteroid
(dexamethasone) is the treatment of choice. The highest
level of evidence and grade of recommendation applies to
cyclophosphamide and anthracycline-based chemotherapy and to a lesser extent carboplatin.
Literature search strategy
Current guideline references were used as the basis for the
selected references up to year 1997. A Medline search
(from 1997 to 2004, 7 March) was conducted of articles
using the search terms: “acute emesis” and “chemotherapy”. An additional number of Medline searches were
completed using the term “acute emesis” and an antiemetic as the second search term. The antiemetic search
terms that were used were ondansetron, granisetron, dolasetron, tropisetron, ramosetron, azasetron, palonosetron,
metoclopramide, prochlorperazine, metopimazine, domperidone, dexamethasone, prednisolone, methylprednisolone, prednisone, benzodiazepines, cannabinoids, and
aprepitant. Medline searches using the term “acute emesis” and a chemotherapy agent as the second search term
were also done. The chemotherapy terms used were anthracyclines, doxorubicin, epirubicin, cyclophosphamide,
carboplatin, and ifosfamide. Finally a search using the
same terms and also multiple cycles/courses was carried
out. The studies included in the last search were all
identified in at least one of the previous searches. This
strategy ensured very sensitive, but non-specific results,
including from 10 (ifosfamide) to 476 (ondansetron) references in each search. Subsequently each search was
manually reviewed, and studies not investigating chemotherapy-induced emesis and those investigating emesis
in pediatric populations were excluded. All the searches
were thereafter critically reviewed by at least three of the
authors, who identified references to be included. If two
or more of these concluded that a reference was important, it was included in the final list of references. All
these references were reviewed, but primarily studies
adding new knowledge to the previous guidelines of
MASCC, ASCO, ASHP and ESMO were included in the
reference list of this paper. Only randomized studies were
included, and with the exception of a few trials only
double-blind studies were considered.
Overview of the literature
The majority of randomized trials followed patients
through the first cycle of chemotherapy only. A few
studies followed patients through multiple cycles of
Table 1 Previous consensus guideline recommendations
Group
Reference
Recommendation
Confidence/evidence/consensus/grade of recommendation
MASCC
4
5-HT3-receptor antagonist plus dexamethasone
ASCO
5
5-HT3-receptor antagonist plus dexamethasone
ASHP
ESMO
6
7
5-HT3-receptor antagonist plus dexamethasone
5-HT3-receptor antagonist plus dexamethasone
Level of confidence: high
Level of consensus: high
Level of evidence: I
Grade of recommendation: A
Level of evidence: A
Level of evidence: I
Grade of recommendation: A
99
chemotherapy, and these studies are described separately.
Studies in patients receiving multiple-day chemotherapy
and studies in patients with refractory emesis or with
breakthrough emesis are not discussed here.
Since the publication of the present guidelines, studies
confirming the optimal doses of 5-HT3-receptor antagonists and of dexamethasone have been published. Furthermore two phase III studies with a new 5-HT3-receptor
antagonist, palonosetron, in patients receiving MEC have
recently been published.
Dose and schedule
Recommended doses of 5-HT3-receptor antagonists are
given in Table 2. All the 5-HT3-receptor antagonists can
be given as a single intravenous (i.v.) dose as prophylaxis
of acute emesis. Kaizer et al. [22] showed that a single
16 mg i.v. dose of ondansetron is as effective as 8 mg i.v.
followed after 12 h by 8 mg orally. A strong indication
that 8 mg i.v. is as effective is found in the results from a
recent study by the Italian Group for Antiemetic Research
[20] in which a complete protection rate in about 90%
was seen using a single 8 mg i.v. dose in combination
with dexamethasone. The new agent, palonosetron has
been investigated in two phase III trials in patients receiving MEC [8, 13]. In both these trials a single i.v. dose
of 0.25 mg was as effective as 0.75 mg. The recommended dose of this agent for protection against emesis
induced by MEC is therefore a single 0.25 mg i.v. dose.
No oral dose of palonosetron is currently available.
Granisetron, dolasetron and tropisetron can be given as
single oral doses of 2 mg, 100 mg and 5 mg, respectively.
As for ondansetron Beck et al. [4] showed that 8 mg
orally twice daily is as effective as 8 mg orally three times
daily, but no randomized, blinded studies have investigated single oral doses of ondansetron in MEC. A study
has shown that a single 16 mg dose of ondansetron given
as a suppository is as effective as 8 mg orally twice daily
[6].
The Italian Group for Antiemetic Research, in a randomized double-blind trial, investigated a single i.v. dose
of dexamethasone 24 mg versus 8 mg versus 8 mg plus
4 mg orally times four. No significant differences were
seen in the prophylaxis of acute emesis in this trial designed to find differences larger than 15% [20]. The
recommended dose of dexamethasone is therefore 8 mg
Table 2 Doses of 5-HT3-receptor antagonists
i.v. (single dose) although it is unknown if smaller doses
are as effective as 8 mg.
Corticosteroids
The most intensively investigated corticosteroid is dexamethasone, but no studies have actually indicated that
there is a difference in antiemetic effect or toxicity between the various corticosteroids. As described in the
previous guidelines [2, 12], dexamethasone has been
consistently equal or superior to metoclopramide and
equal to 5-HT3 -receptor antagonists such as ondansetron
[21] and granisetron [19] in patients receiving cyclophosphamide- or anthracycline-based chemotherapy. Two
randomized studies have indicated that dexamethasone
plus prochlorperazine [31] or prednisolone plus metopimazine [28] is inferior to granisetron in patients receiving
MEC. In the first study chemotherapy also included cisplatin (20–50 mg/m2) and in the second study prednisolone was given in a dose equal to only 50% of the recently
established optimal dose of dexamethasone [20].
Dexamethasone has in randomized, double-blind trials
improved the antiemetic effect of ondansetron [24],
granisetron [19], tropisetron [1] and dolasetron [24] in
patients treated with MEC.
5-HT3-receptor antagonists
The 5-HT3-receptor antagonists, ondansetron, granisetron, dolasetron and tropisetron have all been reviewed in
the previous guidelines. There was consensus that no
clinically meaningful differences exist between the agents
for efficacy and toxicity in MEC, but it was recognized
that tropisetron has not been as intensively investigated as
the others [2, 12]. Two large double-blind studies have
confirmed that granisetron and ondansetron both combined with dexamethasone are equally effective in patients receiving MEC [25, 26], and the latter study, including more than 1000 patients, also showed that a single
oral dose of granisetron 2 mg is as effective as a single
32 mg i.v. dose of ondansetron [26].
Studies with ondansetron have shown that this agent
can be given as a suppository [6] or as an orally disintegrating tablet [7] with the same effect as conventional oral
administration.
5-HT3-receptor antagonist
Oral dose
Intravenous dose
Ondansetron
Granisetron
Dolasetron
Tropisetron
Palonosetron
8 mg twice daily
2 mg daily
100–200 mg daily
5 mg daily
NA
8 mg daily
1 mg daily
1.8 mg/kg daily
5 mg daily
0.25 mg daily
100
Several studies have, as mentioned above, confirmed
that the effect of a 5-HT3-receptor antagonist is improved
by the addition of dexamethasone, and this combination is
still considered the standard antiemetic therapy in patients
receiving MEC. Several additional 5-HT3-receptor antagonists have also been studied. These include azasetron
[10], ramosetron [23], itasetron [11] palonosetron [8, 13].
They have all been included in studies of patients receiving cisplatin, but only palonosetron has been investigated in large phase III comparative trials in patients
receiving MEC.
Palonosetron has a half-life of approximately 40 h and
also a higher binding affinity for 5-HT3-receptors than the
other 5-HT3-receptor antagonists. Gralla et al. [13] compared the effect and toxicity of palonosetron and ondansetron in a randomized, double-blind phase III trial
including 570 patients. Patients received MEC and were
randomized to palonosetron 0.25 mg i.v. single dose, or
palonosetron 0.75 mg i.v. single dose or ondansetron
32 mg i.v. single dose. Concomitant corticosteroid was
not permitted. The study included both chemotherapynaive patients and non-naive patients. Patients were
stratified for gender and prior chemotherapy experience.
In the first 24 h after chemotherapy, palonosetron 0.25 mg
was significantly superior to ondansetron in preventing
acute emesis. In another phase III study in 592 patients
receiving MEC, Eisenberg et al. [8] compared palonosetron (single i.v. dose of 0.25 mg versus 0.75 mg) and
dolasetron (100 mg i.v., single dose). Approximately onethird of the patients had received prior chemotherapy and
only 5% received dexamethasone in combination with
palonosetron/dolasetron. No significant differences were
seen in the acute phase between palonosetron and dolasetron. Studies comparing palonosetron plus dexamethasone with other 5-HT3-receptor antagonists plus dexamethasone involving MEC for acute nausea and vomiting
(the recommended antiemetic prophylaxis against acute
emesis) are warranted.
Dopamine D2 receptor antagonists
The role of dopamine D2 receptor antagonists in the
prophylaxis of acute emesis from MEC seems to be
limited to (1) patients with refractory emesis after previous antiemetic therapy with a combination of a 5-HT3receptor antagonist plus a corticosteroid or (2) patients
who are not suitable for treatment with corticosteroids.
Herrstedt et al. have shown that the addition of metopimazine 30 mg four times daily to ondansetron reduces the
incidence of acute nausea (P=0.006) and vomiting
(P=0.02) compared with ondansetron alone in patients
who received i.v. CMF/CEF/C chemotherapy [17]. In
daily clinical practice, dopamine antagonists are also used
in patients with break-through emesis, but this indication
has not been investigated in a randomized trial.
Other antiemetics
These include benzodiazepines and cannabinoids. The use
of cannabinoids is restricted by the adverse event profile.
Lorazepam has, in a randomized, double-blind trial [16],
improved the effect of ondansetron plus dexamethasone
in patients with emesis in the previous cycle of MEC, in
spite of treatment with ondansetron plus dexamethasone.
NK1-receptor antagonists
Two large randomized studies [18, 27] have compared
3 days of therapy with aprepitant combined with standard
antiemetic therapy (5-HT3-receptor antagonist plus
dexamethasone) versus standard antiemetic therapy alone
in patients receiving cisplatin-based chemotherapy. No
studies have been published to date (April 2004) in patients receiving MEC.
Multiple cycles of MEC
A majority of patients receive multiple cycles of chemotherapy, but only a few trials have addressed additional
courses. The conflicting results obtained in these trials
could be due to the different number of cycles followed in
the studies, the use of an open study design after cycle
one, and differences in the statistics used. De Wit et al.
demonstrated that differences in results could be due to
analysis based on conditional instead of cumulative
probabilities [32].
Three studies prospectively followed patients through
six to nine cycles of MEC using a randomized, doubleblind design. In the first study 223 patients were followed
through nine cycles of CMF/CEF chemotherapy (total
number of cycles 898). Neither granisetron alone nor
prednisolone plus metopimazine was able to maintain
antiemetic efficacy [28]. These antiemetic regimens are,
however, no longer recommended as a standard for prophylaxis of emesis induced by MEC. In another study,
Soukop et al. [30] followed 187 women receiving adjuvant cyclophosphamide-based chemotherapy through six
cycles. Although ondansetron plus dexamethasone was
superior to dexamethasone plus metoclopramide, the effect of both regimens declined during multiple cycles. In a
third randomized, double-blind trial, Sigsgaard et al. [29]
compared the effect of ondansetron plus metopimazine
with ondansetron plus metopimazine plus prednisolone in
221 women receiving CMF/CEF chemotherapy and followed through nine cycles (total of 1462 cycles). In the
first cycle, the only significant difference observed, between the two regimens, was less delayed nausea (days 2–
5) with the three-drug regimen. Using analysis based on
cumulative probabilities, the effect of both antiemetic
regimens declined through the subsequent cycles. The
101
cumulative emetic protection rate after nine cycles of
chemotherapy was 0.75 with the three-drug regimen as
compared with 0.52 with the two-drug regimen
(P=0.0014).
Conclusion
The standard antiemetic therapy for acute emesis in patients receiving MEC is a combination of a 5-HT3-receptor antagonist plus dexamethasone. This is important
not only for protection in the initial 24 h, but the use of
this combination for acute emesis induced by MEC also
decreases the incidence of delayed emesis compared with
less-effective regimens. The new 5-HT3-receptor antagonist, palonosetron, used as a single agent, has been investigated in two phase III trials and is at least as effective
as dolasetron and ondansetron in the first 24 h after MEC.
The effect of palonosetron in combination with dexamethasone for acute emesis in MEC should be investigated. Results of studies with the NK1 receptor antagonist, aprepitant, in patients receiving MEC will soon be
available and might change the present recommendations.
Patients with refractory emesis after treatment with
MEC and standard antiemetic prophylaxis might benefit
from the addition of a dopamine receptor antagonist or a
benzodiazepine in the subsequent cycles. No randomized
trials have demonstrated maintenance of antiemetic efficacy during multiple (more than three) cycles of MEC.
Therefore investigations of multiple cycles of MEC
should be initiated investigating the use of both palonosetron and aprepitant in this setting. The statements of the
Perugia Consensus Conference which took place in
March 2004 are given in the appendix.
Appendix: Consensus statements
1. A 5-HT3-receptor antagonist plus dexamethasone is
recommended for prophylaxis of acute nausea and
vomiting in the first course of MEC.
MASCC Level of confidence: high. Level of consensus: high
ASCO Level of evidence: I. Grade of recommendation: A
2. There is no difference in the effectiveness of oral or
i.v. administration of a 5-HT3-receptor antagonist
(palonosetron is only available as an i.v. formulation).
MASCC Level of confidence: high. Level of consensus: high
ASCO Level of evidence: I. Grade of recommendation: A
3. Recommended doses of 5-HT3-receptor antagonists in
MEC (palonosetron is only available as an i.v. formulation).
– The recommended oral dose of ondansetron is 16 mg
(randomized studies have tested the 8 mg twice-daily
schedule).
MASCC Level of confidence: high. Level of consensus: high
ASCO Level of evidence: I. Grade of recommendation: A
– The recommended i.v. dose of ondansetron is 8 mg or
0.15 mg/kg as a single dose.
MASCC Level of confidence: moderate. Level of
consensus: high
ASCO Level of evidence: III. Grade of recommendation: B
– The recommended oral dose of granisetron is 2 mg as a
single dose.
MASCC Level of confidence: high. Level of consensus: high
ASCO Level of evidence: I. Grade of recommendation: A
– The recommended i.v. dose of granisetron is 1 mg or
0.01 mg/kg as a single dose.
MASCC Level of confidence: high. Level of consensus: high
ASCO Level of evidence: I. Grade of recommendation: A
– The recommended oral dose of dolasetron is 100 mg as
a single dose.
MASCC Level of confidence: moderate. Level of
consensus: high
ASCO Level of evidence: II. Grade of recommendation: A
– The recommended i.v. dose of dolasetron is 100 mg or
1.8 mg/kg as a single dose.
MASCC Level of confidence: moderate. Level of
consensus: high
ASCO Level of evidence: II. Grade of recommendation: A
– The recommended oral dose of tropisetron is 5 mg as a
single dose.
MASCC Level of confidence: low. Level of consensus: high
ASCO Level of evidence: III. Grade of recommendation: B
– The recommended i.v. dose of tropisetron is 5 mg as a
single dose.
MASCC Level of confidence: moderate. Level of
consensus: high
ASCO Level of evidence: III. Grade of recommendation: B
– The recommended i.v. dose of palonosetron is 0.25 mg
as a single dose.
MASCC Level of confidence: high. Level of consensus: high
ASCO Level of evidence: I. Grade of recommendation: A
102
4. Effectiveness and toxicity of the 5-HT3-receptor antagonists.
– There are no clinically relevant differences in the effectiveness of the 5-HT3-receptor antagonists in the
prophylaxis of acute nausea and vomiting when given
according to guidelines in the first cycle of MEC.
MASCC Level of confidence: high. Level of consensus: high
ASCO Level of evidence: I. Grade of recommendation: A
– There are no clinically relevant differences in the
toxicity of the 5-HT3-receptor antagonists.
MASCC Level of confidence: high. Level of consensus: high
ASCO Level of evidence: I. Grade of recommendation: A
5. The recommended dose of dexamethasone for prophylaxis of acute nausea and vomiting from MEC is
8 mg i.v. as a single dose.
MASCC Level of confidence: moderate. Level of
consensus: high
ASCO Level of evidence: II. Grade of recommendation: B
6. The antiemetic effect of the standard prophylaxis (5HT3-receptor antagonist plus dexamethasone) declines
during multiple cycles (more than 3) of MEC.
MASCC Level of confidence: high. Level of consensus: high
ASCO Level of evidence: I. Grade of recommendation: A
7. A dopamine antagonist can be used as supplement in
the subsequent cycles in patients who experience
nausea/emesis from MEC after treatment with standard
antiemetic therapy (5-HT3-receptor antagonist plus
dexamethasone).
MASCC Level of confidence: moderate. Level of
consensus: high
ASCO Level of evidence: II. Grade of recommendation: B
8. A benzodiazepine can be used as supplement in the
subsequent cycles in patients who experience nausea/
emesis from MEC after treatment with standard antiemetic therapy (5-HT3-receptor antagonist plus dexamethasone).
MASCC Level of confidence: moderate. Level of
consensus: moderate
ASCO Level of evidence: II. Grade of recommendation: B
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