Annals of Oncology 7: 277-282, 1996.
O 1996 Kluwer Academic Publishers. Printed in the Netherlands.
Original article
Optimum anti-emetic therapy for cisplatin induced emesis over repeat courses:
Ondansetron plus dexamethasone compared with metoclopramide,
dexamethasone plus lorazepam
D. Cunningham,1 M. Dicato,2 J. Verweij,3 R. Crombez,4 P. de Mulder,5 A. du Bois,6
A. Stewart,7 J. Smyth,8 P. Selby,9 D. van Straelen,10 R. Parideans,11 B. McQuade12 &
J. McRae12
1
The Institute of Cancer Research & The Royal Marsden Hospital, Sutton, Surrey, U.K.; 2 Centre Hospitaller de Luxembourg,
Luxembourg;
^Rotterdam Cancer Institute, Rotterdam, The Netherlands; AAZ Sint-Lucas, Brugge, Belgium; iAcademisch Ziekenhuis, Ntjmegen, St.
Radboud, The Netherlands; 6 Universita'ts-Freuenklinik, Freiburg, Germany; 7Christie Hospital, Manchester, U.K.; 8 Western General
Hospital, Edinburgh, U.K.; 9St James' University Hospital, Leeds, U.K.; '" Virga Jesse Ziekenhuis, Hasselt, Belgium; " Centre Hospitaller
Universitatre de Liege, Belgium; nGlaxo Research and Development Limited, Greenford, Middlesex, U.K.
Summary
P" 0.014). This was maintained over the three treatment
cycles; 38% of O+D and 20% of M+D+L patients remained free of emesis (P — 0.003). Maintenance of control of
nausea grade as none or mild on days 1-5 over the three
courses was significantly better in the O+D group (48%)
than in the M+D+L (26%, P - 0.003).
The most commonly occurring adverse events in the
O+D group were constipation (25%) and headache (19%).
In the M+D+L group drowsiness (38% of patients), malaise/fatigue (16% of patients), constipation (13% of patients), anxiety (11% of patients) and dizziness (10% of
patients) were the most commonly reported adverse events.
Extrapyramidal symptoms were reported by 20% of patients
in the M+D+L group. Despite the inclusion of lorazepam,
14% of patients in the M+D+L group were withdrawn from
the study due to extrapyramidal symptoms, which in the
opinion of the investigators, were probably or almost certainly related to study medication.
Conclusion: This study shows that O+D is significantly
more effective and better tolerated than M+D+L for the
control of emesis and nausea over a series of three courses of
cisplatin chemotherapy.
Background: This study was undertaken to compare the efficacy and tolerability of ondansetron plus dexamethasone
(O+D) with metoclopramide plus dexamethasone plus lorazepam (M+D+L) over three consecutive courses of cisplatin
chemotherapy.
Patients and methods: This was an international, multicentre, double-blind, double-dummy, parallel group study.
O+D patients were randomised to receive ondansetron 8 mg
intravenously (i.v.) plus dexamethasone 20 mg i.v. prior to
cisplatin (50-100 mg/m2) chemotherapy. On the following 4
days they were treated with ondansetron 8 mg bd orally and
dexamethasone 4mg bd orally. M + D+L patients were randomised to receive metoclopramide 3 mg/kg i.v., dexamethasone 20 mg i.v. and lorazepam 1.5 mg/m2 i.v. (max 3 mg)
prior to cisplatin chemotherapy and a further dose of metoclopramide 3 mg/kg i.v. approximately 2 hours following the
first dose of metoclopramide. Treatment for the following 4
days was metoclopramide 40 mg tds and dexamethasone 4
mg bd orally. Two hundred and thirty-seven patients were
recruited into the study (117 patients received O + D and 120
received M+D+L).
Results: On the first course of chemotherapy, O + D was
significantly superior to the M+D+L regimen for complete Key words: cisplatin, emesis, nausea, ondansetron, repeated
control of emesis (days 1-5, 54% versus 37%, respectively, treatments
Introduction
Cisplatin is one of the most effective chemotherapy
agents currently available but also one of the most
emetogenic with emesis and nausea occurring in almost
all patients within 24 hours (acute emesis) of its administration if anti-emetics are not given. In addition, the
majority of patients will experience emesis and nausea
in the following 2-4 days (delayed emesis) [1-3]. The
control of nausea and vomiting is critical to the patient's quality of life and perception of chemotherapy
[4]-
Ondansetron, a highly selective 5-HT3 receptor
antagonist, has been shown to be superior to high dose
metoclopramide for the control of acute emesis induced by cisplatin [3, 5, 6]. In addition dexamethasone
has been shown to enhance the efficacy of both ondansetron and metoclopramide in this situation [7-9]
Lorazepam or diphenhydramine may be combined
with metoclopramide plus dexamethasone to help
counter the extrapyramidal side effects of metoclopramide as well as improving efficacy [1]. Prior to the
introduction of the 5-HT3 receptor antagonists the
combination of metoclopramide and dexamethasone
278
with lorazepam or diphenhydramine was regarded as
the optimal anti-emetic treatment for both acute and
delayed emesis in patients receiving high-dose cisplatin
chemotherapy [10].
Ondansetron plus dexamethasone has recently been
shown to be superior to metoclopramide, dexamethasone and diphenhydramine in the control of acute
emesis over three courses of cisplatin therapy [11]. The
aim of this study was to compare the efficacy and safety
of two combination anti-emetic regimens, ondansetron
and dexamethasone (O+D) with metoclopramide,
dexamethasone and lorazepam (M+D+L) over the
emesis course (acute + delayed) after three consecutive
courses of cisplatin chemotherapy.
All analyses were stratified by cluster of centres. The clusters
ranged in size between approximately 25 and 50 patients and were
based on country and, where appropriate, geographical region within the country. Separate analyses were performed for the first course
(course 1) alone and for the series of courses. On day 1 and on the
worst day of days 1-5, the proportions of patients with a complete
response (0 emetic episodes) were compared between treatments
using stratified Mantel-Haenzel x2 tests. The proportions of emesis
free days and of nausea grades were compared between treatment
groups using a Wilcoxon rank sum test Life-table estimates of maintenance of control of emesis and nausea over the three courses were
determined and the 'survival' curves were compared between treatment using a stratified log-rank test Fisher's exact tests were used to
analyse the proportions of patients experiencing the most common
adverse events.
Treatment
Patients and methods
Conduct of the study
This was an international multicentre randomised, double-blind,
parallel group study involving 11 centres in 5 European countries.
The study was carried out according to Good Clinical Practice
Guidelines and to the principles of the Declaration of Helsinki as
modified by the 41st World Assembly, Hong Kong, 1989. Written
informed consent was obtained from all patients.
Patients
Male and female patients aged at least 18 years, scheduled to receive
their first course of cisplatin chemotherapy at a dose of 50-100 mg/
m2 administered as a single intravenous infusion over a period of up
to 4 h either alone or in combination with other cytotoxics for three
identical courses were included. Patients were excluded if they had
received non-cisplatin chemotherapy during the previous 6 months,
had a severe concurrent illness (other than cancer), had other aetiologies for emesis (e.g., gastrointestinal obstruction, central nervous
system metastases), had received anti-emetic therapy concurrently
or in the 24 h before chemotherapy, had received benzodiazepines
(except when given for night sedation) or concurrent corticosteroids
(except when judged clinically necessary for physiological supplementation, bone metastases or respiratory problems), had vomited
in the 24 h prior to chemotherapy, received what are currently
accepted as moderately or highly emetogenic cytotoxics on days 2-5
(Table 6) following cisplatin chemotherapy, or were pregnant.
Patients received the same anti-emetic regimen for three consecutive
courses of cisplatin chemotherapy. Each course of chemotherapy
was separated from the next by at least three weeks.
Patients were randomly assigned to one of two anti-emetic regimens (Table 1). Ondansetron (8 mg) and dexamethasone (20 mg)
were given as i.v. infusions over 15 minutes and placebo as an i.v.
injection in the hour prior to the start of the cisplatin chemotherapy
on day 1. A further dose of placebo (i.v. infusion over 15 minutes)
was given approximately 2 hours following the first dose of ondansetron on day 1. Similarly, metoclopramide (3 mg/kg) and dexamethasone (20 mg) were given as 15 minute i.v. infusions and lorazepam
(1.5 mg/m2, max. 3 mg) as an i.v. injection in the hour prior to start
of the cisplatin chemotherapy treatment A further dose of metoclopramide (3 mg/kg i.v.) was given as a 15 minute infusion approximately 2 hours following the first dose of metoclopramide on day 1.
According to the randomisation code patients received from day 2
to day 5 either ondansetron (8 mg bd) and dexamethasone (4 mg bd)
orally or metoclopramide (40 mg tds) and dexamethasone (4 mg bd)
orally.
Intervention therapy in the form of 8 mg ondansetron as a slow
intravenous injection was available to all patients who experienced
>3 emetic episodes in the first 24 hours following the start of cisplatin administration.
Assessments
All measurements were performed identically over the three treatment cycles.
Statistical analysis
Table 1. Anti-emetic regimens.
The determination of study size was based on the assumption that,
during the first 24 h of the first course of chemotherapy, M + D+L
would provide complete control of emesis in 70% of patients and
that O + D would provide complete control of emesis in 85% of
patients. Using two-sided tests at the 5% significance level, a study
with 125 patients on each treatment would have a power of 0.82 to
detect a difference between these success rates. The sample size/
power calculations were based on the arcsine-square root transformation of proportions without continuity correction.
The primary analysis was performed on the Intent-to-Treat
population (i.e., all patients who were randomised and who received
at least one dose of study medication and cisplatin containing
chemotherapy). For inclusion in an analysis of a series of courses of
treatment, patients must have been eligible for an Intent-to-Treat
population analysis on course 1. The safety analysis was performed
on patients who were randomised and who received at least one
dose of study medication.
Group
Anti-emetic schedule
prior to chemotherapy
(day 1)
Anti-emetic schedule after
chemotherapy and for days
2-5
Placebo (i.v.)
Dexamethasone
(20 mg i.v.)
Ondansetron (8 mg i.v.)
Placebo (i.v.) 2 hours post
chemotherapy
Ondansetron (8 mg bd orally)
Placebo (od orally)
Dexamethasone (4 mg bd
orally)
Lorazepam (1.5 mg/m2
i.v., max 3 mg)
Dexamethasone
(20 mg i.v.)
Metoclopramide (3 mg/
kg i.v.)
Metoclopramide (3 mg/kg
i.v. 2 hours post chemotherapy than 40 mg tds
orally)
Dexamethasone (4 mg bd
orally)
279
Efficacy
The number and time of emetic episodes occurring in the 24 hours
after chemotherapy were recorded in the clinic. Assessments of both
emesis and nausea on days 2-5 were recorded on a diary card by the
patient The time of any intervention anti-emetic therapy was recorded. An emetic episode was defined as a single vomit or a single
retch or any number of continuous vomits or retches; each episode
was by definition separated from another by at least one minute. A
complete emetic response was defined as no emetic episodes and no
rescue or withdrawal due to a lack of response. Nausea was graded
as none, mild (did not interfere with normal daily life), moderate
(interfered with normal daily life) or severe (bedridden due to
nausea).
Safety
All adverse events were documented throughout the study period.
The severity of the adverse events and the relationship to the study
treatments were assessed by the investigator.
Results
Two hundred and thirty-seven patients were randomised: 117 in the O+D group and 120 in the M+D+L
group. Although the actual number of patients recruited (237) was slightly less than planned in the statistical
power calculation (250), this number still has 80%
power to pick up the difference in control rates specified by the protocol. All randomised patients were eligible to be included in the Safety Population and the
Intent-to-Treat populations which were identical. The
O+D and M+D+L treatment groups were found to be
similar in terms of patient characteristics e.g., age,
male/female ratio, primary tumour site and cisplatin
dose on each treatment cycle (Tables 2 and 3). Although there were slightly more current alcohol users
(>4 units/day) in the M+D+L group (13% vs. 6%) this
is unlikely to have influenced the results.
One hundred and thirty-seven patients did not complete the three courses of scheduled anti-emetic, 61 in
the O+D group and 76 in the M+D+L group. The
most common reasons were lack of response, adverse
events, and disease progression leading to withdrawal
from chemotherapy treatment. Withdrawals for reasons
related to treatment mainly occurred during or at the
end of course 1: 21 patients (18%) in the O+D group
compared with 32 patients (27%) in the M + D + L
group. Over the series of courses 17 patients (14%)
withdrew from the M+D+L group due to extrapyramidal symptoms e.g., trismus, restlessness, agitation
compared with no patients from the O+D group.
The Efficacy population for course 1 excluded
major protocol violators, and consisted of 89 patients
in the O+D group and 96 patients in the M+D+L
group. The majority of protocol violations was because
patients received their cisplatin after 5.30 p.m. Hence
there was a possibility that the patient may have been
asleep during the peak of emetic stimulus. Although
the protocol inclusion criteria stated that cisplatin had
to be given prior to 5.30 p.m., this proved difficult to
control in clinical practice.
Table 2. Patient demography (intent-to-treat population).
Sex
Male
Female
Age (years)
Mean
SD
Range
Ondansetron + dexamethasone
n- 117
Metoclopramide +
dexamethasone +
lorazepam
n-120
Total
n-237
52 (44%)
65 (56%)
50 (42%)
70 (58%)
102 (43%)
135(57%)
58
11
26-79
56
11
28-77
57
11
26-79
Body surface area (m2)
Mean
SD
Range
Alocohol use*
Current > 4 units/day
Previous >4 units/day
Primary tumour site
Head and neck
Lung
Thorax
Gastrointestinal
Genito-urinary
Gynaecological
Skin
Bone/soft tissue
Other
1.73
0.17
135-2.15
1.77
0.20
135-236
1.75
0.19
1J5-236
7 (6%)
10 (9%)
15(13%)
14(12%)
22 (9%)
24 (10%)
9(8%)
17 (15%)
0(0%)
19 (16%)
10(8%)
50 (43%)
5(4%)
1 (1%)
6 (5%)
8 (7%)
14 (12%)
3 (2%)
20(17%)
12(10%)
49 (41%)
6(5%)
0(0%)
8 (7%)
17(7%)
31 (13%)
3(1%)
39 (16%)
22(9%)
41 (42%)
11 (5%)
1 (1%)
14 (6%)
• Unit of alcohol - one measure of spirit, one glass of wine or 250 ml of beer.
Table 3. Cisplatin dose (mg/m2) (intent-to-treat population).
Ondansetron +
dexamethasone
Metoclopramide +
dexamethasone +
lorazepam
Course 1
N
Median
Range
117
70.2
48.3-101.1
120
70.2
50.0-102.7
Course 2
N
Median
Range
76
60.6
40.0-100.0
68
67.5
32.9-102.7
Course 3
N
Median
Range
57
60.0
25.9-101.5
46
59.7
48.8-104.2
N - number of patients starting treatment course.
Efficacy during first course of chemotherapy
Emesis and nausea results for the Intent-to-Treat population are summarised for the first treatment course in
Table 4. A significantly higher proportion of patients
receiving O+D had relief of emesis on day 1 and over
the 5 day study period (days 1-5). Nausea control
was also significantly better with O+D both on day 1
and over the 5 day study period. There was no significant difference in the incidence (19% O+D, 22%
M+D+L) or time to ondansetron rescue therapy on
day 1 of course 1. However, the time to first emetic epi-
280
Table 4. Emesis & nausea control course 1 (intent-to-treat population).
Ondansetron + dexamethasone
Number of patients
117
Day 1
No emesis
85 (73%)
None or mild nausea
95 (81%)
Days 1-5
No emesis
63 (54%)
None or mild nausea
75 (64%)
p = 0 003
Metoclopramide +
dexamethasone +
lorazepam
]
% Patients controlled
120
1
i
2
Treatment Course
67(56%)
92(77%)
P- 0.008
P- 0.301*
44 (37%)
58 (48%)
Figure 2. Maintenance of nausea control (none or mild nausea) over
P- 0.014
P — 0 034* c o u r s e 1~3, days 1-5 (intent-to-treat population).
* Based on distribution of nausea grades as none, mild, moderate,
severe.
0
0 Ondanselron regimen * — g Metoclopramide regimen
Safety
The overall incidence of adverse events during treatsode was significantly longer (P-0.028) after O+D ment was lower in the O+D group than in the
and no patient in this group experienced emesis within M+D+L group with 57% patients and 78% patients
4 hours of cisplatin compared with 15 patients (21%) in reporting adverse events respectively (Table 5). The
the M+D+L group. An analysis of course 1 data for most commonly reported adverse events in the O+D
the Efficacy population produced similar results al- group were headache (19%) and constipation (25%)
though the differences between treatment groups were which were generally mild in nature whilst in the
M+D+L group drowsiness (38%), malaise/fatigue
less marked (not shown).
(16%), constipation (13%), anxiety (11%) and dizziness
(10%) were the most common unique events whilst a
Efficacy over the series of chemotherapy courses
range of extrapyramidal type symptoms (e.g., trismus,
restlessness, irritability, agitation) were reported in
Over the three courses of chemotherapy, 53% of O+D
20% of patients. During treatment, five patients (4%)
patients were completely free of emesis on day 1 of all
withdrew in the O+D group, two due to constipation,
their evaluable courses compared with 33% of
one due to fever and two due to multiple symptoms
M+D+L patients (P — 0.002). There was also a signiand 25 patients (21%) withdrew in the M+D+L group,
ficant treatment difference in the proportion of courses
many due to multiple symptoms, the most common
that were emesis free over days 1-5 (P = 0.009), with
being extrapyramidal in nature (17 patients) such as
41% of O+D patients completely free of emesis on all
restlessness, irritability, agitation, muscle spasm and
evaluable courses compared with 24% of M+D+L patients. From life tables (Figure 1), 38% of patients
maintained complete emetic response through all three Table 5. The most common* adverse events reported during all
courses with O+D compared with 20% with M+D+L courses of treatment.
(P = 0.003). A similar analysis for nausea (Figure 2) reOndanseMetoclof-value
vealed that 48% of patients receiving O+D maintained
tron + dexapramide +
a nausea grade of 'none' or 'mild' compared with 26%
methasone
dexamethaof patients receiving M + D + L (P - 0.003).
(/t-117)
sone +
lorazepam
(n-120)
IOO
-
ao p = 0 003
60 "
d
% Patients controlled
1
40 ~
S3
20 "
1
2
Treatment Course
O
© Ondanselron regimen
Metoclopramide regimen
Figure 1. Maintenance of complete emetic response over courses
1-3, days 1-5 (intent-to-treat population).
Number of patients
with adverse events'1
Constipation
Headache
Dizziness
Drowsiness
Malaise/fatigue
Anxiety
EPS typec
67 (57%)
29 (25%)
22 (19%)
6 (5%)
5 (4%)
5 (4%)
2 (2%)
2(2%)
94 (78%)
16 (13%)
4 (3%)
12 (10%)
46 (38%)
19 (16%)
13(11%)
24 (20%)
<0.001 d
0.036
<0.001
0.242
<0.001
0.014
0.007
< 0.001
P-values based on 2 sided Fisher exact tests.
* Most common is defined as occurring in 10% or more patients in
any treatment group.
b
Patients could experience more than one adverse event.
c
Includes restlessness, agitation, muscle spasm, trismus, tremor.
d
Chi-squared test.
281
Table 6. Highly/moderately emetogenic chemotherapy excluded.
Highly emetogenic
Dacarbazine
Mechlorethamine
Streptozotocin
Nitrogen mustard
Moderately emetogenic
Carboplatin
Carmustine
Cyclophosphamide (>1000 mg/m2)1
Daunorubicin
Epirubicin (>50 mg/m2)"
Actinomycin-D
Lomustine
Plicamycin
Procarbazine
Methotrexate (>200 mg/m2)*
Ifosfamide
Doxorubicin f>35 mg/m2)1
Mitoxantrone
1
These cytotoxics, at doses below those indicated, could be given
on day 1 provided that administration commenced before 2 p.m.
trismus. Two patients (2%) in the O+D group reported
tremor, a symptom which has a number of possible
aetiologies other than extrapyramidal effects. Neither
of these two patients was withdrawn from the study.
In the M+D+L group 38% of patients reported
drowsiness as an adverse event Clearly this could have
had the effect of 'unblinding' the physician or nurse
assessing the patient. It should be emphasised however
that the study medication was administered doubleblind, the i.v. infusions were prepared in the hospital
pharmacy by a pharmacist independent of the trial
and oral medication was packaged and supplied in a
double-dummy fashion.
Discussion
Effective control of emesis and nausea over repeated
courses of chemotherapy is important for the patients'
quality of Me and willingness to complete their prescribed treatment [12].
Prior to the introduction of 5HT3 receptor antagonists the combination of metoclopramide, dexamethasone and lorazepam or dephenhydramine was regarded
as the optimal anti-emetic treatment for patients receiving cisplatin chemotherapy [1, 11, 13, 14]. The introduction of ondansetron provided the possibility of
improved efficacy with fewer side effects. Indeed
ondansetron has been shown to be superior to high
dose metoclopramide [3, 5, 6] and the combination of
ondansetron plus dexamethasone is superior to ondansetron alone in the control of cisplatin induced
emesis [7, 9].
This study was therefore conducted to establish if
the combination of ondansetron plus dexamethasone
provided optimal control of emesis by comparing it
with a combination of the previous gold standard antiemetic combination, high dose metoclopramide plus
dexamethasone and lorazepam. The results show that
the ondansetron regimen was significantly superior to
the metoclopramide regimen in the control of acute
plus delayed emesis both on the first course of treatment (complete control days 1-5, 54% versus 37%
P " 0.014) and in the maintenance of control over days
1-5 on all three treatment courses (38% versus 20%
patients emesis free throughout P — 0.003). Similarly
the control of nausea was superior with the ondansetron regimen throughout (course 1 days 1-5, 64% versus 48% none or mild, P = 0.034*, courses 1-3 with no
more than mild nausea, 48% versus 26% P - 0.003*).
Maintenance of anti-emetic control over a series of
chemotherapy courses has not been extensively studied. However, the results are in agreement with the
recent findings from a multicentre, double-blind study
comparing ondansetron plus dexamethasone with
metoclopramide plus dexamethasone plus diphenhydramine over three courses of cisplatin chemotherapy
[11]. This study showed that the ondansetron regimen
was significantly superior to the metoclopramide regimen in the control of acute emesis on each of the three
courses of cisplatin chemotherapy. Furthermore, the
control of emesis was better maintained over the series
of courses in the ondansetron group than in the metoclopramide group. Similarly, a multicentre, doubleblind study [15] comparing ondansetron plus dexamethasone with metoclopramide plus dexamethasone
in the control of emesis and nausea following cyclophosphamide (3*500 mg/m2) containing chemotherapy
for breast cancer revealed the ondansetron regimen to
be significantly superior to the metoclopramide regimen both on the first course and in the maintenance of
response over six courses of treatment. In this study
quality of life as measured using the Rotterdam Symptom Checklist, was also shown to be better in the
ondansetron group.
The safety profile of ondansetron is well established,
as confirmed in this study, with headache and constipation among the most commonly reported events. The
most common adverse events in the metoclopramide
group were the extrapyramidal related events which
resulted in a significant proportion (14%) of patients
discontinuing their anti-emetic schedule despite the
inclusion of lorazepam to counter these events. Furthermore, sedative side effects were frequently reported in the metoclopramide group compared with the
ondansetron group.
Conclusions
This study demonstrates that ondansetron plus dexamethasone is significantly more effective and better
tolerated than a combination of metoclopramide, dexamethasone and lorazepam in the control of emesis and
nausea induced by cisplatin chemotherapy. This difference in anti-emetic response with the ondansetron regimen was maintained over at least three courses of treat' Based on the distribution of nausea grades as none, mild, moderate, severe.
282
ment. The ondansetron regimen was well tolerated,
whilst the use of the metoclopramide resulted in a
higher incidence of adverse events with extrapyramidal
symptoms necessitating discontinuation of anti-emetic
treatment in a significant number of patients despite
the inclusion of lorazepam which also resulted in sedative side effects in many patients. The combination of
ondansetron plus dexamethasone should therefore be
considered the gold standard anti-emetic combination
for the prevention of cisplatin-induced emesis.
7.
8.
9.
10.
Acknowledgements
This clinical investigation was supported by Glaxo Research and Development Ltd, Greenford, Middlesex,
UK.
11.
12.
13.
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Received 30 October 1995; accepted 14 February 1996.
Correspondence to:
B. McQuade
Gastrointestinal Clinical Research
Glaxo Wellcome Research and Development Ltd.
Greenford Road
Greenford
UB6 0HE Middlesex, U.K.