The comparative effectiveness of ondansetron and granisetron

in a once daily dosage in the prevention of nausea and

vomiting caused by cisplatin: a double-blind clinical trial
pharmaceutical-journal.com/the-comparative-effectiveness-of-ondansetron-and-granisetron-in-a-once-daily-
dosage-in-the-prevention-of-nausea-and-vomiting-caused-by-cisplatin-a-double-blind-clinical-trial/20002162.article
The Pharmaceutical Journal 8 JUL
2000

The Pharmaceutical Journal Vol 265 No 7104p59-62

July 8, 2000 Original Papers

By Linda Stewart, MPharm, MRPharmS, S. M. Crawford, FRCP, and P.

A. Taylor, MPharm, MRPharmS

Aim To compare the effectiveness of ondansetron and granisetron in the prevention of 1/10
Aim To compare the effectiveness of ondansetron and granisetron in the prevention of
nausea and vomiting caused by cisplatin.
Design Double-blind crossover study with random allocation using a Latin square design in
sets of four. Patients were given either ondansetron 8mg plus IV bolus dexamethasone 8mg
or granisetron 3mg by IV infusion plus IV bolus dexamethasone 8mg immediately prior to
chemotherapy and oral dexamethasone 4mg three times a day on days 2 to 4.
Subjects and setting 21 patients attending Airedale general hospital for treatment with
highly emetogenic chemotherapy.
Outcome measures Nausea and vomiting scores on days 1 to 7 post chemotherapy. The
criterion for success of prevention of nausea and vomiting was that patients would suffer
from no more than mild nausea on day 1.
Results 40 courses of ondansetron and 49 courses of granisetron were studied. In 90% of
courses patients suffered from no nausea or mild nausea on day 1 and in 77.5% of courses
patients suffered from no vomiting on day 1 when given ondansetron. In comparison, in
94% of courses patients suffered from no nausea or mild nausea on day 1 and in 88% of
courses patients suffered from no vomiting on day 1 when given granisetron. The mean
nausea score for days 1 to 7 for patients treated with ondansetron was always more than
for those treated with granisetron. The biggest difference was on day 2 when 35% (95% CI
20.6?51.7) of patients treated with ondansetron suffered from moderate to severe nausea
compared with 22% (95% CI 20.6?51.7) of patients treated with granisetron. The mean
number of episodes of vomiting on days 1 to 7 for patients treated with ondansetron was
nearly always more than for those treated with granisetron. The biggest difference was on
day 2 when 50% (95% CI 33.8?66.2) of patients treated with ondansetron as the antiemetic
suffered from 2 or more episodes of vomiting compared with 18% (95% CI 8.8?32) of
patients treated with granisetron.
Conclusions Granisetron is more effective than ondansetron when used in combination with

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dexamethasone in the prevention of acute and delayed vomiting caused by highly
emetogenic chemotherapy. It is significantly better on day 2 when the majority of patients
suffer most.

Recent developments in our understanding of the pathophysiology of emesis and the

availability of a wide selection of drugs should allow good control of acute emesis in patients
undergoing chemotherapy. Effective antiemetic cover is especially important with the first
cycle of treatment to avoid problems with anticipatory vomiting on subsequent courses.1
There is, however, considerable room for improvement, particularly with regard to the
problem of delayed emesis, which remains a significant cause of treatment-related
morbidity in cancer patients despite the use of various antiemetic drugs including 5-
hydroxytryptamine type 3 (5HT3) antagonists. There are currently three licensed in many
countries - ondansetron, granisetron and tropisetron - and there are others in an advanced
state of clinical evaluation.2 Although their chemical structures are similar, they show some
differences in potency, pharmacokinetic and pharmacodynamic characteristics. A variety of
dosage schedules of administration have been suggested and possible differences in
efficacy among these compounds cannot be excluded.3
Various studies have been published comparing the 5HT3 receptor antagonists, but
convincing data on clinically significant differences are still lacking for many of them,
particularly in relation to delayed emesis.4 Ondansetron and granisetron are both claimed
to be highly effective in the prevention of acute nausea and vomiting caused by
chemotherapy.5 Granisetron has a longer half-life than ondansetron and is claimed to be
more effective in the prevention of delayed nausea and vomiting associated with
chemotherapy, but this is usually in combination with dexamethasone. The effectiveness of
ondansetron is improved when used in combination with dexamethasone.6
Dexamethasone is known to be useful in the control of delayed emesis when used in
conjunction with other antiemetics.7,8
The Italian Group for Antiemetic Research carried out a study comparing intravenous
ondansetron 8mg versus granisetron 3mg. Dexamethasone was added to both treatments,
20mg by IV infusion 45 minutes before the cisplatin and 8mg IM twice a day on days 2 and 3
and 4mg twice a day on day 4. The group concluded from this study that ondansetron 8mg
and granisetron 3mg combined with dexamethasone in this schedule showed similar
efficacy and tolerability in the prevention of cisplatin-induced emesis.4 The use of oral
dexamethasone for the prevention of delayed emesis was not investigated in this study.
Combinations of antiemetics may be more effective than a single drug but further studies
are needed to establish the most effective combinations and whether particular
combinations are more suitable for specific chemotherapy regimens or specific patients.
The optimum dose of ondansetron has been investigated in several studies. A single dose of
32mg IV was found to be no different to six-hourly doses of 8mg over a 24-hour period.
However, there were some differences in the hour-to-hour control of nausea and vomiting.9
Krzakowski et al compared the effectiveness of IV ondansetron 8mg in combination with IV
dexamethasone 20mg with oral ondansetron 24mg in combination with oral
dexamethasone 12mg in once daily regimens administered to patients receiving cisplatin
50mg/m2 or greater. Complete control of emesis was achieved in 85 per cent of patients in
the oral group and 83 per cent in the IV group. No nausea was reported in 70 per cent of
patients in the oral group and 68 per cent in the IV group.10
The Italian Group for Antiemetic Research also carried out a double-blind, dose-finding
study of four intravenous doses of dexamethasone in combination with ondansetron 8mg
IV in the prevention of cisplatin-induced emesis. Complete protection from vomiting was
significantly superior in patients who received 20mg compared with those who received
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4mg and 8mg of dexamethasone (P>0.005) and was superior, but not significantly,
compared with those who received 12mg. Complete protection from nausea was superior,
but not significantly, in patients who received 20mg of dexamethasone.11
A double-blind, placebo-controlled comparative study by Goedhals concluded that
granisetron plus dexamethasone did not appear to confer any benefit over the use of
dexamethasone alone in controlling delayed nausea and vomiting.12
Similarly, in a study comparing the use of tropisetron in combination with dexamethasone
or dexamethasone alone in the control of cisplatin-induced delayed emesis, no significant
differences were recorded regarding the control of delayed emesis.13
The Italian Group for Antiemetic Research identified the dose of cisplatin, the dependence
effect and the interaction between antiemetic treatment and the results of acute emesis
control as important determinants for the occurrence of delayed emesis. The group was
unable to demonstrate that age, sex, Karnofsky performance status, treatment modality or
type of cancer were important factors influencing the occurrence of delayed emesis.14
Different cytotoxic drugs have different emetogenic potential and comparison of the
efficacy of antiemetic drugs must be made in the light of similar emetic challenge.15 Other
factors that influence the severity of emesis must also be considered in the design of the
trial. Female patients are more likely to experience emesis. Age can be a determinant of the
side effects seen with different antiemetics.16 Previous treatment with chemotherapy may
also influence the severity of nausea and vomiting.1
There is some question as to whether 5HT3 antagonists maintain their efficacy over
repeated cycles of treatment with cisplatin. Tzekova et al assessed the antiemetic efficacy of
granisetron in repeated cycles of chemotherapy with platinum derivatives. The study
included 50 patients who received between two and five cycles of chemotherapy with
cisplatin or carboplatin. Total control of emesis was achieved in 60 per cent of patients after
the first cycle of chemotherapy, and this percentage did not change significantly over the
first five cycles of chemotherapy.17 However, this study did not look at delayed emesis and
patients were not given dexamethasone with the granisetron. De Wit et al assessed the
sustainment of efficacy of granisetron in combination with dexamethasone in 125 patients
scheduled to receive 70mg/m2 either alone or in combination with other drugs. Patients
received IV dexamethasone and granisetron on day 1 and oral dexamethasone and
granisetron on days 1 to 6. Irrespective of the type of analysis used, the antiemetic efficacy
of granisetron/dexamethasone decreased over cycles. The initial complete acute emesis
control decreased from 66 per cent to 30 per cent. For delayed emesis, the initial complete
protection rate of 52 per cent decreased to 21 per cent. In addition they observed that the
protection failure in the delayed emesis period adversely influenced the acute emesis
protection in the next cycle.18
Improved antiemetic control makes cancer chemotherapy more acceptable and allows
more chemotherapy to be given in the outpatients setting and admissions to be shorter.
This would be more convenient and more economical than treating patients in hospital.
With less vomiting there is less risk from dehydration and consequent renal failure.
These considerations prompted us to perform a study to compare the effectiveness of
ondansetron 8mg with granisetron 3mg in combination with intravenous dexamethasone
on day 1 and oral dexamethasone on days 2 to 4 in controlling acute and delayed emesis
caused by highly emetogenic chemotherapy.
Following a submission to the local research ethics committee at Airedale general hospital, it
was agreed to investigate the comparative effectiveness of ondansetron and granisetron in
the prevention of acute and delayed nausea and vomiting associated with highly
emetogenic chemotherapy.

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Method
Study protocol The study protocol was as follows:
Inclusion criteria Patients attending Airedale general hospital over an 18-month period for
treatment with highly emetogenic chemotherapy, including cisplatin.
Exclusion criteria Hypersensitivity to on-dansetron, granisetron or related substances.
Consent Informed consent was obtained from all patients who were then randomly
allocated to receive either ondansetron or granisetron for each treatment period within a
course of chemotherapy, as part of a set protocol for the prevention of nausea and
vomiting.
Design of randomisation Many comparisons employ crossover studies whereby drug A and
drug B are crossed over within the same patient on the first two cycles of chemotherapy.
However, patients failing to achieve adequate antiemetic control on the first cycle may
possibly be subject to so-called period interaction and are likely to experience a similar
pattern of emesis with the second cycle.1 For these reasons and because of the difficulty in
matching patients for disease, treatment and other factors, it was decided to use a double-
blind, crossover study with random allocation using a Latin square design in sets of four.
This would also address the possible problem of lack of sustainment of antiemetic efficacy
after repeated cycles of cisplatin. Possible combinations using this design are shown in
Table 1.
Treatment courses 5 to 8 would follow a similar pattern to this.
As only relatively small numbers of patients were likely to be involved, each patient would
receive in their first four treatment courses at least two courses of ondansetron and two of
granisetron, rather than all one or the other. This would ensure that information would be
obtained on both ondansetron and granisetron. The same antiemetic would not always be
used for the first treatment course. It was intended that 20 patients would be entered into
the study and each patient would receive at least six courses of chemotherapy and possibly
up to 10. It was, therefore, anticipated that approximately 120 treatment courses would be
studied. Using this method of double-blind, crossover design, patients act as their own
controls to rule out the effect of individual variation and prescriber influence on patients'
expectations.

Table 1: Possible course combinations

Course 1 Course 2 Course 3 Course 4

Patient 1 Ondansetron Ondansetron Granisetron Granisetron

Patient 2 Ondansetron Granisetron Granisetron Ondansetron

Patient 3 Ondansetron Granisetron Ondansetron Granisetron

Patient 4 Granisetron Ondansetron Ondansetron Granisetron

Patient 5 Granisetron Ondansetron Granisetron Ondansetron

Patient 6 Granisetron Granisetron Ondansetron Ondansetron

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Treatment protocol Antiemetic therapy to be given immediately prior to the chemotherapy
on day 1 was: ondansetron 8mg in 100ml sodium chloride 0.9 per cent given as an
intravenous infusion over 10 minutes, plus dexamethasone 8mg IV bolus, or granisetron
3mg in 100ml sodium chloride 0.9 per cent given as an intravenous infusion over 10
minutes, plus dexamethasone 8mg IV bolus. On days 2 to 4 therapy was dexamethasone
4mg three times a day orally and/or metoclopramide 10 or 20mg orally.
Data collection It is important to make comparisons between drugs at therapeutic doses
and to assess both the acute and delayed phases of emesis. Using a standard data
collection form, information was collected for each course of chemotherapy for each
patient. Information regarding the severity of nausea and the number of episodes of
retching or vomiting recorded. The layout of the form was explained to each of the patients
at the beginning of each course of chemotherapy (day 1). Patients were asked to record on
the form, by ticking the relevant boxes, details of the severity of nausea and the number of
episodes of retching and vomiting on days 1 to 7. The form was then returned to the
investigators in the stamped, addressed envelope provided. Data were also collected from
patients' notes and through interview.
The severity of nausea and the number of episodes of retching or vomiting for each 24-hour
period was scored as outlined in Table 2.
It was agreed that if at any time during the study it became apparent that either treatment
was vastly superior the study would be terminated.

Table 2: Scoring for severity of nausea and the number of episodes of retching or
vomiting for each 24h period

Severity of nausea Score Number of episodes Score

None 0 None 0

Mild 1 1 1

Moderate 2 2 2

Severe 3 3 3

4 4

More than 4 5

Results
Twenty-one patients (12 women, nine men) were entered into the study. Results were not
collected from five patients for the following reasons:
In one patient, the protocol for the use of antiemetics was not followed. Additional
doses of intravenous ondansetron were given as well as the patient taking oral
ondansetron 8mg twice a day which had been supplied by her general practitioner.
Two patients each received only one course of chemotherapy and questionnaires for
these patients were not returned.
One patient received four courses of chemotherapy but only the questionnaires for
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 the first two courses were returned. The patient had the same antiemetics for both of
these courses and therefore no comparisons could be made. The patient was
therefore withdrawn from the study.
One patient received three courses of chemotherapy but questionnaires were only
returned for the first two courses where the same antiemetics was used. This patient
was therefore withdrawn from the study.

Data on control of emesis were collected for 16 patients (10 women, six men) who had
received at least one treatment with each of ondansetron and granisetron.
The mean age of patients included in the results was 56 (range 37?74). All patients received
cisplatin mean dose 74mg/m2 (range 59?100mg/m2). A total of 40 courses of ondansetron
and 49 courses of granisetron were studied.
The criterion for success of prevention of nausea and vomiting with ondansetron and
granisetron would be that patients would suffer no more than mild nausea on day 1.
In 90 per cent of courses, patients suffered from no nausea or mild nausea on day 1 and in
77.5 per cent of courses patients suffered from no vomiting on day 1 when given
ondansetron as the antiemetic.
In comparison, in 94 per cent of courses, patients suffered no nausea or mild nausea on
day 1 and in 88 per cent of courses patients suffered from no vomiting on day 1 when given
granisetron as the antiemetic.
Figure 1 shows the mean nausea scores on days 1 to 7 post chemotherapy for the group as
a whole when treated with ondansetron or granisetron as the antiemetic prior to
chemotherapy. The mean nausea score on day 1 was 0.65 with ondansetron and 0.44 with
granisetron for the group of patients as a whole. The mean number of episodes of vomiting
on day 1 was 0.68 with ondansetron and 0.43 with granisetron.
The mean nausea score for days 1 to 7 for patients treated with granisetron was always
lower than for those treated with ondansetron. The biggest difference was on day 2. On
further analysis of the results for day 2, it was found that the number of courses where
patients suffered from more than mild nausea (score 2 to 3) were greater when the patient
had been given ondansetron rather than granisetron. When treated with ondansetron as
the antiemetic 35 per cent (95 per cent CI 20.6?51.7), patients suffered from moderate to
severe nausea. When treated with granisetron 22 per cent (95 per cent CI 11.8?36.6) of
patients suffered from moderate to severe nausea.
Figure 2 shows the mean number of episodes of vomiting on days 1 to 7 for the group as a
whole when patients were given either ondansetron of granisetron prior to chemotherapy.
Patients given granisetron suffered a weekly mean of 4.48 episodes of vomiting compared
with those treated with ondansetron who suffered a weekly mean of 7.39. On most days,
patients given ondansetron suffered more episodes of vomiting than those given
granisetron. The biggest difference was on day 2.
When prescribed ondansetron as the antiemetic, 50 per cent (95 per cent CI 33.8? 66.2) of
patients suffered from two or more episodes of vomiting on day 2 whereas 18 per cent (95
per cent CI 8.8?32) of patients given granisetron as the antiemetic suffered from two or
more episodes of vomiting on day 2. The criterion for successful prevention of nausea and
vomiting for ondansetron and granisetron would be that patients would suffer no more
than mild nausea on day 1.
The mean nausea and vomiting scores for each of the days of the week post chemotherapy
for courses 1+2, 3+4, and 5+6 were compared. They showed that the scores varied but did
not seem to be affected by the number of previous courses.

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Figure 1: Mean nausea score on days
1 to 7 post chemotherapy in patients
given ondansetron ( n ) or granisetron
(n)
Figure
2: Mean
number of vomiting episodes on days 1 to
7 post chemotherapy in patients given
ondansetron ( n ) or granisetron ( n )

Discussion

The incidence of acute emesis and nausea in the first 24 hours after chemotherapy is
greater than 90 per cent in patients receiving highly emetogenic chemotherapy such as
cisplatin, unless treated with antiemetic agents. Good control of these symptoms following
chemotherapy is an important prognostic factor for later control of delayed emesis and
nausea and of emesis and nausea experienced in subsequent cycles of chemotherapy. It is,
therefore, important that emesis and nausea should be well controlled on the first cycle of
chemotherapy, as this may have a significant effect on a patient's quality of life and
willingness to complete the course of treatment. Furthermore, uncontrolled emesis
frequently results in patients whose nutritional status is poor. This study has demonstrated
the efficacy of both IV ondansetron and graniseton in combination with IV dexamethasone
on day 1 and oral dexamethasone on days 2 to 4 in controlling both acute and delayed
nausea and vomiting. The highest incidence of nausea and vomiting occurred on day 2,
when granisetron was significantly better than ondansetron in controlling vomiting. The
crossover design of this study ensured that any period effect or effect of age, sex, or
condition being treated were taken into account, because patients acted as their own
controls. The Italian Group for Antiemetic Research carried out a study comparing
intravenous ondansetron 8mg versus granisetron 3mg in prevention of cisplatin induced
acute and delayed nausea and vomiting in 973 patients. The group concluded from that
study that ondansetron and granisetron showed similar efficacy and tolerability.10
Dexamethasone was added to both treatments, 20mg by IV infusion 45 minutes before the
cisplatin and 8mg IM twice a day on days 2 and 3 and 4mg twice a day on day 4. The use of
oral dexamethasone for the prevention of delayed emesis was not investigated in this study,
which only looked at one course of treatment in each patient.
In our study dexamethasone was given intravenously at a dose of 8mg on day 1 and 4mg
three times a day orally on days 2 to 4. Each patient acted as his or her own control and all
patients received at least one course each of ondansetron and granisetron. The total
number of courses was typical for patients receiving this type of chemotherapy.
The difference in outcome in our study compared with the Italian work is likely to reflect
differences in the steroid dose which masked the differing efficacy of the 5HT3 antagonists.

Conclusion

Granisetron is more effective than ondansetron when used in combination with 8/10
Granisetron is more effective than ondansetron when used in combination with
dexamethasone in the prevention of acute and delayed vomiting caused by highly
emetogenic chemotherapy. It is significantly better on day 2 when the majority of patients
suffer the most. With the trend towards day-case chemotherapy, it is more desirable to use
effective once daily control. Day 2 is usually the day when patients go home and the medical
staff may be unaware of the problems on this day unless there is close questioning of
patients on their return. Patients receiving highly emetogenic chemotherapy should receive
a combination of granisetron injection and intravenous and oral dexamethasone as defined
in the protocol to prevent unnecessary suffering. It would be useful to repeat this study in
the same design on a larger number of patients.
Ms Stewart is clinical economy pharmacist, Dr Crawford is consultant oncologist and Professor
Taylor is director of pharmacy and clinical professions at Airedale general hospital.
Correspondence to Ms Stewart at Pharmacy Department, Airedale General Hospital, Keighley,
West Yorkshire BD20 6TD.

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Citation: The Pharmaceutical Journal, July 2000, online | URI: 20002162

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