A Randomized Cross-over Trial of Granisetron and Dexamethasone ...

A Randomized Cross-over Trial of Granisetron and Dexamethasone versus
Granisetron Alone: The Role of Dexamethasone on Day 1 in the Control of
Cisplatin-induced Delayed Emesis
Ikuo Sekine, Yutaka Nishiwaki, Ryutaro Kakinuma, Kaoru Kubota, Fumihiko Hojo, Taketoshi
Matsumoto, Hironobu Ohmatsu, Michiya Yokozaki and Tetsuro Kodama
Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba
We studied the role of dexamethasone (DEX) administered on day 1 in controlling cisplatininduced
delayed emesis. Forty patients were randomly allocated to receive either granisetron
(GRN) and DEX on day 1, or the same dose of CRN alone. On days 2-5, all the patients
received metoclopramide and DEX. They were corssed over to the other antiemetic regimen with
their second course of chemotherapy. Thirty-one patients were evaluable for efficacy. The mean
visual analogue scale scores for nausea on days 1 and 2 were 9.1 and 18.8 mm for GRN and
DEX, and 16.3 and 28.5 mm for GRN alone, respectively (P< 0.05 on day 2). The mean numbers
of emetic episodes on days 1-3 were 0.036, 0.46 and 0.36 for GRN and DEX, and 0.39,
0.89 and 0.57 for GRN alone, respectively (P2> Such delayed emesis is one of the major
problems associated with cisplatin-based chemotherapy
because it is observed in 20-93% of patients
receiving high-dose cisplatin and may cause dehydration,
malnutrition, and poor compliance with
further chemotherapy. 1 " 31 Although metoclopramide
(MET) and dexamethasone (DEX) for 4 to 7 days
after high-dose MET and DEX on day 1 have been
reported to be effective against delayed emesis to
some degree, total control is hardly ever
achieved.^ The severity of emesis on day 1 is
anoter important factor influencing delayed erne-
Received: September 7, 1995
Accepted: December 15, 1995
For reprints and all correspondence: Ikuo Sekine, Division
of Thoracic Oncology, National Cancer Center Hospital
East, 5-1, Kashiwanoha 6-chome, Kashiwa, Chiba 227
sis. 1 ' 2) However, few studies have been conducted
from this standpoint. 7 '
We investigated the role of DEX administered on
day 1 in controlling cisplatin-induced delayed emesis
in a randomized trial of granisetron (GRN) and
DEX versus GRN alone on day 1 followed by
MET and DEX on days 2-5.
Patients and Methods
Patients with histologically or cytologicaUy proven
lung cancer who had had no prior chemotherapy
were entered into the study if they were scheduled
to receive at least two cycles of chemotherapy containing
cisplatin at a dose of 80 mg/m 2 . Eligible
patients were aged 80 or less, and had an Eastern
Cooperative Oncology Group (ECOG) performance
status of 0-2, no history of nausea or vomiting before
treatment, and adequate renal and hepatic
function as indicated by a serum creatinine level of

This study was a single-blind, randomized, twoperiod
two-treatment cross-over trial. Patients with
non-small cell lung cancer received cisplatin
[80 mg/m 2 intravenously (i.v.)] on day 1, and
vindesine (3 mg/m 2 i.v.) on days 1 and 8, with or
without mitomycin C (8 mg/m 2 i.v.) on day 1.
Those with small cell lung cancer received cisplatin
(80 mg/m 2 i.v.) on day 1, and etoposide
(100 mg/m 2 i.v.) on days 1-3. Cisplatin was administered
by 1-h drip infusion with 2.5 to 3 liters
of hydration.
Patients were randomly assigned to receive either
GRN + DEX: GRN (40/tg/kg) diluted in 100 ml of
normal saline given i.v. 30 min before 4 h after
cisplatin infusion, and DEX (16 mg i.v.) 30 min before
cisplatin infusion, or GRN alone at the same
doses as those described above. The two fixed
doses of granisetron were administered to all patients
to avoid any influence of differing drug
doses. All patients were given MET (40 mg) diluted
in 100 ml of normal saline i.v. over 30 min
twice daily on days 2-5, and DEX (8 mg i.v. on
days 2 and 3, and 4 mg on days 4 and 5). They
were crossed over to the other antiemetic regimen
on their second course of chemotherapy.
All patients were requested to record the severity
of nausea using a graded scale (none, mild,
moderate, or severe) and a visual-analogue scale
(VAS; 0 = no nausea, 100 = intolerable nausea), the
number of episodes of vomiting, and side effects
on a diary card on days 1-5. Complete response
(CR) was defined as absence of vomiting episodes
and none on the graded scale of nausea.
Patients were considered evaluable for efficacy if
they received both courses of antiemetic therapies.
Mean values of VAS for nausea and the number of
emetic episodes for each of the two regimens were
calculated. The sample size was determined on the
assumption that the CR rate on day 2 for GRN
alone and that for GRN + DEX were 20 and 40%,
respectively. With a power (1-6) of 80%, the estimated
required sample size was 40 patients. 8 ' The
cross-over difference (the difference between the
two regimens) and its statistical signficance was examined
by the Hills-Armitage method, which is
based on Student's t test. The statistical significance
of patient preference was examined by McNemar's
test. 9 '
Results
Between May 1993 and April 1994, 40 patients
were entered into the study. Nine patients were not
evaluable for efficacy. One of them could not be
given DEX because of aggravation of diabetes mellitus.
The other 8 patients received only one course
of chemotherapy: seven because of disease progres-
DEXAMETHASONE FOR DELAYED EMESIS
Table I. Characteristics of Evaluable Patients
Characteristics
GRN + DEX
then
GRN alone
Number of patients 16
Median age (range) 56.5 (39-71)
Male/Female
10/6
Chemotherapy regimens
cisplatin + vindesine
cisplatin + vindesine +
8
mitomycin C
7
cisplatin + etoposide 1
GRN alone
then
GRN + DEX
15
65.0 (22-77)
10/5
sion, and one because of impaired renal function.
The characteristics of 31 evaluable patients who
completed both courses of antiemetic therapy are
summarized in Table I. There was significant difference
between the two antiemetic treatment groups.
Of the 31 patients, 26 were fully evaluable. Two
patients were evaluable only for the number of
emetic episodes from their medical records because
their diary cards were lost. The other 3 patients
were included only in the assessment of the CR
rate, because they were unable to fill out their
diary cards due to severe vomiting.
Nausea was assessed in 26 patients. As shown in
Fig. 1, the VAS scores on days 1 and 2 for
GRN + DEX were lower than those for "GRN alone,
though statistical significance was obtained only on
day 2 (P

30
25
•a 20
3
GRN+DEX
GRN alone
SEKINE ET AL.
Dayl Day 2 Day 3 Day 4 Day 5 Dayl Day 2 Day 3 Day 4, Day 5
Fig. 1. Severity of nausea on days 1-5 assessed by the
visual-analogue scale, VAS (n 26). The VAS scores on days
1 and 2 for GRN + DEX were lower than those for GRN
alone, respectively (/>

therapy/ 1 ** There is controversy about the efficacy
of DEX combined with a 5-HT3 receptor antagonist
for delayed emesis. A randomized trial
comparing tropisetron monotherapy on days 1-6
with a combination of tropisetron and DEX on
days 1-6 showed that significantly more patients in
the latter arm were free of delayed nausea or
vomiting, 10 ' whereas a comparison of a combination
of GRN and DEX for 6 days with one of
MET and DEX for 6 days showed that patients
treated with the latter combination had a tendency
to suffer more episodes of vomiting. 11 ' Another
important factor in controlling delayed emesis is the
degree of acute emesis, though the mechanism is
not fully understood. 1 ' 2) Thus, delayed emesis is
not an isolated pehnomenon and should be studied
in conjunction with antiemetic therapy in the acute
and delayed phases.
This study showed that DEX administered on
day 1 enhanced the control of nausea and vomiting
on day 2 as well as that on day 1. This result
is consistent with that of a randomized trial of
OND and DEX versus high-dose MET, DEX, and
diphenhydramine on day 1 with MET and DEX on
days 2-5, which also showed better control on day
2 in the OND and DEX arm. 7) In addition, the
present results suggest that early use of DEX may
contribute to prevention of delayed emesis.
The mean number of vomiting episodes on day
2 did not differ significantly between the treatments.
The power was calculated at 30% from the
true difference in the treatments, 0.428, and the
standard error, 0.27, suggesting that the number of
patients was too small for a difference to be
demonstrated. 8 ' However, we discontinued the trial
because a significant difference was observed in the
mean number of vomiting episodes on day 1 and
in the VAS score on day 2.
In this trial, one fourth of the patients refused to
receive MET because of severe hiccups and/or restlessness.
Repeated administration of MET seemed
to increase the incidence and severity of these symptoms.
Other effects were mild and self-limiting.
Although a cross-over design has been commonly
applied in trials of antiemetic drugs, 12 ' its limitation
are also well recognized. 9 ' First, drop-outs
tend to occur frquently, especially in trials of
chemotherapy for non-small cell lung cancer because
of the low response rate. In this trial, 9
(23%) of 40 patients were excluded from the evaluation
of efficacy. The second problem is the unstable
condition of patients with cancer. We excluded
patients who had poor performance status, short
life expectancy, or any condition which may have
caused nausea and vomiting, consciousness disturbance,
or alteration of mental status. Third, we
should consider carry-over effect in trials of anti-
DEXAMETHASONE FOR DELAYED EMESIS
emetic agents because the psychological status induced
by the first treatment may influence outcome.
Testing for a carry-over effect using patient
totals showed no evidence of such an effect in the
number of vomiting episodes on day 1 or in the
VAS score on day 2." However, a cross-over design
should be considerably advantageous in trials
of delayed emesis, because fewer patients are required
to obtain the same degree of precision as a
result of elimination of inter-patient variation. 8 '
Otherwise, many patients would be required before
phase III studies could establish a standard
treatment.
In conclusion, addition of DEX to GRN on day
1 was of great benefit for the control of nausea on
day 2. Although the regimen of GRN + DEX on
day 1 with MET + DEX on days 2-5 was well
tolerated and highly effective on day 1, antiemetic
efficacy in the delayed phase was hot satisfactory.
Further trials of delayed emesis is conjunction with
acutue and delayed antiemetic regimens are warranted.
Acknowledgments
This study was supportd in part by Grants-in-Aid for
Cancer Research (5S-1) from the Ministry of Health and
Welfare, Japan.
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