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Introduction
Cancer is increasing at an alarming
rate globally. Chemotherapy is the primary treatment for
cancer and in some cases the only resort.
Most of the chemotherapeutic drugs have
been found to cause release of large amounts of
serotonin from enterochromaffin cells in the gut 1,
serotonin acts on 5-HT3 receptors in the gut
and brain stem and stimulate vagal affarents to initiate
the vomiting reflex.
Chemotherapy induced nausea and vomiting (CINV) remains
a significant problem for cancer patients, having a long
lasting effect on their quality of life.
There is
evidence that emesis control during chemotherapy acts on
the quality and cost of treatment by allowing a better
compliance to scheduled drug dose. It improves the
quality of life of patients by reducing the intensity
and number of side effects and thereby reducing the
length of hospitalization and treatment related
expenditure 2.
5-HT3
receptor antagonists or
serotonin antagonists suppress
nausea and vomiting by inhibiting serotonin binding to
the 5-HT3 receptors.
Serotonin antagonists are found to be very effective in
controlling CINV and are used along with dexamethasone
as a potent antiemetic regimen in chemotherapy 3-6.
Nowadays the stores in India are flooded with many
options of serotonin antagonists coming at different
prices. So comparison of their relative efficacies and
safeties in Indian patients against their prices is
needed before prescribing them indiscriminately. Hence
we have performed a double blind, randomized controlled
trial to compare the relative efficacies of ondansetron,
granisetron and palonosetron for both acute and delayed
onset emesis, in moderately and highly emetogenic
chemotherapy against their respective prices in Indian
market.
Patients and methods
Eligible patients for this double
blind, randomized controlled trial were men and women
aged 15
years or above with confirmed malignant disease and
admitted to any department of Bankura Sammilani Medical
College and Hospital, India from November 05, 2007 to
September 30, 2009 for the purpose of receiving either
one day of moderately or highly emetogenic chemotherapy
or moderately or highly emetogenic chemotherapy for Day
1 and lower emetogenic drugs on the subsequent days.
Emetogenic levels of common chemotherapy and biotherapy
agents are given in Figure 1 7-9.
Exclusion criteria included: severe, uncontrolled,
concurrent illness other than neoplasia; asymptomatic
metastases to the brain; seizure disorder needing
anticonvulsants unless clinically stable; intestinal
obstruction; concurrent intake of any other emetogenic
drug or radiotherapy or a known hypersensitivity to
5-HT3-receptor
antagonists or dexamethasone.
1213
patients were found to be eligible for the study, among
them 487 were on highly emetogenic and 726 were on
moderately emetogenic chemotherapy. The study was
approved by the ethical board of institute and all
patients provided written informed consent before
enrolment. Patients were randomly assigned to receive
ondansetron or granisetron or palonosetron. All study
personnel and patients were blinded to the treatment
assignment for the duration of the study and the nursing
staffs injecting the drugs were prohibited from
divulging any information on drug assignment even to the
doctors giving the chemotherapeutic drugs.
Ondansetron 8 mg or granisetron 3 mg were given on Day 1
and Day 2 or palonosetron 0.75 mg was given on Day 1,
intravenously, 30 min before chemotherapy, along with 16
mg of intravenous dexamethasone on Day 1 and 4 mg on Day
2 and Day 3. Patients were followed for 5 days for the
efficacy endpoints and 8 days for the safety endpoints.
The
primary efficacy endpoints of this study were the
proportion of patients with a complete response during
the acute phase (0–24 hours post chemotherapy).
Secondary efficacy endpoints included complete response
during successive 24 h time periods (i.e., 24–48 h,
48–72 h, 72–96 h, and 96–120 h) and for the overall
chronic phase (24-120 hours post chemotherapy).
Complete response was defined as no emetic episodes, no
rescue medication use, and no more than mild nausea.
People having 0–1 vomits and/or moderate nausea for a
maximum of 4 hours were termed as partial response.
Failure delineated ≥ 2 vomits, or severe nausea or
nausea lasting more than 4 hours.
Statistical Analysis
All data were analyzed using SAS
software, version 9.1. Chi-square test or Fisher’s exact
test was used to compare the proportions. A both sided p
value of ≤ 0.05 was considered statistically
significant.
Results
In the group receiving highly
emetogenic chemotherapy, 287 (58.9%) were females and
200 (41.1%) were males and in the group receiving
moderately emetogenic chemotherapy, 370 (50.9%) were
females and 356 (49.1%) were males. Overall, previous
history of chemotherapy was present in 916 patients
(75.5%), while 297 (24.5%) were chemotherapy-naive.
Highly emetogenic regimens chiefly had cisplatin
(96.3%), and as a part of antiemetic therapy 237
patients were prescribed ondansetron, 186 granisetron
and 64 palonosetron. While the moderately emetogenic
regimens consisted of lower dose (<1500 mg/m˛)
cyclophosphamide (85.8%) and doxorubicin (12.8%) and for
combating the emesis 379 patients were put on
ondansetron, 254 on granisetron and 93 on palonosetron.
Baseline and demographic characteristics of the
patients are given in Table 1.
The
doses of the serotonin antagonists were administered as
per previous research data regarding their optimal dose
related efficacy. Ondansetron 8 mg is found to be
equally efficacious to ondansetron 32 mg for both highly
and moderately emetogenic chemotherapy 10-11.
Although United States Food and Drug Administration
deemed that the 10 µg/kg dose for granisetron was fully
effective, results suggest that there is some benefit to
the higher 40 µg/kg (3mg) dose in certain patient groups
12, hence the higher dose was used. A clear
dose–response relation was noted over a 120 h study
period when 0.075 mg, 0.25 mg, and 0.75 mg doses of
palonosetron were given with dexamethasone to prevent
CINV associated with highly emetogenic chemotherapy,
indicating a significant difference in response with the
0.075 mg dose compared with the two higher doses 13.
Also another study with moderately emetogenic regimen
revealed dose-dependent increases in complete response
with more than a 10% difference in the highest complete
response recorded in the 0.75 mg dose group compared
with the 0.25 mg, in both delayed and overall phases
14. Three doses of palonosetron were
well-tolerated and did not show any increase in adverse
effects related to dose. The better efficacy with the
0.75 mg dose than with the lower doses and the similar
safety profile suggested that palonosetron 0.75 mg be
the recommended dose for use in this trial.
Overall, irrespective of the emetogenicity of the
regimens, palonosetron is found to be the best acting
drug followed by granisetron, although the difference in
the efficacies of the drugs was not huge. 472 patients
(76.6%) in ondansetron group, 340 (77.27%) in
granisetron group and 138 (87.8%) in palonosetron group
showed complete response in the acute phase (0-24 hours)
(p value = 0.021); compared to 350 patients (56.8%) in
ondansetron group, 279 (63.4%) in granisetron group and
106 (67.5%) in palonosetron group in chronic phase
(24-120 hours) (p value= 0.013). Complete responses
obtained for each drug on daily basis is illustrated in
Figure 2. All the responses obtained for each drug from
Day 1 to 5 have been given in Table 2.
For
highly emetogenic regimens it was postulated that
palonosetron is superior to ondansetron, which was found
to be false, as p values were > 0.05. 52 patients
(81.2%) had complete response during the acute phase
(0-24 hours) in palonosetron group compared with 181
patients (76.4%) in the ondansetron group and 130
patients (69.9%) in granisetron group (p value = 0.246).
During the overall chronic phase (24-120 hours), 41
patients (64%) had complete response in the palonosetron
group compared with 133 patients (56.1%) in the
ondansetron group and 114 patients (61.2%) in
granisetron group (p value = 0.461).
Complete responses obtained for each drug on a 24 hourly
basis is illustrated in Figure 3. Responses of each drug
in the highly emetogenic regimen, from Day 1 to 5 have
been given in Table 3.
For
moderately emetogenic regimens it was postulated that
palonosetron is superior to granisetron which was
superior to ondansetron, which was found to be true, as
p values were ≤ 0.05. 86 patients (92.5%) had complete
response during the acute phase (0-24 hours) in
palonosetron group compared with 291 patients (76.8%) in
the ondansetron group and 210 patients (82.6%) in
granisetron group (p value = 0.01). During the delayed
phase (24-120 hours), 63 patients (67.7%) had complete
response in the palonosetron group compared with 216
patients (57%) in the ondansetron group and 162 patients
(63.8%) in granisetron group (p value = 0.05).
Complete responses obtained for each drug on a 24 hourly
basis is illustrated in Figure 4. Responses of each drug
in the moderately emetogenic regimen, from Day 1 to 5
have been given in Table 4.
There
were no clinically relevant differences between groups
with regard to overall incidence of side effects (p
value = 0.99998). As was expected, headache and
constipation were the most common side effects (6)
occurring in 11 (1.8%) and 26 (4.2%) patients
respectively among ondansetron users; while it was 8
(1.8%) and 19 (4.3%) for granisetron users and 3 (1.9%)
and 8 (5.1%) for palonosetron users. Hypokalemia
occurred in 9 (1.5%) ondansetron users, 7 (1.6%)
granisetron users and 2 (1.3%) palonosetron users.
Elevation of liver enzymes alanine transaminase (ALT)
and aspartate transaminase (AST) was also noted,
although none of the patients reported increase in serum
bilirubin. Table 5 has details of the treatment related
side effects.
Discussion
Nausea and vomiting are still the major
distressing health issues in patients undergoing
chemotherapy. Although 5-HT3-receptor antagonists along
with a corticosteroid are proved to be the key treatment
regimen against CINV (3-6), the standard serotonin
antagonist to be used in various chemotherapy regimens
is yet to be known.
There are some differences in metabolism and receptor
specificities among the different serotonin antagonists
15. Palonosetron is a highly potent,
selective, second-generation 5-HT3
receptor antagonist with a receptor binding affinity
higher than other 5-HT3 receptor antagonists (pKi 10.5
compared with 8.91 for granisetron, 8.39 for ondansetron)
16-17. Palonosetron shows a 40 h half life
18-19 which is significantly longer than
others in its class [ondansetron, 4 h 20;
tropisetron, 7.3 h 21; dolasetron, 7.5 h
22; granisetron, 8.9 h 23]. It shows
both competitive binding and allosteric interactions
with the 5-HT3-receptor
and requires only a single dosing contrary to
ondansetron and granisetron, which show strictly
competitive antagonism. As the allosteric interactions
can induce changes in the receptor conformation; it is
speculated that palonosetron’s dual action induces
amplification of its inhibitory effect at the primary
receptor binding site 24.
In our
study when considered irrespective of the emetogenicity
of the regimens, palonosetron is found to be the best
acting drug followed by granisetron more so from Day 2
onwards, i.e. the period after the initial 24 hours. But
in highly emetogenic regimens no momentous difference
was found between the efficacies of the drugs, contrary
to previous studies 25, 26. In moderately
emetogenic regimens the superiority of palonosetron was
clearly established in the acute phase (0-24 h) 27,
although apparent, much difference was not found in the
subsequent hours (24-120 h).
All the
patients were observed till Day 8 for the occurrence of
any side effects. Side effect profiles of the drugs were
found to be similar 26 (p value = 0.99998),
with no life threatening adverse effects occurring (see
Figure 5). 39 (6.3%) patients in ondansetron group, 28
(6.4%) in granisetron group and 17 (10.8%) in
palonosetron group were found to be having at least one
antiemetic drug related side effect (p value= 0.118).
The incidence of prolongation of the
heart-rate-corrected QT interval (QTc) was found in 5
(0.8%) patients on ondansetron, although caused no
further complications. 3 patients on ondansetron and 2
patients on granisetron died within Day 5-8 of
chemotherapy initiation, although the cause of the
deaths were found to be due to the malignant processes
itself and unrelated to the antiemetic treatment.
There are several brand names for a given 5-HT3 receptor
antagonists in India. The cost of drug expenditure was
based on the mean price of all parenteral combinations
available in Indian market as in December 2009. In our
study, ondansetron and granisetron were given on Day 1
and 2, whereas palonosetron was given only on Day 1.
Calculations of expenses for each drug/cycle are given
in Table 6. Palonosetron was found to be the most
expensive drug, followed by granisetron, also supply of
palonosetron in the medicine shops is inadequate in lieu
of its cost. The cost of dexamethasone was not included
in analysis, since it is the same for the 3 arms of
treatment. Information available was not sufficient for
a detailed cost analysis and hence there should be
further research regarding the detailed cost analysis of
the drugs.
Conclusion
Our
study is the first one to compare the efficiency and
cost of 5-HT3
receptor antagonists in Indian patients. It suggests
that ondansetron, granisetron and palonosetron have
similar efficacy and side-effect profiles in prophylaxis
of CINV secondary to moderately or highly emetogenic
chemotherapy. Preference among them must be based on
other parameters such as cost, ease of administration,
patient preferences, co morbid illnesses and drug
interactions.
Acknowledgment: Dr. Partha
Bhowmik, Statistician, AIIH & PH, Kolkata, India.
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