Table
2 summarizes the comparative studies among
different antiemetic regimens for
chemotherapy
side effects evaluating their
impact on HRQL.
Twelve out of 13 studies are randomized, and 9 of
them were double-blind.
The first randomized double-blind study comparing
different antiemetic prophylactic treatments for
chemotherapy side effect that
evaluated the impact on quality of life was carried
out on breast cancer patients submitted to the first
cycle of a cyclophosphamide-containing regimen [17].
Ondansetron (8 mg i.v. followed by 8 mg oral dosing
three times daily for 5 days) was compared to
metoclopramide (60 mg i.v. followed by 20 mg oral
dosing three times daily for 5 days) during 6 cycles
of chemotherapy. Both antiemetics were combined to a
16 mg single dose i.v. of dexamethasone before
chemotherapy. Nausea and vomiting were recorded
daily on a diary card while quality of life was
assessed before each chemotherapy treatment and at
the end of each 5-day chemotherapy treatment period using the
Rotterdam Symptom Checklist questionnaire [18].
This includes 38 items summarized in three subscales
(physical, psychological and functional activity).
Each item of the physical and psychological
subscales is rated on a four-point scale (0 = not at
all, 1 = a little, 2 = somewhat, 3 = very much) as
well as the items related to functional activity (0
= unable, 1 = only with help, 2 = without help, with
difficulty, 3 = without help). A separate analysis
was performed for the psychological, physical and
functional activity subscales. The "lack of sexual
interest" and ability to "go to work" questions were
excluded from the analyses since > 5% of patients
failed to complete them.
Due to much missing data, the mean and not the total
of each subscale was considered. The study showed
that at the first cycle of
chemotherapy ondansetron
plus dexamethasone was significantly superior to
metoclopramide plus dexamethasone (complete
protection from
vomiting over the 5-day
chemotherapy treatment
period in 81% and 48% of patients, respectively).
Furthermore, ondansetron induced a statistically
significant improvement in the psychological
subscale scores with respect to metoclopramide. No
differences were observed in the physical and
functional activity subscales. Interestingly,
patients' psychological distress was stronger before
chemotherapy than after. This was probably due to
the apprehension in receiving chemotherapy for the
first time. Instead, physical parameters worsened to
the same degree after chemotherapy reflecting
associated side effects. During the 6 cycles of
chemotherapy 67% of patients receiving ondansetron
and 28% of patients receiving metoclopramide had
less than 3 emetic episodes. Over the 6 chemotherapy cycles
quality of life results revealed a more pronounced
difference in favour of ondansetron in the
psychological subscale score as well as trends in
favour of ondansetron in the physical and functional
activity subscales. Unfortunately, quality of life
data were not available for all patients for all 6
cycles of chemotherapy; therefore, a possible selection bias favouring ondansetron cannot be excluded, especially
considering that the analysis of the 6 cycles refers
to 475 assessments of ondansetron-treated patients
and 380 assessments of metoclopramide-treated
patients.
Another randomized, double-blind study evaluating
the impact of CIE (Chemotherapy-induced emesis)
on HRQL
(Health-related Quality of life) compared oral ondansetron
(8 mg every 8–12 hours for 3–5 days starting 2 hours
before
chemotherapy) with alizapride (150 mg i.v.
followed by 50 mg orally administered every 8–12
hours for 3–5 days starting 2 hours before
moderately-highly emetogenic chemotherapy) [19].
Nausea and vomiting episodes were recorded on a
diary card, while quality of life was assessed using
the FLIC and the FLIE questionnaires filled out by
the patients before chemotherapy and 4 days after
the chemotherapy.
The total score for each questionnaire was obtained
by calculating the average score for each item.
Complete control of acute (57% versus 31%) and
delayed (62% versus 48%) emesis was significantly
superior in the ondansetron group than in alizapride
group. Both groups experienced deterioration in FLIC
and FLIE score from pretreatment to day 4. No
difference in quality of life scores was shown
between the ondansetron and alizapride groups when
quality of life was measured by the FLIC, but when
quality of life was measured by the FLIE,
ondansetron was found superior to alizapride in
preventing a decrease in quality of life following
chemotherapy (mean difference in the scores for each
question was 1.45 with ondansetron and 1.93 with
alizapride, P < 0.04).
The third double-blind randomized study compared
ondansetron (8 mg orally b.i.d. for 3 days) with
prochlorperazine (10 mg orally b.i.d. for 3 days) in
breast cancer and
lymphoma patients submitted to
moderately emetogenic
chemotherapy [20].
Patients completed the FLIC and FLIE questionnaires
before and at the end of the 3-day study period (day
4). Total scores were transformed to standardized
scores so that the highest possible score on either
scale equated to 100. Ondansetron was significantly
superior to prochlorperazine in the complete control
of emesis during the three days (60% versus 21%).
Quality of life was evaluated in only 57 of 133
patients (34 receiving ondansetron and 23
prochlorperzine). Baseline scores of the FLIE did
not differ between groups. Vomiting subscale scores
were significantly different between groups (from
97.1 pre to 89.2 post treatment with ondansetron and
from 96.7 pre to 70.4 post with prochlorperazine, P
< 0.01). No significant difference was seen for the
nausea subscale scores. There were no significant
differences between groups in FLIC scores at
baseline or at the end of the 3-day study period.
In two randomized double-blind studies quality of
life was evaluated with the EORTC QLQ-C30. In the
first [21], carried out in
patients submitted to moderately emetogenic
chemotherapy, the efficacy of dolasetron and
ondansetron on day 1 and on day 1–7 was compared as
well as the efficacy of the addition of
dexamethasone to both. In the first 24 hours
dolasetron was significantly less effective than
ondansetron but no difference was shown between the
two drugs over 7 days. The addition of dexamethasone
significantly improved the efficacy of both drugs
during the entire period.
There were no statistically significant differences
between ondansetron and dolasetron at baseline for
any of the HRQL domains assessed. Post-treatment,
there were no significant changes in global quality
of life or other domains, except for diarrhoea (more
common with dolasetron) and constipation (more
common with ondansetron). Dexamethasone-treated
patients fared significantly better with respect to
global quality of life, physical functioning and
social functioning and nausea, anorexia, diarrhoea,
fatigue and pain.
In the second study [22] the
efficacy of 5-HT3 antagonists,
ondansetron or dolasetron added to dexametasone
versus dexamethasone alone in the prevention of
delayed emesis induced by moderately emetogenic
chemotherapy was evaluated. Patients received in the
first 24 hours a combination of a 5-HT3
receptor antagonist plus dexamethasone. The
continuation of the 5-HT3 receptor
antagonist improved slightly but not significantly,
the complete control of delayed emesis (47% versus
41%). Minimal differences in quality of life were
observed. Social functioning deteriorated
significantly more in patients treated with
dexamethasone alone than in those receiving the
combination (-6.0 points versus -0.8 points in the
combination). On the other hand, patients taking
5-HT3 receptor antagonists reported a
significantly greater increase in constipation (+26
points versus +13 points). Unfortunately, there is
no method for weighting the sub-components of the
QLQ-C30 with respect to their overall importance
and, therefore, to balance symptomatic changes in
one direction against functional changes in another.
A randomised double-blind study was carried out in
advanced malignant melanoma patients submitted to dacarbazine administered in 1, 5 or 10 days,
evaluating HRQL by unidimensional linear scales [23].
Two different doses of tropisetron were compared: 5
and 10 mg iv. Patients evaluated their mood, food
intake and quality of life by recording scores in a
diary card every day from the day before
chemotherapy until the end of the
chemotherapy cycle. The scores
ranged from 0 (very bad) to 8 (very good). The two
dosages of tropisetron prevented vomiting in 93% and
98% of patients with 5 mg and 10 mg, respectively.
Their well being was maintained during the cycle of
chemotherapy; in fact, mood and quality of life of
the patients remained good as well as food intake.
In another study the efficacy of three antiemetic
regimens (ondansetron 8 mg i.v. followed by 8 mg
orally every 8 hours for 3 days vs ondansetron as
above plus metoclopramide 10 mg every 8 hours for 3
days vs ondansetron 8 mg i.v. single dose) in
breast
cancer patients submitted to CMF or FEC
chemotherapy
was evaluated [24].
Quality of life impact was assessed by FLIC
questionnaires completed by the patients during a
5-day period following chemotherapy. Chemotherapy
cycles, and not patients, were considered as a
statistical unit. Responses were evaluated in 182
cycles: in 116 cycles patients received CMF and in
66 FEC. The high-dose ondansetron regimen was
similar (CMF-treated patients) or superior (FEC-treated
patients) to the combination of ondansetron plus
metoclopramide and always superior to the single
dose of ondansetron. Quality of life was always
worse with ondansetron single dose i.v. while no
differences were shown between ondansetron for three
days versus ondansetron plus metoclopramide.
A double-blind multicentre study evaluated two
antiemetic regimens, in patients with vomiting or
moderate to severe nausea in the previous cycle of
cisplatin based
chemotherapy despite antiemetic
treatment with a combination of a 5-HT3
antagonist plus a corticosteroid: ondansetron plus
methylprednisolone versus ondansetron plus
methylprednisolone plus metopimazine [25].
The impact on the patient's quality of life was
assessed using the FLIC and the FLIE that were
joined together in a single questionnaire. This
questionnaire consisted of 28 items (all 22 of the
FLIC and 6 of the FLIE) and was filled out by the
patient prior to the start of chemotherapy and at
the end of the third day of antiemetic treatment.
Complete protection from vomiting throughout the
cycle of chemotherapy was achieved more frequently
by patients receiving the triple combination (53%
versus 38%, P < 0.008).
Modification in quality of life (FLIC questionnaire)
was similar between the two treatment groups. The
FLIE showed a decrease in quality of life that was
inferior albeit not significantly with the triple
combination.
In another double-blind study the role of
tropisetron in the prevention of cisplatin-induced
delayed emesis was evaluated. On the first day all
patients received 5 mg oral tropisetron and then
were randomly assigned to receive either tropisetron
or placebo on days 2 through 5 [26].
A newly developed quality of life questionnaire was
employed that consisted of seven scales: physical
scale, mental and related symptom scale, respiratory
condition related scale, social scale, an active
scale, a scale for the influence of nausea and
vomiting on patient's daily life, and a global scale
[27]. This questionnaire was
printed in diary form and filled out every morning.
The rate of complete protection from delayed emesis
in the tropisetron group and placebo group was
respectively 46.3% and 36.5%.
All scales, except social well being, changed
immediately in both groups and reached a nadir on
days 2–3, after that returning to the control levels
during the two weeks after cisplatin administration.
Tropisetron treated patients showed significantly
better physical wellbeing, mental wellbeing,
functional wellbeing and global quality of life
scores with respect to placebo-treated patients.
Finally two open, randomized, multicenter studies
have been published [28,29].
The first compared tropisetron (5 mg i.v. on day 1
followed by 5 mg oral every day on days 2–6) with a
metoclopramide-cocktail (metoclopramide 3 mg/kg i.v.
plus dexamethasone 20 mg i.v. plus lorazepam 1 mg
oral on day 1 followed by metoclopramide 10 mg
orally or 20 mg as suppositories three times a day
on days 2–6) in patients submitted to consecutive
cycles of cisplatin
chemotherapy [28].
Nausea and vomiting were recorded on a diary card
while quality of life was assessed by a
non-validated questionnaire consisting of 18
questions about various symptoms and 5 questions
about appetite and social life.
On day 1 of the first cycle complete control of
vomiting was not significantly different (63% with
tropisetron versus 64% with metoclopramide cocktail)
while complete control of nausea was significantly
superior with the cocktail (40% versus 61%). The
rate of complete control of vomiting and nausea
increased from day 1 to day 6 with both antiemetic
regimens, and this also happened at the second
chemotherapy cycle. Before both cisplatin
chemotherapy cycles, the two groups
did not differ in the responses to the 23 questions.
In posttreatment evaluations in both treatment
groups, the patients reported more nausea, vomiting,
being ill, being tired or sleepy, and having more
problems with eating than was reported in the
pretreatment evaluation. Patients receiving
tropisetron experienced significantly more
constipation and headache than did those treated
with the metoclopramide cocktail.
Another open, randomized, multicentre study compared
tropisetron (5 mg i.v. day 1 and 2 followed by 10 mg
orally until two days after the end of
chemotherapy)
with tropisetron (as above) plus dexamethasone (20
mg i.v. on day 1 and 2 followed by 4 mg i.v. or
orally until two days after the end of chemotherapy)
and with tropisetron (as above) plus metoclopramide
(20 mg i.v. plus 10 mg orally b.i.d on day 1
followed by 10 mg t.i.d. orally until two days after
the end of chemotherapy) in patients submitted to
highly and moderately emetogenic chemotherapy [29].
Quality of life in this study was documented using a
newly developed, validated but not yet published,
colour scale. Tropisetron plus dexamethasone was
significantly superior to tropisetron alone and
tropisetron plus metoclopramide for both acute and
delayed emesis. Quality of life was rated as "very
good", or "good" by more than half the patients
before starting therapy. The assessment after the
first chemotherapy cycle did not reveal any general
deterioration. No statistical difference was
detectable between the groups; altogether 41% of the
patients reported an improvement in their quality of
life after the first cycle, while 33% stated their
quality of life was unchanged and 33% deteriorated.
In these last two studies no data were reported in
the paper either on the number of patients evaluated
for quality of life or on the missing values.
Considering that the evaluation is carried out in
open studies the risk of selection bias and
confounding is high.
Another open study compared in cisplatin-treated
ovarian cancer patients the antiemetic efficacy of
ondansetron, granisetron, and metoclopramide.
Quality of life was assessed before
chemotherapy, on
day 1 and during 5 days (every evening) using the
Rotterdam Symptom Checklist. In the first cycle 85%
of patients receiving ondansetron, 83% of those
receiving granisetron and 60% of those receiving
metoclopramide achieved complete protection from
vomiting [30].
A statistically significant improvement in the
psychological subscale scores after ondansetron and
granisetron was observed with respect to
metoclopramide. No differences were reported in the
physical activity subscale.
In an open non-randomised study,
breast cancer
patients submitted to moderately emetogenic
chemotherapy received an antiemetic prophylaxis
based on ondansetron or metoclopramide. The
selection of the regimen was left to the attending
physician and represented current practice at the
institution [31]. Complete
control of acute emesis was 77% with ondansetron and
32% with metoclopramide in the first 24 hours and
83% and 55% on days 2–5, respectively.
With both antiemetic regimens the levels of quality
of life 1 day after chemotherapy, assessed with the EORTC QLQ-C30, were lower than prior to
chemotherapy
on all five functional scales, except the emotional
scale. On average, patients who received ondansetron
had a better score on day 1 than prior to
chemotherapy on this scale. The differences between
groups were not statistically significant on any of
the functional scales.
Global quality of life decreased more with
metoclopramide than with ondansetron, but the
difference was not statistically significant (-24
versus -17).
On day 3 all scores, except the emotional dimension,
were lower than prior
chemotherapy. Changes in
scores on global quality of life were similar for
both groups. For the role functioning scale, changes
in scores were significantly better for ondansetron.
Conclusions
In spite of the fact that the impact of
chemotherapy-induced nausea and vomiting on HRQL has
a short-term effect, its evaluation can be useful
for clinical decisions concerning the choice of
antiemetic prophylaxis. Only the results of
antiemetic randomized clinical trials can be used to
reach this aim. Moreover, because of the
subjectivity of the patient's answers, only a
double-blind study can assure reliable results.
Finally, only the correct choice of the antiemetic
treatments to be compared can lead to useful results
[32]. In fact, if the new
antiemetic prophylaxis were compared to a treatment
different from the best, no information about the
differences between the mean scores of the two arms
(new treatment and standard therapy) would be
available. More precisely, the above mentioned
difference could be due only to an inferior efficacy
of the used comparator with respect to the standard
antiemetic therapy. For similar reasons any
comparison involving sub optimal antiemetic regimens
could be regarded as useless for a specific clinical
decision.
Only 9 out of 13 comparative studies identified in
our research were randomized and double-blind; three
of them were concerned with non-standard antiemetic
therapies, and two were dose finding studies.
Therefore, only the results of 4 studies can be
regarded as useful for orienting the choice of an
antiemetic prophylaxis.
Summarizing the results obtained by the comparative
studies carried out until now, the efficacy,
tolerability and impact on HRQL of antiemetic
regimens containing 5-HT3 receptor
antagonists were found superior to those that
referred to the earlier used antiemetic drugs (metoclopramide,
alizapride and prochlorperazine). Furthermore, in
one study the combination of ondansetron plus
dexamethasone, still the standard treatment for the
prevention of acute emesis induced by moderately
emetogenic chemotherapy, was evaluated against metoclopramide plus dexamethasone. Its results show
that the first antiemetic prophylaxis, allowing a
better control of nausea and vomiting during the
first 24 hours, also lead to an improvement in the
patients HRQL.
Among the 13 comparative studies, a great
heterogeneity of instruments aimed at evaluating
HRQL was detected: in 4 studies FLIC and/or FLIE, in
3 the EORTC QLQ-C30, in 2 the Rotterdam Symptom
Checklist, in 2 a uniscale, in 2 an ad hoc designed
instrument was used. The reasons of the choice of
the instrument to use to assess the influence of
emesis on HRQL are clearly described by Uyl-deGroot
et al. [32].
In conclusion, even if the number of the published
studies specifically aimed to evaluate the impact of
the chemotherapy-induced emesis on HRQL can be
considered sufficiently high, those showing results
that are reliable and useful to orient the clinical
decision are few.
