ROLE OF APREPITANT IN

CHEMOTHERAPY INDUCED NAUSEA

AND VOMITING
ABSTRACT
Background:Nausea and vomiting is the most common adverse effect of
most of the chemotherapeutic agents. Large range of antiemetics have been
used since ages. Aprepitant is an NK-1 receptor antagonist which blocks
theemetic effects of substance P. The present study is to determine the
effectiveness of aprepitant in preventing nausea and vomiting in patients
receiving chemotherapy when combined with standard regimen.
Methods: In this is an institutional based single arm randomized study
patientsreceivedaprepitant 125 mg per oral, dexamethasone 8mg
intravenous , palonosetron 0.25 mg intravenous 30 min before
chemotherapy on scheduled D1 followed by aprepitant 80 mg on Day2 and
Day3.The primary end point was the proportion of patients with no emetic
episodes and no rescue medication [complete response (CR)] during the 24 h
after chemotherapy administration (acute period).
Results:Out of 83 patientstotal males49 and females34 and with
performance status 0 are 47.56 (68%) achieved complete response in overall
period. This includes 62 patients (74%) in acute period and 49 patients
(59%) in delayed period. The response rates were significantly higher with
addition of aprepitant.
Conclusion:Aprepitant along with palonosetron and dexamethasone
effectively and significantly prevents chemotherapy induced nausea and
vomiting
Keywords: Aprepitant, nausea and vomiting, palonosetron.

INTRODUCTION
Chemotherapy induced nausea and vomiting (CINV) is the most common and
predictable adverse effect of the cytotoxic drugs.Antiemetic agents are the
most common intervention in the management of treatment-related nausea
and vomiting (N&V). The basis for antiemetic therapy is the neurochemical
control of vomiting. Although the exact mechanism is not well understood,
peripheral neuroreceptors and the chemoreceptor trigger zone (CTZ) are
known to contain receptors for serotonin, histamine (H1 and H2), dopamine,
acetylcholine, opioids, and numerous other endogenous neurotransmitters 1,2.
Many antiemetics act by competitively blocking receptors for these
substances, thereby inhibiting stimulation of peripheral nerves at the CTZ
and possibly at the vomiting centre.
The most significant predicting
factor of CINV is cytotoxic drug itself. They exhibit different emetic potential
and cause emesis by different mechanisms3.
The most common mechanism of nausea and vomiting is acute emesis which
starts within few hours of beginning of chemotherapy lasting up to 24 hours.
Delayed emesis commences from day one lasting at least for five days 4.
Patients with poor control of post chemotherapy emesis have significant
morbidity and dramatic impact on quality of life 5. Increased risk of CINV is
associated with factors like age less than 50, female gender, vomiting during
previouschemotherapy, anxiety. CINV causes electrolyte imbalance,
weakness, weight loss, anorexia, dehydration and decline in behavioral and
mental status. The introduction of serotonin antagonists and their
widespread adoption in the early to mid 1990s led to significant
improvement in the ability to control cinv and its potential negative impact
on patients quality of life (QOL).Palonosetron is a 5-HT3 receptor antagonist
(second generation) that has antiemetic activity at both central and GI sites.
In comparison to the older 5-HT3 receptor antagonists, it has a higher
binding affinity to the 5-HT3 receptors, a higher potency, a significantly
longer half-life (approximately 40 hours, four to five times longer than that of
dolasetron, granisetron, or ondansetron), and an excellent safety profile8.
Aprepitant is an NK-1 receptor antagonist which blocks theemetic effects of
substance P. When combined with standard regimen of dexamethasone and
5HT3 antagonist, aprepitant is effective in preventing CINV in patients
receiving highly emetogenic chemotherapy9.

Materials and methods: This was an Institutional based randomized study.

This study included 100 patients who were scheduled to receive
emetogenicchemotherapyatRegional cancer centre, Indira Gandhi Institute of
Medical Sciences, Patna during the year 2014.

Inclusion criteria:
1. Age> 18 years and <69 years.
2. Histologically confirmed malignant diseases.
3. Eastern Cooperative Oncology Group performance status of 0 to 2.
4. Patients who were naive to chemotherapy
5. Adequate renal hematological hepatic parameters.
6. Females with negative urine beta HCG test.
7. Patients who were not on any other drugs inducing emesis.
Exclusion criteria:
1. Age< 18 and > 70 years.
2. Evidence of CNS disease or psychiatric illness causing vomiting
3. Altered renal, hematological, hepatic parameters.
4. Patient with primary or secondary CNS malignancies
5. Patients with other cause of vomiting (like bowel obstruction) not related
to chemotherapy
6. Patients with nausea and vomiting before the chemotherapy
7. Patients with contraindication to use corticosteroids (any active infection)
8. Patients with prior chemotherapy.
Treatment:
Patients who were enrolled in this study received aprepitant 125 mg per oral,
dexamethasone 8mg intravenous ,palonosetron 0.25 mg intravenous 30 min

before chemotherapy on scheduled D1 followed by aprepitant 80 mg on

Day2 and Day3. Study dairy have been maintained to enroll the patients
before the start of study and followed up to 5 days post chemotherapy. The
frequency of nausea ,vomiting and rescue medication are all recorded daily .
Patients were reviewed twice daily during the 5day study period to record
the events.

Endpoint:
Complete response (no emesis and no rescue therapy) during the five days
of study period in patients receiving first cycle chemotherapy.
Response and analysis:Common Terminology Criteria for Adverse Events
(CTCAE) Version4.0 was used to analyse the response to study drugs.
Results:
Demographics:
A total 100 patients were screened according to protocol for enrollment in to
the study. Out of them 17 were concluded ineligible based on preformed
criteria. The rest 83 patients were enrolled into study and given protocol
antiemetic therapy. Among them 49 were males and 34 were females with
median age group of 49years. Out of 83 patients 56 (68%) achieved
complete response in overall period. This includes 62 patients (74%) in acute
period and 49 patients (59%) in delayed period.
Additional endpoints were also evaluated. No emesis was seen in
65(78%) for overall period, including 69(84%) in acute period and 51(62%) in
delayed period.
Table no 1.
Gender
Male
Female
Performance status
0
1
2
Tumor type
Breast

49
34
47
25
11
15

Cervix
Lung
Head & neck
Ovary
Chemotherapy drug/regimen
Cisplatin
Cyclophosphamide
Epirubicin
5-flourouracil
Docetaxel
Previous chemotherapy
Yes
No
Figure no:1

20
18
21
9
23
15
15
19
13

9
83

90
80
70
60
50

complete response

40

no rescue

30
20
10
0
overall

acute

delayed

Emesis free and no rescue patients (n=83)

Figure no:2

100%
90%
80%
70%
nausea free

60%

severe

50%

moderate

40%

mild

30%
20%
10%
0%
1

Nausea severity (n=83)

Discussion:
Emesis after chemotherapy is one of the most challenging task in
supportive oncology to be taken care of. Anticipation is the key point in
mitigating the maximum post chemotherapy nausea and emesis effects.
Selection of the drugs to prevent CINV has been a challenge since ages
because there are many pre-requisites to be met. Even though there are
wide range of drugs significant incidence has been noted in patients. In this
study, among the 5HT3 antagonists palonosetron has been chosen over
ondansetrondue to its efficacy in protecting patients from emesis and
decreasing interference with functioning10. The chemotherapy induced
nausea and emesis is the most underestimated event by many health
professionals especially delayed vomiting12,13.The incidence of this problem
continues exist even with the most effective drug hence combination therapy
has been studied along with aprepitant and dexamethasone 11. Incidence of
this problem is more in delayed phase than early phase where there is a
need of new strategy always. The complete response ratesforantiemetics are
always behind that of early phase which has to be improved 14. The
metabolism of the 5HT3 antagonists is not interefered by NK1 antagonists
significantly15,16.
Adherenceof physician and compliance of patients are two key issues in
supportive oncology. The treating physicians are with curative intent follow

the therapeutic guidelines than the supportive guidelines which aborts the
toxicities of chemotherapeutic drugs17. Compliance of patients depends on
many factors like socioeconomic status, patient physician relationship 18.
Usually ondansetron is given in three doses 2hours apart but because of
its safety profile even single dose prevent emesis during acute period 19. With
the development of higher efficacy drug like palonosetron whose half-life is
40 hrs gave a drug effect of multiple days even with single dose 20,21. The
emesis during delayed period is covered by a drug like palonosetron which
has extended life or giving drug just before the anticipated time of emesis.
There are many studies showing that 5 day course of treatment is no more
effective than the short course therapy. In this present study aprepitant was
selected due to its higher efficacy and safety profile even with single dose.
Triplet therapy with palonosetron/aprepitant/dexamethasone has been
studied by many groups. Grote 22 studied combination of 3 day aprepitant,
4day dexamethasone and single dose palonosetron which showed 88%
during the acute (024 hours) interval,78% during the delayed (> 24120
hours) interval, and 78% duringthe overall (0120 hours post chemotherapy)
interval.Herrington23 compared 1 and 3 day course of aprepitant , 4 day
dexamethasone and palonosetron single dose shows better results with
aprepitant.Steven M et al studied the three drug regimen which showed the
similar results like that of the present study24. The response rates in this
present study reveals that combination therapy using aprepitant gives higher
prevention rates of emesis in patients taking chemotherapy. A randomized,
open-label, crossover, pharmacokinetic/safety study of a single IV dose of
palonosetron (0.25 mg) with or without aprepitant in healthy subjects
demonstrated that palonosetron can be safely coadministered with
aprepitant, with no dosage adjustment necessary25. In this study aprepitant
has no significant interaction of pharmacokinetics with serotonin inhibitors.
Conclusion:
1. The triplet therapy is safe and highly effective in preventing
chemotherapy induced nausea and vomiting.
2. The only disadvantage is the cost of regimen.

Percentage of tumor types among the patients

11%

Breast
18%

Cervix
Lung

25%
24%

Head & neck

Ovary

22%

Use of different chemotherapy drug among the patients

Regimen Cisplatin
15%

27%

Cyclophosphamid
e
Epirubicin

22%

5-flourouracil
18%

Docetaxel

18%

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Appendix I

APPENDIX:

ECOG PERFORMANCE STATUS

Grad
e

ECOG

Fully active, able to carry on all pre-disease performance without

restriction

Restricted in physically strenuous activity but ambulatory and able to

carry out work of a light or sedentary nature, e.g., light house work,

office work
2

Ambulatory and capable of all self care but unable to carry out any work
activities. Up and about more than 50% of waking hours

Capable of only limited self care, confined to bed or chair more than
50% of waking hours

Completely disabled. Cannot carry on any self care. Totally confined to

bed or chair

Dead

Appendix II
Common Terminology Criteria for Adverse Events (CTCAE) Version4.0
Nausea

Loss of
appetite
without
alteration
in eating

Oral intake
decreased
without
significant
weight loss,

Inadequate
oral caloric or
fluid
intake; tube
feeding, TPN,

habits

Vomiting

dehydration
or
malnutritio
n
1-2
3-5
episodes
episodes
(separated (separated
by 5
by 5
minutes) in minutes) in
24 hrs
24 hrs

or
hospitalizatio
n indicated
>=6 episodes
(separated by
5
minutes) in 24
hrs; tube
feeding,
TPN or
hospitalizatio
n indicated

Lifethreatening
consequences
;
urgent
intervention
indicated

Death