医薬品相互作用研究

Vol.38, No. 3（2015）19（156）

医薬品相互作用研究ノート
38（3） 19-24 （2015）

Investigation of a new antiemetic regimen in patients receiving
highly emetogenic chemotherapy
Mayumi SUZUKI* 1,3), Norihiko HATA2), and Noriko FUKUSHIMA3)
1)

2)

Department of Pharmacy, Kawaguchi Municipal Medical Center
Department of Internal Medicine, Kawaguchi Municipal Medical Center
3)
Graduate School of Pharmaceutical Sciences, Keio University（Received December 2, 2014; Revised January 23, 2015; Accepted February 17, 2015）

It has been suggested that three-drug combination therapy employing aprepitant, palonosetron,and dexamethasone is useful for treating nausea and vomiting associated with cancer chemotherapy(chemotherapy-induced nausea and vomiting, CINV). However, whether this three-drug regimen issuperior to other antiemetic agents available before the release of aprepitant and palonosetron has
been unclear. This study compared the eﬃcacy of the three-drug regimen with that of conventionalantiemetic therapy in 132 patients who received cisplatin at a dose of 50 mg/m 2 or higher during
the period from January 2009 to December 2012. The percentage of patients without vomiting or
salvage treatment ( , those with a complete response) showed a signiﬁcant diﬀerence between
combination therapy including aprepitant and antiemetic therapy without aprepitant. There was no
signiﬁcant diﬀerence between the groups with regard to the percentage of patients without nausea
during the acute phase within 24 hours, but a signiﬁcant diﬀerence was observed during the delayedphase from 24 hours to 72 hours. There was also a signiﬁcant diﬀerence in the percentage ofpatients without vomiting throughout the study period when the three-drug combination therapy
group was compared with the granisetron group and the granisetron plus aprepitant group. Whenused in combination with aprepitant, superiority of palonosetron over granisetron has not beenreported in Japan, but the present results suggested such superiority. The three-drug regimen may
be useful for preventing CINV in patients receiving highly emetogenic chemotherapy.
Key Words: Aprepitant, Palonosetron, Highly emetogenic chemotherapy, CINV, Antiemetic therapy

Introduction

schedule1,2). In Japan, standard ant iemet ic

Problemat ic side eﬀects of chemotherapy fortherapy since the 1990s has been the two-drug

cancer include nausea and vomiting.

combination of dexamethasone and a

Chemotherapy-induced nausea and vomiting

5-hydroxytryptamine3 (5-HT3) receptor(CINV ) often causes marked impairment of theantagonist (RA).

quality of life in cancer patients. CINV results in

Aprepitant is a select ive neurokinin-1 (NK-1)

electrolyte abnormalities and dehydration, as

RA and is an antiemetic drug that suppresses

well as reducing dietary intake, which leads tonausea and vomiting by preventing substance P

nutritional disorders and weight loss. CINV also

from binding to NK-1 receptors in the central

causes deterioration of the mental state andnervous system, since substance P levels are

physical condition, and often prevents

increased by anticancer drugs 3‒5) . Aprepitant wascompletion of chemotherapy according todeveloped by Merck & Co., Inc., Kenilworth, N.J.,〒333-0833 埼玉県川口市西新井宿180 川口市立医療センター薬剤部〒333-0833 埼玉県川口市西新井宿180 川口市立医療センター内科
3)〒105-8512 東京都港区芝公園1-5-30 慶應義塾大学薬学部・薬学研究科
1)
Department of Pharmacy, Kawaguchi Municipal Medical Center, 180 Nishiaraijuku, Kawaguchi, Saitama 333-0833, Japan2)
Department of Internal Medicine, Kawaguchi Municipal Medical Center, 180 Nishiaraijuku, Kawaguchi, Saitama 333-0833, Japan
3)
Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo 105-8512, Japan*Corresponding author, E-mail: suzuki.kawaguchi.mmc@gmail.com (M. Suzuki)
1)2)

20（157）

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Vol.38, No. 3（2015）

U.S.A, and was released in Japan in 2009, while

time: 2 hours) and received one of the following

fosaprepitant (an injectable product) wasantiemetic regimens in Kawaguchi Municipal

released in 2011. Palonosetron, aMedical Center from January 2009 to December

second-generation 5-HT 3 RA, was developed by

2012: (1) granisetron (3 mg on the day of

Helsinn in Switzerland and was marketed inchemotherapy) and dexamethasone (9.9 mg i.v.

Japan in 2010. The plasma elimination half-lifeon the day of chemotherapy and 6.6 mg i.v. or 8of palonosetron is longer than that ofmg p.o. on the following two days) in 26 patients

convent ional 5-HT 3 RAs about 40 hours versus(Group G); (2) granisetron (3 mg, one or two

approximately 3‒5 hours and this drug exerts adoses on the day of chemotherapy),

long-lasting antiemetic eﬀect by continuous

dexamethasone (9.9 mg i.v. on the day of

6)

inhibition of serotonin binding . These two drugs

chemotherapy and 6.6 mg i.v. or 8 mg p.o. on theare not only promising for the management offollowing two days), and aprepitant (125 mg onacute nausea and vomiting, but also delayed

the day of chemotherapy and 80 mg on thenausea and vomiting that cannot be adequately

following two days) in 42 patients (Group A); andcontrolled by standard therapy.

(3) palonosetron (0.75 mg), dexamethasone (9.9

In the principal guidelines on antiemetic

mg i.v. on the day of chemotherapy and 6.6 mg

t r e a t m e n t f r o m o ve r s e a s ( A m e r i c a n S o c i e t y o fi.v. or 8 mg p.o. on the following two days), andClinical Oncology, Multinational Association of

aprepitant (125 mg on the day of chemotherapy

Supportive Care in Cancer, and Nationaland 80 mg on the following two days) in 64

Comprehensive Cancer Network) and thepatients (Group P). No anticonvulsant drugs were

"Guidelines on the correct use of antiemetics"

u s e d c o n c o m i t a n t l y, a n d r a d i o t h e r a p y w a s n o t

issued by the Japan Society of Clinical Oncology

performed in any patient. It should be noted that

7)in May 2010 , three-drug combination therapy

dexamethasone was administered for three days

with aprepitant, a 5-HT 3 RA, and dexamethasone

at our Center, although the "Guidelines on theis recommended for patients receiving highly

correct use of antiemetics" issued by the Japanemetogenic chemotherapy (HEC). Our previous

Society of Clinical Oncology stipulate

study showed that this three-drug regimen was

a d m i n i s t r a t i o n f o r ﬁ ve d a y s . T h e d i ﬀ e r e n c e o f

useful for preventing CINV in patients receivingsuch dosing period is due to the fact that8)

HEC . There have been several other studies thatchemotherapy regimen was not prepared in oursuggested the eﬃcacy of this three-drug

hospital as of 2012. Now, we have chemotherapy

combination therapy

9, 10). However, there have notbeen any studies that compared the three-drug

regimen which is in accordance with theAntiemetic Guideline.

regimen with antiemetic treatment available
before the release of aprepitant and2. Data collection

palonosetron, and the superiority of three-drug

The gender, age, details of cisplat in therapy,

combination therapy has not been demonstrated.

type of cancer, number of vomiting episodes andTherefore, we performed this study to compare

severity of nausea during ﬁve days from thethree-drug combination therapy (aprepitant,

init iat ion of chemotherapy, use of salvage

palonosetron, and dexamethasone) withtreatment, and details of salvage treatment wereconventional therapy available before

retrospectively extracted from the electronic

intro duct ion of these newer agents in pat ients

medical records of the patients.

receiving HEC.

3. Evaluation
Methods
1. Patients and treatment

Symptoms that occurred within 24 hours of theadministration of anticancer drugs wereThis study was conducted in 132 patients whoc l a s s i ﬁ e d a s a c u t e s ym p t o m s , w h i l e s ym p t o m sreceived inpatient chemotherapy with cisplatinthat occurred from 24 hours onward wereat a dose of 50 mg/m 2 or higher (administration

classiﬁed as delayed symptoms. The percentage

医薬品相互作用研究

Vol.38, No. 3（2015）21（158）of patients without vomiting or salvage

inter-group diﬀerences of sex, age, and cisplatintreatment (dose ( Table 1).

, those with a complete response )d u r i n g t h e w h o l e s t u d y p e r i o d ( ﬁ ve d a y s a f t e r

There was a signiﬁcant diﬀerence in theadministration of cisplatin) was calculated inpercentage of patients without vomiting or

each group. Both acute and delayedsalvage treatment (nausea/vomiting were also evaluated. Acute andstudy perio d between Group G and Group A, as

delayed nausea/vomiting were graded according

well as between Group G and Group P, with theto the Common Toxicity Criteria for Adverse

percentages being higher in Groups A and P than

Events version 4.0 ( Japanese version, translated

in Group G (Fig. 1). There was diﬀerence in theby the Japan Clinical Oncology Group).

percentage of patients without acute nausea, CR) during the wholeamong the three groups, but there was a

4. Statistical analysis

signiﬁcant diﬀerence of the percentage with

Statistical evaluation was performed by using

delayed nausea between Groups G and A or

the chi-square test and Fisherʼs exact test w ith

between Groups G and P, w ith the percentages

S P S S ve r s i o n 1 8 . 0 s o f t w a r e . I f t h e p r o b a b i l i t ybeing larger in Groups A and P than in Group G(2-sided) was <0.05, the diﬀerence was(Fig. 2). The percentage of patients without

considered signiﬁcant.

vomiting during the whole study period showed asigniﬁcant diﬀerence between Groups G and P or

5. Ethical considerations

b e t w e e n G r o u p s A a n d P, w i t h t h e p e r c e n t a g e

This study was approved by the Inst itut ional

being higher in Group P than in Group G or

Review Board of Kawaguchi Municipal Medical

Group A. In Group P, 100% of the patients were

Center prior to commencement.

without vomiting (Fig. 3). Residual analysis
performed for any two groups between which a

Results

signiﬁcant diﬀerence was conﬁrmed showed

The mean age of the patients was 61.2 ± 10.5

signiﬁcant diﬀerences of all pairs. Salvage

years, and there were 84 men and 48 women.

treatment was used for 14 of 26 patients in

Only 5 patients had received chemotherapyGroup G, 11 of 42 patients in Group A, and 15 ofcontaining cisplatin prior to this study. The most

6 4 p a t i e n t s i n G r o u p P, w i t h m e t o c l o p r a m i d ecommon malignancy was lung cancer, followed

being the main salvage agent. The percentage ofby gynecologic cancer and gastrointestinal

patients on salvage therapy diﬀered signiﬁcantly

cancer ( Table 1). There were signiﬁcantbetween the groups, with Group P containing theTable 1: Characteristics of the groups100%ͤP<0.05

90%

PopulaƟon of paƟents (%)

80%

ͤP<0.05

70%

71%

77%

60%
50%
40%

46%

30%
20%
10%
0%
G⩌ G
Group

A⩌ A
Group

P⩌ P
Group

ͤthe chi-square test and Fisher’s exact test

Fig. 1: Overall complete response22（159）

医薬品相互作用研究

Vol.38, No. 3（2015）

120%

Group GG⩌

120%Group AA⩌

ͤP<0.05

Group PP⩌100%

ͤP<0.05

ͤP<0.05

88% 90%80%
77%

ͤP<0.05

60%

77%

ͤP<0.05

64%

62%

40%
20%

31%

31%

ͤP<0.05

100%

PopulaƟon of paƟents (%)

PopulaƟon of paƟents (%)

100%

100%

80%

60%

83%
69%

40%

20%

0%

0%
Entire ඲ᮇ㛫study period

ᛴᛶᮇ
Acute
phase

G⩌ G
Group

㐜Ⓨᮇ
Delayedphase

Percentage of paƟents without nausea

A⩌A
Group

P⩌ P
Group

ͤthe chi-square test and Fisher’s exact testͤthe chi-square test and Fisher’s exact test

Fig. 2: Overall complete response

Fig. 3: Percentage of patients without vomiting during
the whole study period

smallest number of such patients. In Group G,

aprepitant, palonosetron, and dexamethasone on

Grade 2 nausea was noted in three patients,

nausea and vomit ing in comparison w ith prior

while all other nausea was Grade 0 or 1. In

treatment in patients receiving HEC withG r o u p A , G r a d e 2 n a u s e a w a s o b s e r ve d i n t w ocisplat in at doses of 50 mg/m 2 or higher. CINV

patients and all other nausea was Grade 0 or 1.

associated with cisplatin has a biphasic pattern,

I n G r o u p P, a l l n a u s e a w a s G r a d e 0 o r 1 , a n dsince acute symptoms occur within 24 hours andnausea of Grade 2 or more severe was notdelayed symptoms are seen from 24 hours

observed. Only one patient each in Groups G andonward, with the peak of delayed nausea andA vomited ﬁve t imes or more. No vomit ing was

vomiting at 48‒72 hours after administration 1 2 ,o b s e r v e d i n G r o u p P. C I N V w a s t r e a t e d w i t h

13)a p p r o p r i a t e s a l v a g e t h e r a p y, a n d n o s e r i o u s

diﬀerence among the three groups with regard toadverse reactions occurred that requiredp r e ve n t i o n o f a c u t e n a u s e a . S u z u k i

cessation of chemotherapy in any group.

a l s o r e p o r t e d s i m i l a r r e s u l t s 1 4 ) . T h i s m a y h a ve

. In the present study, there was no signiﬁcant. h a vebeen because acute CINV is closely asso ciatedDiscussion

with serotonin 15) and 5-HT 3 RAs (granisetron and

The main objective when managing CINV is topalonosetron) were used as prophylaxis in thisprevent its onset. It is important to ut ilize thestudy. Thus, it can be concluded that there wasbest preventative measures when a patient is at

no appreciable diﬀerence between the present

risk of nausea and vomiting because good

three-drug combination therapy and priorcontrol of CINV can increase the completion rate

treatment in terms of the eﬀect on acute phaseof chemotherapy and improve survival. Neymark

nausea. The CR rate and the prevent ion rate of

et al.11) reported that patients with lung cancer

delayed nausea were higher in Groups A and P

from the EORTC08975 trial who discontinued(which received aprepitant) than in Group G

protocol treatment had worse survival than(which did not receive aprepitant), and thepatients who completed protocol treatment, anddiﬀerences were signiﬁcant. This suggested thatthat vomiting was an independent risk factor for

CR and control of delayed nausea were g reatly

failing to complete protocol treatment.

inﬂuenced by aprepitant. It has been reported

Therefore, prevent ion of CINV can be the mostthat delayed CINV is not only associated with

important factor in achieving continuation ofserotonin but also w ith substance P16). Thischemotherapy.

report was supported by the results of our study.

T h e p r e s e n t s t u d y i nve s t i g a t e d t h e e ﬀ e c t o fthree-drug combination therapy using

Ichihara. also reported that aprepitant had afavorable eﬀect on delayed nausea and医薬品相互作用研究

Vol.38, No. 3（2015）23（160）

vo m i t i n g 1 7 ) . T h e r e w e r e s i g n i ﬁ c a n t d i ﬀ e r e n c e spatients with gynecologic cancer and it isbetween Groups P and G or between Groups P

believed that female patients are more likely to

and A with regard to the prevention of vomitingd e v e l o p C I N V. H o w e v e r , t h e p e r c e n t a g e o fduring the whole study period. In particular, thepatients without delayed-phase nausea wassigniﬁcant diﬀerence between Groups P and G

signiﬁcantly higher in Group A than in Group G.

suggests that the sustained eﬀect of

In conclusion, this study showed thatpalonosetron, a long-acting 5-HT3 RA,

three-drug combination therapy with aprepitant,contributed to the control of vomiting. When an

palonosetron, and dexamethasone is superior toNK-1 RA was not used, superiority of

conventional antiemetic therapy available before

palonosetron over granisetron was suggested in

the release of aprepitant and palonosetron forpatients receiving moderately emetogenic

prevent ion of nausea and vomit ing in pat ients18). However, in combined use withreceiving HEC. To our knowledge, this is the ﬁrst

an NK-1 RA, superiority of palonosetron overstudy performed in Japan to indicate the7, 19).

superiority of palonosetron over granisetron

In the present study, a signiﬁcant diﬀerence inwhen used concomitantly w ith aprepitant. Our

the percentage of patients without vomiting wasresults may be useful for establishing ano b s e r v e d b e t w e e n G r o u p A a n d G r o u p P.

appropriate antiemetic regimen to treat patients

Although the sample size was small, superiority

receiving HEC. We plan to perform furtherof palonosetron over granisetron was suggested

investigations of this issue.

chemotherapy

other 5-HT 3 RAs has not been demonstrated

when combined with an NK-1 RA. These results
suggested that three-drug combination therapy

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