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ORIGINAL
Translational and Randomized Study of 5-HT3 Receptor
Antagonists for Evaluation of Chemotherapy-induced
Nausea and Vomiting Related Biomarkers
Yukari Tsubata MD, PhD1), Mika Nakao MD1), Yoshihiro Amano MD1), Takamasa Hotta MD1), Megumi Hamaguchi MD1),
Tamio Okimoto MD, PhD1), Kiyotaka Miura MD1), Shunichi Hamaguchi MD1), Takashige Kuraki MD, PhD1),
Masayuki Itakura MD, PhD2), and Takeshi Isobe MD, PhD1)
1)
Department of Internal Medicine, Division of Medical Oncology & Respiratory Medicine, Shimane University Faculty of Medicine, Shimane, Japan, 2)Department of Surgery, Shimane University Faculty of Medicine, Shimane, Japan

Abstract : Purpose We assessed the efficacy of palonosetron (PAL) in comparison to granisetron (GRA) for thetreatment of CINV using the self-assessment questionnaires. In addition, we analyzed the serum levels of emetic
various biomarkers. Methods We conducted a randomized study of 70 patients naïve to chemotherapy. The primary endpoint was the late phase score on the MAT questionnaire. The plasma concentrations of the biomarkers
were measured on days 1 and 3. Results There were no statistical differences in the scores on the questionnaires,but the mean values in response to PAL were higher than those in response to GRA. The value of ghrelin on day 1
was significantly higher for GRA than for PAL. Conclusions For the primary endpoint, the score of the late phaseon the MAT questionnaire was not statistically different between the PAL and GRA treatment groups. Further
studies are needed to clarify the role of ghrelin for the treatment of CINV. J. Med. Invest. 66 : 269-274, August, 2019
Keywords : Chemotherapy-induced nausea and vomiting (CINV), Self-assessment questionnaire, Quality of life (QOL), Emetic biomarkers,
Ghrelin

INTRODUCTION
Chemotherapy-induced nausea and vomiting (CINV) is among
the most feared and distressing side effects of chemotherapy forcancer patients. Inadequate control of CINV may cause treatment delay or discontinuation and impair the patient’s quality oflife (QOL). Oncologists should recognize that antiemetic therapy
is important for the completion of chemotherapy while maintaining the QOL of the patients. The antiemetic guidelines provided
by American Society of Clinical Oncology (ASCO) (1), National
Comprehensive Cancer Network (NCCN) (2), and the Multinational Association of Support Care in Cancer (MASCC) (3)allow us to control CINV with appropriate antiemetic therapy.
These current antiemetic guidelines classify the risks of CINV
with anticancer drug by the regimen (e.g., high emetic risk chemotherapy (HEC), moderate emetic risk chemotherapy (MEC),
low and minimal emetic risk chemotherapy) and the occurring
phase (acute, delayed and anticipatory nausea and vomiting).
Moreover, the guidelines list the recommended antiemetic drugs
while showing the correct dosage.
CINV has physiologic mechanisms in each occurring phases,
and various guidelines are recommended to choose the drug
to use accordingly (1-3). For instance, it is thought that therelease of serotonin (5-HT) from enterochromaffin cells in thesmall intestine is related to acute phase CINV. 5-HT3 receptor
antagonists (RAs) are reported to have complete response (CR)rates (i.e., no emesis, no use of rescue medication) of 50-70% (4-5)
when using these drugs as single agents for antiemetic therapy
Received for publication September 12, 2018 ; accepted May 7, 2019.
Address correspondence and reprint requests to Takeshi Isobe, MD,
PhD, Professor and Chairman, Department of Internal Medicine,
Division of Medical Oncology & Respiratory Medicine, Shimane
University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 6938501, Japan and Fax : +81-853-20-2580.

of acute CINV (occurring within 24 hours of chemotherapy) inpatients receiving MEC. However, it has been reported in theprevention of delayed CINV (occurring > 24 hours after chemotherapy) that the effectiveness is low even if 5-HT3 RAs areadministered together with a steroid (6).
Recently, new antiemetic agents have been developed suchas the 5-HT3 RA, palonosetron (PAL) (7-9), and the neurokinin-1 (NK 1) RA (10-12), aprepitant. PAL is a highly potent,
second-generation selective 5-HT3 RA. It has been shown tohave an approximately 100-fold stronger binding affinity for the
5-HT3 receptor compared with other 5-HT3 RAs and an extended
plasma elimination half-life of approximately 40 hours (7). The
PROTECT study (8), a phase III trial, showed that PAL withdexamethasone exerts efficacy against CINV which is non-inferior to that of granisetron (GRA) with dexamethasone in theacute phase and is better than that of GRA in the delayed phase.
Aprepitant is the first approved substance P (SP)/NK1-RA, andit has been shown to significantly improve the prevention of
acute and delayed CINV for use in combination with a 5-HT3RA
and dexamethasone (10-12).
While the strategy for the prevention of CINV is in progress,
the self-assessment of patients using questionnaires is attractive
because questionnaires can estimate the patient’s QOL objectively. The MASCC Antiemesis Tool (MAT) (13) was developed
as a tool for subjective patient self-evaluation of CINV in 2004
in which the patient can easily evaluate the onset time of CINV
(14). The Functional Living Index-Emesis (FLIE) questionnaire
is a validated patient-reported measure of the impact of CINV
on daily living (15-16). However, there are few clinical trials thathave examined these questionnaires as a major index of CINV
evaluation.
On the other hand, it is well known that various emetic
biomarkers, such as 5-HIAA, SP and ghrelin, affect emesis
expression or appetite suppression. Serotonin (5-HIAA is a oneof the metabolites of serotonin) has long been appreciated as the

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Y. Tsubata, et al. CINV related biomarkers and questionnaires

primary mediator of acute vomiting, a conclusion consistent withthe efficacy of 5-HT3 RAs in treating early phase CINV (17-18).
SP is a regulatory peptide found in areas of the central nervous
system and the gastrointestinal tract and known to cause CINV
by binding to the NK-1 receptor of the vagal afferents (19-21).
Ghrelin is a growth-hormone-releasing acylated peptide predominately produced by gastric endocrine cells and known to havean intense appetite-enhancing effect in addition to the growth
hormone secretion-promoting effect (22-24). Moreover, the association between emetic biomarkers and CINV is unclear.
Therefore, our study was designed to evaluate the effectiveness of PAL compared to GRA using questionnaires in standard
antiemetic therapy, especially for delayed phase CINV in which
the prevention of CINV is believed to be difficult. Another objective of this study was to assess the plasma biomarker levels(5-HIAA, substance P, ghrelin) of patients who received chemotherapy with antiemetic drugs.

PATIENTS AND METHODS
Design and patients

This study was a prospective, randomized, single-center,comparative phase III trial. Eligible patients were 20 years ofage or older with histologically or cytologically confirmed malignant disease, chemotherapy-naive and an Eastern Cooperative
Oncology Group (ECOG) performance status (PS) of 0-2. Eachpatient was scheduled to receive his first course of HEC or MEC.
The classification of HEC and MEC were according to the Japan
Society of Clinical Oncology (JSCO) antiemetic guideline. The
primary exclusion criteria included the following : dementia,
planned whole brain irradiation, active infection, symptomaticbrain metastasis, symptomatic hypercalcemia or hyponatremia.
The primary endpoint was the score of late phase CINV on the
MAT questionnaire. The secondary endpoints were the score ofnausea or vomiting in the FLIE questionnaire, the proportionof patients that achieved a CR (defined as no emetic episode andno use of rescue medication) and the plasma concentrations of
the biomarkers. Written informed consent was obtained from all
patients in this study, which was approved by the institutional
review board. This trial was registered with the UMIN (No.
000005268). At the time of registration to UMIN, because there
was a patient of lung cancer and the breast cancer to start chemotherapy 80 patients at our hospital in a year, we set numberof cases to 60 patients. After an examination start, because mostof the enrolled patients were lung cancer patients, we increased
the enrollment of the breast cancer patient in consideration of thebalance of both groups and the study finished in 70 cases.

Procedures
The patients were randomized 1 : 1 to either the PAL or GRA
treatment group, which were stratified by age, gender and therisk of CINV for chemotherapy (HEC or MEC). The standard
antiemetic therapy for HEC was consisted to be intravenous
PAL (0.75 mg) or GRA (3 mg) and dexamethasone (9.9 mg) on
day 1, followed by oral dexamethasone (8 mg daily) on days 2-4.
Oral aprepitant (125 mg) was administered on day 1 followed by
80 mg daily on days 2 and 3. The standard antiemetic therapy
for MEC was consisted to be intravenous PAL (0.75 mg) or GRA(3 mg) and dexamethasone (9.9 mg) on day 1, followed by oral
dexamethasone (8 mg daily) on days 2 and 3, and without oral or
intravenous aprepitant. After chemotherapy, rescue medication
for the treatment of nausea and vomiting was allowed for all
patients.
For the assessment of the biomarkers, blood samples werecollected at 1 h and 48 h after chemotherapy, according to the re-sults of our preliminary study (data not shown). Approximately
4 mL of peripheral blood were divided into three tubes. For themeasurement of active ghrelin, we used aprotinin/EDTA added
tubes. All tubes were immediately centrifuged at 4℃, 3000 rpm
for 10 min. The plasma was removed and stored at -80℃ until
further use. The plasma concentration of 5-HIAA was measured
by SRL Inc. (Tokyo, Japan) using a high-performance liquid
chromatography system. SP (Cayman Chemical Co, Ann Arbor,
Michigan, USA) and active ghrelin (SCETI Co Ltd, Tokyo,
Japan) were measured using an enzyme-linked immunosorbent
assay kit according to the protocol supplied by the manufacturer.

Assessments
We used two kinds of questionnaires to evaluate nausea andvomiting. The MAT questionnaire is an eight-item scale forthe assessment of acute and delayed CINV that is completed
once per cycle of chemotherapy (25). The validated FLIE questionnaire specifically addresses the impact of CINV on dailyfunctioning and quality of life (QOL) (15-16). On days 2 and 5,
the patients completed a MAT questionnaire to assess the effectof nausea or vomiting. On day 5, the patients also completed
FLIE questionnaires. The study observation period was divided in three distinct phases : the acute phase, from the start ofchemotherapy to 24 h post-chemotherapy administration (days
1-2) ; the delayed phase, from 24 h to 120 h (days 2-5) post-chemotherapy administration ; and the overall phase (days 1-5).
Higher scores indicated more severe disease on the MAT and
FLIE questionnaires.

Statistical analysis
Student’s t-test or the Mann Whitney U test was applied
to assess the data. All of the statistical calculations were performed using the SPSS software program, version 19 (IBM,Tokyo, Japan). A p value < 0.05 was considered to be statisticallysignificant.

RESULTS
Patient

Patients were evaluated between Oct. 2010 and Jan. 2013.
Seventy patients were enrolled and randomized to the PAL or
GRA treatment group. Table 1 shows that the patient baselinecharacteristics, including known risk factors for CINV (gender,

Table 1 Patient characteristics
PAL (N = 35)
Age (yr)

Gender

≦ 49

3

50-69

18

≧ 70

14

4
17
14

Median
68 yr

22

22

Female

13

13

HEC

20

19

MEC

15

16

NSCLC

25

24

SCLC

3

3

BC

6

6

Others1

2

0/1

24 / 1123 / 12Previous radiotherapy Yes / No

8 / 274 / 31

Alcohol habits

20 / 1518 / 17

Risk of emesis
Type of cancer

ECOG PS

MaleMedian
68 yr

GRA ( = 35)

Yes / No

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The Journal of Medical Investigation Vol. 66 August 2019
alcohol consumption or history of radiation therapy), were similar between the two treatment groups. The majority of patientswere male (44/70, 63%) with an average age of 68 years, and
56% of the patients received a HEC regimen. The most common
primary types of malignant disease included lung cancer (54/70,
79%) and breast cancer (12/70, 17%).

Efficacy
For the primary endpoint, the score of the late phase on the
MAT questionnaire was not statistically different between the
PAL and GRA treatment groups (2.7 vs 3.5, P = 0.55) (Figure 1).
The acute phase on the MAT questionnaire and emesis and nausea on the FLIE questionnaire (Figure 1) were also not statis-

tically different between the two treatment groups. A subgroup
analysis of each treatment group stratified by HEC and MEC
also showed no statistically differences. While there were no
statistical differences in the overall score of the questionnaires,the mean values in those receiving PAL were lower than thosereceiving GRA in both the acute and delayed phases. In addition,
the CR (51.4% vs 48.6%) and total control (TC) (37.1% vs 40.0%)
rates were similar during all phases among the PAL and GRA
treatment groups (Table 2). An analysis of the questionnaires
and the rate of total control showed that approximately 60% of
the patients suffered from any vomiting or nausea, thus thesepatients required rescue medication throughout the observation
period.

Figure 1 Results of the questionnaires
Data are expressed as the mean ± SE.

Table 2 Evaluation of the responses
Responses (%)

Complete
Response

Total
Control

ALL

HEC

MEC

PALO
(N = 35)

GRA(N = 35)

PALO(N = 20)GRA(N = 19)

PALO(N = 15)GRA(N = 16)

Acute

80.0

82.9

70.0

68.4

93.3

100

Delayed

51.4

48.6

35.0

36.8

66.7

62.5

Overall

51.4

48.6

35.0

36.8

66.7

62.5

Overall

37.1

40.0

25.0

31.6

60.0

50.0

Complete response ; defined as no emetic episodes and no use of rescue medication
Total control ; defined as no emetic episodes, no use of rescue medication, and no nausea Acute ; 0-24 h,
Delayed ; 24-120 h, Overall ; 0-120 h

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Y. Tsubata, et al. CINV related biomarkers and questionnaires

Biomarker assessment
The plasma concentrations of SP and 5-HIAA were not significantly different between the PAL and GRA treatment groups ondays 1 and 3, while the plasma ghrelin levels were significantly
higher for GRA than PAL on day 1 (Figure 2). The ghrelin levels
on day 3 were significantly decreased compared with on day 1
in the GRA group. A subgroup analysis of each treatment group
stratified by HEC and MEC, having CINV or not, and a highor low score on the questionnaires also showed no statisticallysignificant differences.

DISCUSSION
For all time points or intervals not mentioned, a similar trend
favoring PAL compared with GRA was observed, although thisdifference did not reach statistical significance. It is especially
important to note that at least 50% of the patients experienced
CINV following an initial cycle of HEC and MEC, despite substantial recent progress. These patients required rescue medication throughout the observation period. In addition, the results ofthe biomarker study indicated that the plasma concentration ofghrelin, which is an appetite increaser hormone, may be related
to the type or dosage of 5-HT3RA.
Our results regarding the CR and TC rates are in agreementwith previous triple therapy studies. The reason that significant
differences were not detected in our study is because the sample
size was too small. However, all the scores on the questionnaires
showed an advantage with PAL treatment. In particular, because the FLIE questionnaire is a qualifying tool for evaluating
the QOL of the patient, the fact that PAL treatment resulted
in higher scores is thus considered to be an important finding.
These finding suggest the possibility that PAL is useful for QOL
maintenance of the patients compared with GRA. The evalua-tion of CINV is typically subjective, especially during the delayedphase. Clinicians tend to underestimate the incidence of nausea
and vomiting, as well as a worsening of a patient’s QOL duringchemotherapy, and therefore improved communication between
medical professionals and patients regarding CINV may help
improve the outcomes (25-26). Thus, clinicians are sometimes
troubled with the grading decision of the adverse events of CINV
because the evaluation is not objective. Although we adopted
standard antiemetic therapy in this study, which complied withthe guidelines, the FLIE questionnaire clarified that approximately half of the patients felt that their QOL was inhibited by
CINV. The MAT and FLIE questionnaires are a short, easy,
self-administered instrument containing two domains – one fornausea and one for vomiting. These questionnaires are reliable
for assessing the patient’s QOL and easy-to-use in the clinicalsetting, thus they are useful tools for CINV management.
Various reports in the literature have shown that there iscross-talk between ghrelin, NK-1 and the 5-HT receptor signaling pathway (27-31). Rojas et al. (28) have shown the possibility
that 5-HT3 RAs can inhibit cisplatin-induced activation of the SP
response. Moreover, 5-HT2C receptor gene expression may leadto anorexia in cisplatin-treatment patients, and administrationof a 5-HT2C agonist inhibited hypothalamic ghrelin secretion(30). Recent reports indicate that both the 5-HT2C receptor
and the 5-HT2B receptor, but not the 5-HT3 receptor, mediate
cisplatin-induced ghrelin suppression in rodents (32). In thisstudy, we showed that there was a difference in the influence on
the plasma ghrelin level between the PAL and GRA treatmentgroups. This phenomenon may be caused by the pharmacologic
differences of the affinity of 5-HT3 RA to the 5-HT2C or 5-HT2B
receptor. It was thought that 5-HT3 RAs, especially GRA, might
have the potential to increase the ghrelin level and desacylation
through various serotonin receptors. Because half-life is short in
GRA with 4-9 hours, it is thought that the blood concentrationof the ghrelin of day 3 decreased briefly as for the time to affectFigure 2 Results of the biomarkers
Data are expressed as the mean ± SE. *Statistically significant by student’s t-test.

The Journal of Medical Investigation Vol. 66 August 20195-HT receptor. Further studies are needed to clarify any differences in the effects of both 5-HT2C and 5-HT2B and also elucidate
their influence on ghrelin secretion and the metabolism during
5-HT3 RA treatment.

CONCLUSION
However the score of the late phase on the MAT questionnaire was not statistically different between the PAL and GRA
treatment groups, this study provided important information on
the clinical assessment of CINV, and demonstrated that questionnaires, such as MAT and FLIE, are helpful for improving
patient care during cancer chemotherapy. Though we provided
treatment according to the antiemetic guidelines as standard
therapy, half of the patients felt that their QOL was inhibited bychemotherapy. Further studies should investigate the control of
CINV over the duration of cancer therapy and should consider
not only the CR rate during the first cycle, but also the QOL of
all cancer patients.

CONFLICT OF INTEREST
All authors have no conflict of interest to disclose.

ACKNOWLEDGEMENTS
We thank patients and their families who participated in thistrial. This work was supported by efforts from the promotion
plan for the platform of human resource development for cancer.

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