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\begin{document}

\title{Does a single dose of Palonosetron have any role in preventing
chemotherapy-induced nausea and vomiting in pediatric patients? A
double-blind, randomized controlled trial.}



\author[1]{Zheng Li}%
\author[2]{Chun Li}%
\author[3]{Ping Li}%
\author[4]{Yugang Li}%
\author[5]{Jin Lai}%
\author[6]{Sanjay Rastogi}%
\affil[1]{Chengdu Jinniu District People's Hospital}%
\affil[2]{China-Japan Friendship Hospital}%
\affil[3]{Ya'an People's Hospital}%
\affil[4]{The First Affiliated Hospital of Chengdu Medical College}%
\affil[5]{The 72nd Group Army Hospital of PLA}%
\affil[6]{Regional Dental College}%


\vspace{-1em}



  
  \date{June 08, 2024}


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\selectlanguage{english}
\begin{abstract}
Objectives: Chemotherapy-induced nausea vomiting (CINV) is a troublesome
side-effect of chemotherapy in pediatric patients undergoing
Osteosarcoma treatment. The role of 5HT3 antagonists needs to be
explored for the same. The study aims to evaluate the superiority of
single-dose Palonosetron over Granisetron in pediatric patients
undergoing moderate emetogenic therapy for osteosarcoma. Materials and
Methods: In this double-blind, case-controlled, randomized study,
pediatric patients were assessed for acute nausea and vomiting following
moderate emetogenic chemotherapy for osteosarcoma. These children were
assigned to group I (palonosetron) and group II (Granisetron) without
other antiemetic prophylaxis. The primary objective variable was
children's segment with complete response during the acute phase of the
first on-study chemotherapy cycle. Risk factors associated with the
trial were analyzed. The patients were followed for the first 24 hours
following chemotherapy. Results: A total number of 200 children were
evaluated, and other factors which might alter the response were
assessed into two groups. These 200 children underwent 604 blocks of
chemotherapy. The complete responses (CR) were documented in 83\% and
72\% receiving palonosetron and Granisetron, respectively, during the
acute phase. The only dexamethasone, used as rescue medication, was
found to be a significant risk factor that predisposed the response
(p\textless{}0.05) Conclusion: Palonosetron is an effective alternative
to Granisetron as a single dose for preventing CINV in children
receiving MEC for osteosarcoma.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Cancer is tormenting and devastating, but with the incessant emergence
of medical brilliance, chemotherapy is launched as one of the reassuring
measures. The advent of chemotherapy combined with radiotherapy and
surgery reinstated the hope for survival. However, along with it came a
profusion of anguishing side effects. Side-effects of chemotherapy are
nephrotoxicity, neurotoxicity, ototoxicity, myelosuppression, nausea,
and vomiting. Among them, nausea and vomiting are annoying, especially
for children, leading to a compromised quality of life
post-chemotherapy. Delayed emesis is also one of the reasons adolescents
and children disagree with further treatment.\textsuperscript{1,2}

According to emetogenic classification of Pediatric Oncologic group of
Ontario3 (POGO), August 2013; various drugs were classified as highly
emetogenic drugs (carboplatin, cisplatin, cyclophosphamide,
methotrexate, doxorubicin) and moderately emetogenic drugs (epirubicin
and ifosfamide), which are commonly used for Osteosarcomas's
chemotherapy in children. Moreover, even with the best antiemetic
regimes, nausea and vomiting continue to be the most irksome aftermath
of chemotherapy in children3.

Cisplatin or doxorubicin-induced emesis was predominant before the
1980s. In the 1990s, a combination of a corticosteroid and a
5-HT\textsubscript{3}~receptor antagonist became a customary practice.
High dose metoclopramide and Dexamethasone (Allan et al.,
1984)\textsuperscript{4} proved to be effectual to a certain degree.
However, specific adverse effects, especially extrapyramidal reactions,
commonly found in children and adolescents, have curbed high dose
metoclopramide use.

5-hydroxytryptamine 3 (5-HT3) receptor antagonists are now gold standard
for chemotherapy-induced nausea and vomiting (CINV) prevention therapy
since emesis is triggered by activation of 5-HT3 receptors by serotonin
released from enterochromaffin cells in the small intestine, located on
vagal afferents\textsuperscript{5,6}. The effectiveness of the first
generation 5-HT3-receptor antagonists ranges from 50\% to 70\% in
preventing acute chemotherapy induced nausea and vomiting
(CINV)\textsuperscript{3}. Although, there was significant improvement
in the drug therapy for the treatment of the CINV, about fifty percent
of the patients have significant amount of acute and delayed CINV
following moderate or highly emetogenic
chemotherapy\textsuperscript{7,8}. So, there is an ample scope of
research in the field of controlling CINV.

The combination of dexamethasone\textsuperscript{10-14} with
first-generation 5-HT3-receptor antagonists is effective against the
acute CINV, however, the second generation 5-HT3-receptor antagonist,
palonosetron, is a dynamic, extremely selective, and having intense
receptor binding capacity along with prolonged plasma half life (40 hr),
is quite potent as a single dose in preventing both acute and delayed
CINV related to moderate and highly emetogenic
chemotherapy\textsuperscript{9-13}. However, very few studies have been
done so far to establish the single-dose palonosetron efficacy over the
combination of the drug therapy to control CINV in patients undergoing
moderate emetogenic therapy (MEC) \textsuperscript{9, 14-16}.

No standard paediatric antiemetic treatment has yet been implemented,
considering all the advancements and the inclusion of newer and improved
medication regimens in the treatment of chemotherapy-induced nausea and
vomiting. This research was carried out on this unique population prone
to nausea and vomiting and on the need to assess the effectiveness and
side effects of antiemetics.

The goal of this study was to compare the incidence of
chemotherapy-induced nausea and vomiting in paediatric patients who
received moderately emetogenic Osteosarcoma chemotherapy by comparing
Granisetron with palonosetron. The research primarily focused on
estimating the frequency of CINV in the two groups.

\textbf{Materials and Methods}

\textbf{Patient recruitment and Selection:}

To fulfill the research objective, the authors planned and executed a
randomized controlled, double-blind clinical trial which was performed
at the Department of Paediatrics, Chengdu University. The study was
approved by the institutional review board and the local ethical
committee (protocol CU \# RC/IRB/2016/1042). The study followed the
benchmark set by the Declaration of Helsinki. All patients without
systemic complications who strictly satisfied the inclusion criteria
were included.

This study enrolled consecutive children with osteosarcoma,
\textless{}18 years of age, but not below 3 years of age, receiving
moderate emetogenic chemotherapy in the outpatient (daycare) or
inpatient settings from August 2016 to August 2019.

The following exclusion criteria were followed:

Children with abnormal Liver function test (LFT) or Renal function test
(RFT) or those with organic disorders likely to cause vomiting, Children
who were on concurrent radiotherapy or received radiotherapy within the
study period of one week, patients who were on antiemetic therapy within
first 24 hours of recruitment, known hypersensitivity towards any study
drug, other associated adverse effects of chemotherapy. Furthermore, the
anticipatory vomiting could create confusion in the results; the
participants were avoided successive chemotherapy. Patients were asked
to give written Informed consent before participating in the study.

The moderate emetogenic therapy regimen as suggested by the POGO
Guidelines for the treatment of Osteosarcoma were
used\textsuperscript{3,14}. The regimen are as follows:

a) Epirubicin (75 mg/m2) plus iphosphamide (2,500 mg/m2)

b) Epirubicin (75 mg/m2) plus carboplatin (600 mg/m2)

c) Iphosphamide (2,500 mg/m2) plus carboplatin (600 mg/m2)

The Pediatric Oncology Group of Ontario (POGO) guidelines were followed
for classifying the emetogenic potential of each chemotherapy
regimen\textsuperscript{3}. A single- or multiple-day chemotherapy was
considered as one session.

Standard antiemetic prophylaxis for moderate emetogenic chemotherapy
included intravenous 5-HT3 antagonists (Palonosetron administered as a
single fixed 10 \selectlanguage{greek}µ\selectlanguage{english}g/kg dose (maximum total dose of 0.75 mg) infused over
30s or 50 \selectlanguage{greek}μ\selectlanguage{english}g/kg of Granisetron in a single dose administered over five
minutes, and it was based on data available from previous pediatric
studies.\textsuperscript{15} Both drugs were delivered via IV route
30min before initiating moderately emetogenic. Patients with [?] 1-2
episodes of breakthrough vomiting received intravenous Dexamethasone
{[}for body surface area (BSA) [?] 0.6m2; 2 mg twice a day and for BSA
\textgreater{}0.6 m2; 4 mg twice a day{]} as a rescue.

The patient sample size was calculated using:

\textbf{Hosted file}

\verb`image1.emf`  available at \url{https://authorea.com/users/412061/articles/520878-does-a-single-dose-of-palonosetron-have-any-role-in-preventing-chemotherapy-induced-nausea-and-vomiting-in-pediatric-patients-a-double-blind-randomized-controlled-trial}

Where N is the Population size and e is the level of precision. For the
present study, the population's size was determined based on the
previous number of patients admitted because of Osteosarcoma, N is 228
patients for one month, and e is 0.05 at 95\% confidence Interval n =
200. The two groups received equal patients. Although a total number of
228 patients got enrolled in each arm, there was an approximately 12 \%
dropout for different reasons. Therefore, a total number of 200 patients
were evaluated, i.e., 100 patients in each group.

Patients satisfying the eligibility criteria were randomized, regardless
of age and sex, to receive either palonosetron or Granisetron using a
computer-generated randomization schedule. The schedule was packed in a
sealed envelope, which the two designated persons opened during the
beginning of chemotherapy. All patients were randomly allocated to group
I (palonosetron, n=100) and group II (Granisetron, n=100).

Except for the independent pharmacists dispensing the research drugs at
the hospital and the study drug assigner, all study staff and
participants were blinded to treatment assignment for the study
duration. They were also forbidden from releasing any drug allocation
data to other persons.

\emph{Outcome Variables:}

The evaluation of Emesis was based on the following parameters: nausea
(presence or absence) and vomiting (frequency, duration, and severity)

The MANE scale, i.e., Morrow Assessment of Nausea and
Emesis\textsuperscript{18} were used to appraise the parameters;
however, this scale was modified in this study to apply to children.
This scale was initially being used to evaluate adult emesis and
consisted of a questionnaire consisting of the following events:
anticipatory nausea and vomiting, nausea, dry heaving, and
post-chemotherapy vomiting. It considers the quantification of these
events' duration by adult patients based on the amount of time that
nausea and vomiting continue to occur.

It is a method of evaluating symptoms on a six-point scale from the
beginning of chemotherapy treatment to 24 hours later. To be applied to
children, the MANE scale has to be updated, and outside variables that
could affect the results of the research, such as children's parents and
caregivers such as nurses or doctors, could also be part of
it\textsuperscript{14}.

At 2, 4, 6, 8, 12, 18, and 24 hours after the start of chemotherapy
treatment, the child was left to tell us whether nausea was present or
absent. To homogenize the evaluation and adjust the MANE scale to
pediatric patients, the authors made these
modifications\textsuperscript{14}.

The following definitions were used in the evaluation: a) Nausea has
been characterized in the upper gastrointestinal tract as a subjective
sensation of repugnance. Usually, it was a prodromal symptom of
vomiting. (b) Vomiting was a retrograde and vigorous removal of stomach
contents.

Acute emesis was identified as any vomiting during the period starting
with the first chemotherapy dose and continuing until 24 hours after the
last chemotherapy dose was completed in that block (acute phase). A full
response was described as the absence of acute vomiting without rescue
medication (CR). If the patient had 1-2 episodes of vomiting without the
use of rescue medication, the response was deemed partial and failure if
the patient had more than 2 episodes and/or the use of rescue medicine.
Rescue medication was given to the children who had more than 2 vomiting
episodes\textsuperscript{9,15}.

For children who vomit after receiving dexamethasone, add-on, rescue
medicines is allowed to give 0.025 mg/kg/dose of Lorazepam for chronic
vomiting at the discretion of the treating primary care doctor.

A predesigned format was used for all details of the patient. A notebook
was given to the patient or their guardians for easy documentation of
the emetic episodes. For a given session of chemotherapy, the
responsibility was given to the child or their parents to inform us
regarding each and every incidence of vomiting for a period of 2, 4, 6,
8, 12, 18, and 24 hours from the completion of chemotherapy or last dose
of rescue medicines.

The response was reported as episode number and timing (to distinguish
full response/partial response/failure) and rescue medication use. The
primary efficacy endpoint was CR patients' proportion during the acute
period in the first on-study cycle. The secondary endpoint was the
proportion of patients in the first on-study period needing rescue
antiemetic treatment during the acute process. The response was also
analyzed in the group I (Palonosetron) and group II (Granisetron) arms
of all subsequent chemotherapy sessions during the study period.

To avoid the confounding effect of anticipatory vomiting, subjects were
not included during subsequent courses of chemotherapy.

The adverse events related to the palonosetron or Granisetron were
carefully evaluated by taking a relevant history and physical
examination at the time of initiation of chemotherapy, on discharge, and
during the next chemotherapy session. Lab investigations were done as
per the chemotherapy session scheduled, including complete blood count,
Liver function tests, and Renal Function Tests. All sorts of adverse
events were recorded as per the CTCAE, i.e., Common Terminology Criteria
for Adverse Events (CTCAE) version 4.03 available at National Cancer
Institute website
(http://ctep.cancer.gov/protocolDevelopment/electronic\_applications/ctc.htm).
Adverse events were recorded for up to 10 days from the day of
administration of the drug, and the treating physician's opinion on the
relationship of the adverse events to the study drug was also recorded.

\textbf{Statistical Analysis}

The researchers have hypothesized that the palonosetron group is better
than the granisetron group to achieve a complete response (CR) following
moderate emetogenic therapy for Osteosarcoma. Alternatively, a null
hypothesis was given by the researchers which advocates that there was
not statistical difference exists among the two groups. The level of
significance was adjusted to a p-value equal to 0.05. To test the null
hypothesis and compare the CR between the 2 groups, an independent
t-test (continuous variables) and \textsubscript{X}
\textsuperscript{2}test for categorical variables.

The statistical analysis was carried out using IBM SPSS software version
21. The univariate analysis was carried out to evaluate the risk factors
associated with emesis, and the frequency distribution was done for the
various demographic factors considered and other clinical parameters in
the study. The relative risk was measured to evaluate the risk between
the two groups administered Palonosetron and Granisetron. The chi-square
test of association was done to evaluate the association of the response
to antiemetic prophylaxis for the study groups. The statistical analysis
was carried out at a 95\% confidence level with the level of
significance at 0.05, i.e., p\textless{}0.05.

\textbf{RESULTS:}

The study's sample size was 228 patients, and they were randomly
allocated to group I, i.e., Palonosetron and Granisetron, i.e., group
II. A total number of 28 patients were excluded from the study, and 200
were eligible for the assessment.

Essentially, the distribution of all variables in the two groups was
balanced. These 200 patients obtained 604 blocks of chemotherapy.

Figure 1presents the flow diagram for patient recruitment and selection.

Among the 200 subjects equally distributed in the two groups and
administered palonosetron and Granisetron, there were 68\% males and
32\% females in group I and 64\% males and 36\% females in group II. The
mean age in group I was 10.2\selectlanguage{ngerman}±2.8 years, and group II was 10.5±1.9. There
were 37\% patients less than 10 years and 63\% were above 10 years of
age in group I, while group II had 39\% patients less than 10 years and
61\% patients more than 10 years of age. The rescue dose of
dexamethasone was given to 17\% of patients in group I and 28\% in group
II (\emph{Table 1).}

The complete response (CR) was seen in 83\% of patients in group I,
while 72\% showed complete response (CR) in group II which was
statistically significant, i.e., p\textless{}0.05. The relative risk was
0.65, i.e., the risk of vomiting was 0.65 times less in group I than
group II, i.e., p\textless{}0.05, which was statistically significant
(\emph{Table 2).}

The relative risk of breakthrough vomiting was lesser in the
Palonosetron arm across all chemotherapy cycles than the Granisetron
arm, i.e., p\textless{}0.05, which was statistically significant
(\emph{Table 3).}

The rescue medicine, dexamethasone, was the only statistically
significant predisposing factor as the p\textless{}0.05. The other
factors like gender, age, and type of Osteosarcoma were not
statistically significantly associated with emesis (\emph{Table 4).}

Ten patients (2 in Palonosetron arm and 8 in the Granisetron arm) had
headaches, and 6 patients (three in each arm) had constipation requiring
laxatives in the first to-study chemotherapy cycle. Similarly, 14
patients had abdominal pain (8 in the Palonosetron group and 6 in the
Granisetron group), and 10 patients had diarrhea (4 in the Palonosetron
arm and 6 in the Granisetron arm). These were considered related to the
drug by the treating physician. There were no serious adverse events
associated with both drugs and none that required discontinuation owing
to these events.

\textbf{Discussion}

The prime reason behind this cohort study was to compare single-dose
palonosetron with Granisetron for CINV after the treatment of
osteosarcoma in pediatric patients. The outcomes of this study suggest
the confirmation of the alternate hypothesis, i.e., there was a
significant difference among the groups for complete response and
relative risk of breakthrough emesis (p \textless{} .05), because the
group I demonstrated a substantial downside incidence of vomiting and
decreased risk of breakthrough vomiting with group II.

The incidence of complete response in group I and group II were 83\% and
72\% (p\textless{}0.05), respectively, and the risk of breakthrough
vomiting in group I was 0.65 lesser than group II (p\textless{}0.05) at
24 hours of follow-up. Similarly, the alternate hypothesis was valid for
a number of rescue medications, i.e., a significant difference exists
among group I and group II (p\textless{}0.05).

Based on the end results, the use of palonosetron is warranted in the
treatment of moderately emetogenic CINV in the treatment of osteosarcoma
of pediatric patients is warranted and could be associated with a
decreased risk of undesirable side effects, such as breakthrough
vomiting in the post-operative period and inconvenience caused by it to
the patients and parents.

The most annoying adverse effects of chemotherapy are nausea and
vomiting, especially in pediatric patients with osteosarcoma having
moderately emetogenic therapy.

Due to the multiple adverse effects of chemotherapeutic agents, a
combination of antiemetic agents must be tested, such as stimulating the
dopamine D2 receptor in the chemoreceptor trigger zone (CTZ) and binding
of the neurokinin-1 (NK-1) receptor with substance P in the postrema
area\textsuperscript{9,19}.

Although a corticosteroid's addition improves the potency of 5-HT3
receptor antagonists against CINV in different clinical trials, the best
standard single-dose treatment of 5-HT3 receptor antagonists for
pediatric emesis has not been demonstrated, particularly in the acute
chemotherapy phase, i.e., the first 24 hours. Few studies have reported
the potency of the dopamine D2 receptor antagonist for the prevention of
acute emesis\textsuperscript{9}; however, the guidelines for the
prevention of CINV due to faults in the study's design do not consider
these regimens.

Although a 5-HT3 receptor antagonist has been delivered multiple times
to control acute CINV in past clinical trials, particularly randomized
clinical trials, superiority to single-dose prechemotherapy
administration has not been shown\textsuperscript{10}. Contemporary
literature indicates that a 5-HT3 receptor antagonist, steroid, and NK-1
receptor antagonist\textsuperscript{10} are the most common practice for
blocking nausea and vomiting initiated by strongly or moderately
emetogenic chemotherapy\textsuperscript{9}.

Palonosetron interacts with the 5-HT3 receptor competitively while
ondansetron and Granisetron exhibit strict competitive anti-competitive
interactions. The dual activity of Palonosetron in the 5-HT3- receptor
is believed to increase the inhibitory effect on the primary receptor
because alosteric interactions can induce receptor conformation
differences. The dual action of the Palonosetron on the 5-HT3-receptor
is expected at the primary receptor bunding point to trigger an enhanced
inhibitor effect\textsuperscript{9}.

CINV, whether it is delayed or acute, palonosetron was found to be safer
and potent enough for the prevention of CINV in adults with fixed doses.
However, there was no consensus on using palonosetron in fixed doses in
pediatric patients receiving chemotherapy for various malignancies.
Recently, POGO, ESMO, and MASCC guidelines were released on the
inclusion of Palonosetron for pediatric patients receiving MEC and
HEC\textsuperscript{20,21}.

In the present study, a complete response of 83\% was seen in group I,
whereas a complete response of 72\% was seen in group II during the
first on-study cycle of chemotherapy.

At all intervals except zero-two, the Palonosetron mean adjusted MANE
scores were significantly lower (p\textless{}0.001*). The adjusted MANE
scale makes these symptoms sensitive and easy to relate to pediatric
patients, even when they are treated as outpatients. In a similar study,
for the granisetron and metoclopramide plus dimenhydrinate classes, the
proportion of all chemotherapy treatments provided to patients with a
full response (not more than one episode of vomiting) was 80\% and
27.5\%, respectively (p \textless{} 0.001).

Moreover, the current study's finding was in accordance with the
previous studies where the rate of CR of palonosetron was found to be
between 60-94\%,\textsuperscript{15, 21-27}. This was attributed to the
receptor binding proposition property of palonosetron. Furthermore,
long-lasting effects on receptor-ligand binding and functional responses
to serotonin can be associated with this sort of receptor interaction.
Palonosetron was found to be effective and safe.

In certain studies, age, gender, type of tumor, emetogenicity of the
regimen, and choice of prophylactic agents have been shown to influence
the response rate\textsuperscript{15, 18-22}. However, in the present
study, factors like age, gender, treatment regimen, and the number of
rescue medications were risk factors for predicting CR during the
overall phase. Moreover, it was found that Dexamethasone was the only
statistically significant predisposing risk factor (p\textless{}0.05).
The other factors like gender, age, type of osteosarcoma, and treatment
regimen were not statistically significantly associated with emesis.

This study's major strength was that a fixed dose of palonosetron was
used for pediatric patients who underwent MEC especially designed for
osteosarcoma of children, and these dosages were based on BSA and
bodyweight of the child. However, these parameters were in contrast with
other researchers who advocated using a single fixed dose of
palonosetron regardless of the BSA and bodyweight of the
child\textsuperscript{14-15}. Secondly, the modified MANE score was
followed, specially designed for the pediatric group to evaluate the
CINV more effectively. Thirdly, this study was performed exclusively for
pediatric patients who underwent MEC according to the POGO guidelines
for osteosarcoma.

This randomized clinical trial has several limitations. Firstly, this
was a single-center study with a smaller sample size to establish
palonosetron's superiority over granisetron. Large multicenter trials
are needed to lead to a clinically meaningful difference. Secondly, the
potency of the palonosetron needs to be investigated in other pediatric
patients with other malignancies undergoing MEC or HEC chemotherapy so
that CINV can be controlled more effectively and improve their quality
of life. Thirdly, the present study was limited to the acute phase of
the CINV, i.e., the first 24 hours, and it has not explored the response
rate in the delayed phase of CINV.

\textbf{Conclusion:}

Palonosetron seems to be safe and potent in pediatric patients with
osteosarcoma in preventing CINV in a fixed dose of 10\selectlanguage{greek}µ\selectlanguage{english}g/kg. It is quite
a resourceful drug alone in controlling CINV with minimal requirement of
rescue medications. Furthermore, it could be helpful in developing
nations with limited resources.

\textbf{Abbreviations: CNIV: Chemotherapy-induced nausea and vomiting;
MEC: moderate emetogenic chemotherapy; HEC: High emetogenic
chemotherapy.}

\textbf{Declarations:}

Ethics approval and consent to participate

All procedures performed in studies involving human participants were in
accordance with the ethical standards of the institutional and/or
national research committee of the Chengdu Jinniu District People's
Hospital and Ya'an People's Hospital. And comply with the 1964 Helsinki
Declaration and its later amendments or comparable ethical standards.
The written informed consent was taken from all the patients.

Consent to publish: Not Applicable

Availability of data and materials: The datasets used and/or analyzed
during the current study are available from the corresponding author on
reasonable request.

Competing interests: The authors declare that they have no competing
interests

Funding: No Funding was received.

Authors' Contributions: ZL has designed the concept; CL, Data
acquisition; XW drafted the manuscript; PL and YL literature search; JL
and SR Final proof reading and editing. All Authors read and approved
the manuscript before submission.

Acknowledgements: None Declared.

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\end{enumerate}

\textbf{Figure Legend:}

\textbf{Figure 1: Illustrates the patient recruitment and selection.}\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/Fig-1/Fig-1}

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