Cross-cultural Adaptation and Validation of the Pediatric Chemotherapy-induced Neuropathy (P-CIN) for Chinese Pediatric Oncology Patients: A Multi-center Study
Conditions: Pediatric Cancer
Sponsor: The Hong Kong Polytechnic University

 
 
 
 
THE HONG KONG POLYTECHNIC UNIVERSITY 
 
RESEARCH DEGREE PROPOSAL 
 
 
 
1. 
Name of Proposed Chief Supervisor (if applicable): 
 
Prof. HO, Eva Ka Yan 
 
 
2. 
Project Title: 
 
Cross-cultural adaptation and validation of the pediatric chemotherapy-induced neuropathy 
(P-CIN) for Chinese pediatric oncology patients: A methodological and descriptive study  
 
 
3. 
Project Objectives: (Purpose of proposed investigation) 
This study aims to cross-culturally adapt and validate the original P-CIN for Chinese 
pediatric oncology patients. 
4. 
Scope and Background of Research: 
(Please identify key issues/problems to be addressed) 
 
Chemotherapy-induced peripheral neuropathy (CIPN), one of the most common adverse 
effects of neurotoxic chemotherapeutic agents, has been defined as a single, or a 
combination of motor, sensory and autonomic impairments that results from the damage, 
inflammation, and degeneration of peripheral nerve fibers. CIPN is a marker of multiple 
serious consequences, including decreased physical activity, falling, pain, fatigue, sensory 
and motor deficits, poorer quality of life, mortality, and psychological distress. The 
development of CIPN may lead to dose reduction, interruption or cessation of the 
chemotherapy treatment, which can impact the treatment efficacy and decreasing their 
survival.[1] Clinical abnormalities attributable to CIPN including sensory and motor 
neuropathy, functional deficits and CIPN pain are common in pediatric oncology patients 
and can persist into adulthood. Systematic review has reported that CIPN incidence in 
pediatric patients varies from 2.8% to 100% depending on the assessment measures.[1] 
Therefore, it is crucial to accurately identify and assess CIPN at the earliest possible stage. 
The severity of CIPN may fluctuate during treatment courses, the overall trend tends to 
show increasing severity, even as dose intensity and treatment frequency may decrease over 
time. In addition, CIPN may last for months to several years after the end of anticancer 
chemotherapies.[2] Thus, early identification is imperative for the intervention 
implementation that can improve long term care and relieve disease burden. There is limited 
evidence to a feasible, simple and accurate assessment measure for pediatric CIPN and 

 
numerous CIPN measures have been developed. According to our previous updated 
systematic review, the Total Neuropathy Score (TNS) variants including Pediatric-modified 
Total Neuropathy Score (Ped-mTNS) and Total Neuropathy Score-Pediatric Vincristine 
(TNS-PV), as an objective measure, is the most widely used assessment measure of CIPN. 
However, both have limitations associated with the pediatric oncology patients in clinical 
settings. The Ped-mTNS includes many physical examinations, such as light touch 
sensation, pin sensibility, vibration sensation, and strength and deep tendon reflexes. These 
measurements are not only the time-consuming and clinical space using for assessments but 
also induce discomforts associated with some testing procedures, e.g., pin prick. The TNS-
PV is only for assessing CIPN severity in children taking Vincristine. In addition, a trained 
registered clinician performs these two measurements. Hence, the Ped-mTNS and TNS-PV 
maybe not feasible to be used widely in the clinical settings in China. Other pediatric CIPN 
assessment measures, the Functional Assessment of Cancer Therapy-Gynecologic Oncology 
Group-Neurotoxicity (FACT-GOG-Ntx) only validated in pediatric patients with Hodgkin 
lymphoma and the Bruininks-Oseretsky Test of Motor Proficiency version 2 (BOT-2) only 
used to assess the motor skills in pediatric patietns with CIPN. Thus, these assessment 
measures cannot comprehensively evaluate the CIPN severity in pediatric oncology patients. 
Furthermore, the few existing pediatric CIPN measures are not well validated.  
There is a critical need for pediatric CIPN measures. The Pediatric Chemotherapy-
Induced Neuropathy (P-CIN), which includes the core elements of CIPN symptoms, was 
specially developed for assessing CIPN severity in pediatric patients. The P-CIN consists of 
13 self-reported items using age-appropriate language and graphics without involving 
clinician examination, and it takes only a few minutes and can be completed by pediatric 
patients themselves or their parents’ assistance. The P-CIN can be feasibly applied by 
pediatric oncology patients themselves or their parents in China where healthcare service 
space and service time lacking and short-staffing of pediatricians. In turn, the P-CIN helps in 
the early identification of CIPN in pediatric oncology patients and evaluate the effectiveness 
of an intervention.  
The original P-CIN was developed in 2021 and the first electronic CIPN patient reported 
outcome measure (PROM). The European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire - Chemotherapy-Induced Peripheral Neuropathy 20-
item sub-scale (EORTC QLQ-CIPN20) served as a model when developing P-CIN specific 
items, and further validated in pediatric patients with CIPN in the United States. The P-CIN 
contains four items to rate CIPN subjective symptons - numbness and tingling in the hands 
and feet. If pediatric patients reported experiencing these symptoms, they were directed to 
answer four additional questions regarding painful numbness and tingling. Five items were 
used to quantify CIPN functional deficits experienced such as picking up a penny or heel-

 
walking. Evidence indicates that the P-CIN is reliable and valid in United States contect. 
However, there is a lack of measures for CIPN assessment in China after a systematic search 
and the P-CIN has never been validated for use with pediatric patients with CIPN in China. 
This lack of validated assessment measures preclude understanding the severity of the CIPN 
and hinders the development of appropriate interventions to promote CIPN symptoms 
managment. On the other hand, a culturally sensitive assessment is critical in defining, 
identifying, describing and understanding the signs and symptoms of CIPN[3] as the culture 
and language can impact the expression and interpretation of symptom characteristics.[4] 
For instance, in East Asia, terms like “burning” were never used, with patients may report 
“numbness”.[4, 5] Due to the aforementioned concerns, it may be not appropriate to apply 
the P-CIN to assess the CIPN severity of pediatric patients before cross-cultural adaptation 
and validation. It is essential that assessment measures are appropriately adapted and 
validated in a new cultural setting to ensure valid and reliable measures. 
 
 
 
5. 
Research Methodology: 
 
Study design 
This methodological, descriptive study will be conducted in Shenzhen, Zhengzhou, 
Shanghai, mainland China, from November 2024 to April 2025. Pediatric oncology patients 
will be enrolled from inpatient ward in Shenzhen Children’s Hospital, Henan Cancer 
Hospital and Shanghai Children’s Medical Center.  
This study will follow the Strengthening the Reporting of Observational Studies in 
Epidemiology (STROBE) reporting guideline.  
Data collection 
Research team contacts with the dean of Nursing Department of each site. After 
approval, the name list of pediatric oncology patients receiving the neurotoxicity agents will 
be provided. Well-trained registered nurses will identify potentially eligible participants 
through checking the medical records and confirm the eligibility based on the inclusion and 
exclusion criteria. In addition, the registered nurse will approach these potential participants 
and ask all children and their parents who accompanied children for hospitalization in 
inpatient clinic or medical consultation in the outpatient clinic, and introduce the study. The 
information sheet including research purpose, procedures, confidentiality measures, and 
their rights as participants will be provided. All pediatric patients agree to participate the 
study will invite to sign an informed consent form with their legal guardian in accordance 
with the Declaration of Helsinki. We assure participants’ responses would remain 
confidential. After obtaining written consent, each child will be asked to complete the 
questionnaire independently. For those children who are unable to self-report, parents will 

 
be asked to assist them in completing the questionnaire. To assess test-retest reliability, a 
sample of 50 children will be randomly selected to respond by phone to the P-CIN 2 weeks 
later.  
Participants 
Eligible participants are children 6 to 18 years of age[6] who (1) diagnosed with cancer, 
(2) had received or were currently receiving neurotoxic chemotherapy drugs (e.g., 
Vincristine, Cisplatin, Carboplatin, Oxaliplatin, Paclitaxel, Docetaxel, Ixabepilone, 
Bortezomib, Thalidomide), (3) children’s, and parents’ willingness to participate in the study 
voluntarily, (4) able to communicate, read, and write in Chinese without significant hearing 
and vision problems to ensure they understand our interview. The exclusion criteria are 
children who (1) diagnosis of a tumour involving the central nervous system (CNS) cancer, 
(2) diagnosis of relapsed cancer or secondary cancer, (3) in the terminal period, (4) plan to 
receive multiple cancer treatment (e.g., radiotherapy, immunotherapy), (5) suffering from 
other neuromuscular diseases (e.g., traumatic brain injury and cerebral palsy), (6) have a 
developmental deficit (e.g., Down’s syndrome, other chromosomal disorders), (7) suffering 
from psychiatric diseases or using antipsychotic drugs, (8) severe cardiovascular system 
diseases and severe liver and kidney function abnormalities, (9) peripheral neuropathy 
symptoms caused by diabetes, genetic diseases, spinal cord injury, or alcoholism, (10) have 
other neuromuscular disorders (e.g., traumatic brain injury, cerebral palsy). 
Sample size 
Although there is no golden standard for the sample size calculation for validation study 
in nursing research, the recommended sample size for factor analyses is between 150 to 
180.[7] In addition, the Exploratory Factor Analysis (EFA) and Confirmatory Factor 
Analysis (CFA) must be conducted on different datasets.[8] We therefore determined to 
recruit 300 pediatric oncology patients in our validation study.  
CIPN measurements 
Pediatric chemotherapy-induced peripheral neuropathy (P-CIN)  
It was originally developed for children ≥ 6 years old who had received or were 
receiving neurotoxic chemotherapy and reported peripheral neuropathy to quantify 
numbness and tingling in the hands and feet and the functional deficits in the past two to 
three days[6]. The P-CIN comprises 13 items, with eight items to rate CIPN symptoms in 
the hands and feet and five items to rate the difficulty of performing functional tasks, e.g., 
standing on one leg and closing eyes for 15 seconds[6]. Each item is rated using a 6-point 
faces scale. The total score ranges from 0 to 65 with higher scores indicating more severe 
CIPN[6].  
Clinician diagnosis of pediatric CIPN 

 
In our previous systematic review of assessment measures for CIPN among pediatric 
oncology patients(reference), it was concluded that the method of choice for assessing 
pediatric CIPN was combination of subjective and objective assessment measures. The 
diagnosis of pediatric CIPN in our study was established solely if the abnormal Nerve 
Conduction Studies (NCS) criteria, NCI-CTCAE score ≥ 2, and clinical consultation 
(including the chemotherapeutic drugs used, cumulative doses, and clinical characteristics 
and time course of neuropathy symptoms) of CIPN symptoms were simultaneously observed 
based on the consensus of pediatric neurologists in the three hospitals.   
(1) NCS criteria:  
For the NCS, the motor responses of median and ulnar nerves in the bilateral upper limb and 
the fibular and tibial nerves in the bilateral lower limb and the sensory responses of median 
and ulnar nerves in the bilateral upper limb and sural and medial plantar nerves in the 
bilateral lower limb were recorded. Nerve conduction parameters recorded included distal 
motor latency (DML), peak to peak sensory nerve action potential amplitude, motor nerve 
conduction velocity (MNCV), and sensory nerve conduction velocity (SNCV). Pediatric 
individuals who are at least 4 years old are deemed to have achieved the NCS reference 
ranges typically seen in adults.[14] The reference values for each nerve were according to 
reference limits of NCS parameters for Chinese subjects from Fong et al. as follows:   
 Table 1 Reference lists of NCS parameters for Chinese subjects and range in all subjects  
Parameters  
Reference limits 
Range all subjects 
Chinese 
Motor 
 
 
Median 
 
 
DML (ms) 
4.1 
2.5-4.3 
Amplitude (mV) 
7.3 
7.0-17.9 
MNCV (m/s) 
52 
50-65 
Ulnar 
 
 
DML (ms) 
3.0 
2.0-3.1 
Amplitude (mV) 
6.4 
6.3-15.6 
MNCV (m/s) 
53 
52-68 
Fibular 
 
 
DML (ms) 
4.2 
2.6-4.4 
Amplitude (mV) 
3.3 
2.4-10.9 
MNCV (m/s) 
43 
42-58 
Tibial 
 
 
DML (ms) 
3.9 
2.4-4.3 

 
Amplitude (mV) 
7.5 
5.1-26.7 
MNCV (m/s) 
41 
38-57 
Sensory 
 
 
Median 
 
 
Amplitude (mV) 
7 
5-34 
SNCV (m/s) 
48 
45-67 
Ulnar 
 
 
Amplitude (mV) 
6 
2-22 
SNCV (m/s) 
48 
46-66 
Sural 
 
 
Amplitude (mV) 
6 
2-34 
SNCV (m/s) 
42 
38-61 
Medial plantar 
 
 
Amplitude (mV) 
3 
2-37 
SNCV (m/s) 
40 
26-36 
 
NCS parameters including distal latencies, amplitudes, and velocities were considered 
abnormal, if values were more than 2.0 standard deviation of the normal reference values. In 
our study, the pediatric neurologist considered CIPN as the presence of abnormal NCS 
parameters in two or more nerves.  
(2) National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE) Version 5.0 
The CTCAE (version 5.0) consists of over 330 items scoring adverse events (AE) due to 
cancer treatment divided into 26 different categories. Grade refers to the severity of the 
adverse events. Possible grades range from grade 1 (Mild, asymptomatic or mild symptoms, 
clinical or diagnostic observations only), grade 2 (Moderate; minimal, local or noninvasive 
intervention indicated; limiting age-appropriate instrumental Activities of Daily Living 
(ADL)), grade 3 (Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL), grade 4 (Life-threatening consequences; urgent intervention indicated) to grade 5 
(Death related to AE).  The NCI-CTCAE items used for the assessment of CIPN are 
peripheral sensory neuropathy, peripheral motor neuropathy, constipation, diarrhea, and 
neuralgia due to the sensory, motor and autonomic symptoms of pediatric CIPN[15]. The 
maximum CTCAE sum score of these 5 items is 22. Participants with a total score of 2 or 
higher are considered to have CIPN[16, 17].  
Wong-baker FACES Pain Rating scale 

 
This scale combines pictures and numbers to enable the user to rate pain which demonstrates 
six faces with increasing degree of pain from left to right, where each face is rated on a scale 
of 10 in which 0 indicated no hurt, 2 indicated hurts a little, 4 indicated hurts little more, 6 
indicated hurts, even more, 8 indicated hurts a whole lot, 10 indicated hurts worst[18]. It can 
be used for children over the age of 3, and for adults[18]. This scale has adequate 
psychometric properties and it is easy and quick to[19] and it has been validated among 
Chinese children with acute fever[20].   
Chinese version of the Pediatric Quality of Life Inventory (PedsQL) Cancer Module 
The PedsQL Cancer Module will be used to assess the participants’ QoL. This scale contains 
27 items grouping into eight subscales including (1) pain and hurt, (2) nausea, (3) procedural 
anxiety, (4) treatment anxiety, (5) worry, (6) cognitive problems, (7) perceived physical 
appearance, and (8) communication. There are parallel and identical versions for pediatric 
patients (young child: 5-7 years old, child: 8-12 years old, and adolescent: 13-18 years old) 
and parents (toddler: 2-4 years old plus the above three age groups). The participants rated 
how frequently a particular problem occurred in the past month, using a three-point Likert 
scale (0 = Never, 2 = Sometimes, 4 = Almost always) for children 5-7 years old and a five-
point Likert scale (0 = Never, 1=Almost never, 2=sometimes, 3=often, 4 = Almost always) 
for children of 8-18 years old and for the parents of patients of all ages. Each item score will 
be reversely scored and then linearly transformed into 0-100 scale (0 = 100, 1 = 75, 2 = 50, 3 
= 25, 4 = 0). The scale is the average of the total item scores. Higher scores represent better 
quality of life (QoL). The psychometric properties of the Chinese version of the scale have 
been well-examined[21]. This scale has been demonstrated as a valid and reliable tool in 
assessing QoL for Hong Kong Chinese adolescent with cancer[21].  
Psychometric evaluation 
Reliability assessment 
Reliability refers to the ability of a instrument to determine that a measurement yields 
reproducible and consistent results. Three important reliability criteria are: internal 
consistency, and stability. Internal consistency shows if all subparts of an instrument 
measure the same characteristic. Cronbach’s alpha coefficient and the corrected item-total 
correlation will be used to assess internal consistency of the P-CIN. Stability estimates the 
consistency of measurement repetition and can be performed using test-retest method. The 
time span between measurements will influence the interpretation of test-retest reliability; 
therefore, the time span from 10 to 14 days is considered adequate for the test and retest. A 
group of 50 children will be randomly selected for the achievement of statistical significance 
for an alpha value is 0.05 and with a power of 0.90.[22] The intraclass correlation coefficient 
(ICC) is one of the most used tests to estimate continuous variables stability, as it takes into 

 
account the measurement errors.  
Validity assessment 
Validity refers to an instrument measures exactly what it proposes to measure. Validity can 
be assessed in different forms such as content validity, convergent validity, criterion 
validity, and construct validity. Content validity can be defined as the extent to which an 
assessment tool accurately and fully reflects the concept being measured. The Delphi 
technique will be used to establish the content validity of the P-CIN. We will obtain the 
opinions of 10 experts through a structured questionnaires delivered two iterations until 
consensus will be reached.  Convergent validity is the degree to which scores on a measure 
associate with scores on other measures that are intended assess similar constructs. Pain 
level, self-reported quality of life are CIPN-related concepts that have been identify pediatric 
oncology patients with CIPN risk[15]. Therefore, convergent validity will be explored using 
well-established CIPN-related measurements, namely, (1) the Wong-baker FACES pain 
rating scale to assess levels of pain; and (2) the Pediatric Quality of Life Inventory (PedsQL) 
Cancer Module to determine level of quality of life with the help of the Spearman’s  
correlation coefficient (r). Criterion validity is the relation between the score of a certain 
instrument and some external criterion. This criterion has to be a widely accepted measure, 
with the same characteristics of the assessment tool. Criterion validity will be evaluated 
using the pediatric neurologists’ CIPN diagnosis as a reference criterion. Spearman’s 
correlation coefficient (r) will be calculated to evaluate the correlations between the P-CIN 
and the CIPN diagnosis. Using diagnostic testing to determine the presence or absence of the 
CIPN is essential. The ROC curve aims to find an optimal cut-off value with the best CIPN 
diagnostic performance. Additionally, the ROC curve is utilized to evaluate the overall 
diagnostic performance of a test and to compare multiple diagnostic tests.[23] The area 
under the curve (AUC) will be used to measure the accuracy of diagnostic test. Generally, an 
AUC ≥ 0.8 is considered acceptable. Youden statistic (calculated as sensitivity + specificity 
- 1) was used to determine the optimal cut-off value.[24] The point at which this value is 
maximized is determined as the optimal cut-off value.[24]  
Factor analysis  
Factor analysis is valuable for evaluating sampling adequacy, internal consistency, factor 
rotation, factor identification, item retention, and other analytical processes. Exploratory 
Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA) are two common 
techniques used in scale adaptation studies. EFA will be conducted to determine the number 
of  underling latent factors and the structure of items. Following the execution of the EFA, a 
measurement model will be applied to examine CFA using three critical results: parameter 
estimates, fit indices, and modification indices. In our study, the sample will be randomly 

 
split into two halves (half for EFA and half for CFA).  
EFA will be performed by using the SPSS software, version 29.0 for Mac (SPSS Inc., 
Chicago, IL, United States). Suitability of the matrix for conducting the EFA will test using 
the Kaiser-Meyer-Olkin (KMO) test and Bartlett’s test of sphericity. The KMO sampling 
adequacy test will be deemed adequate if the value was greater than 0.6. A significant level 
of P-value < 0.05 of Bartlett’s Test of Sphericity indicates EFA can be performed. The 
number of factors that should be retained in the model was determined using eigenvalues 
and scree-plot. All factors with eigenvalues above one was retained according to the 
Kaiser’s criteria. In addition, factors corresponding to data points lying above the point of 
inflexion of the scree-plot were also retained. Principal component analysis will be 
performed to conduct an additional factor analysis, which helps determine the loadings for 
every factor selected. Analyze the factor composition and the factor loading of each item on 
the corresponding factor, and delete items with factor loading < 0.50. Cumulative variance 
contribution rate be above 50%. We will apply the varimax type of rotation. In addition, 
varimax rotation will be chosen since it minimizes factor complexity while, at the same 
time, maximizing the variance of factor loadings. 
Following the execution of the EFA, CFA will be accomplished using IBM SPSS 
Amos, version 29.0. CFA will be used to establish and validate the constrcut validity of the 
P-CIN. Maximum Likelihood was used as the estimation method. To evaluate the goodness 
of fit, the following statistical measures will be utilized: ratio of chi-square and degrees of 
freedom (2/df), root mean square residual (RMR), standardized root mean square residual 
(SRMR), goodness of fit index (GFI), comparative fit index (CFI), root mean square error of 
approximation (RMSEA).  
Feasibility  
Feasibility means percentage of children who completed the P-CIN independently. In this 
study, we use the item ‘Did the children need assistance by a parent or other adults to 
complete the survey?’  to evaluate the feasibility. 
Data analysis  
The IBM Statistical Package for the Social Sciences (SPSS, version 29.0, NY, USA) will be 
performed to conduct all statistical analyses. For demographic data, continuous variables are 
represented by mean (standard deviations), while categorical variables are shown as 
frequencies (percentages). For the psychometric data, Cronbach’s alpha coefficient and 
corrected item-total correlation will be used to assess internal consistency of the P-CIN. 
Cronbach’s alpha value higher than 0.70 is acceptable with the interpretation as follows: 
below 0.70 = poor; between 0.70 and 0.79 = fair; between 0.80 and 0.89 = good; and above 
0.90 = excellent.[25] Values for corrected item-total correlation can be explained as follows: 
values between 0 and 0.19 indicate that the item is not discriminating well, 0.2-0.39 indicate 

 
good discrimination, 0.4 and above indicate very good discrimination. Good internal 
consistency reliability is indicated by a Cronbach’s alpha coefficient ≥0.70 and item-total 
score correlations ranging from 0.30 to 0.70. The intraclass correlation coefficient (ICC) will 
be used to evaluate the test-retest reliability. For the results interpretation, minimum ICC 
values of 0.70 are considered satisfactory, values above 0.8 or 0.9 are often regarded as a 
sign of good or excellent test-retest reliability.[26] Concerning for the content validity, a 
scale with excellent content validity should be composed of I-CVIs of 0.78 or higher and 
UA -CVI/Ave-CVI of 0.8 and 0.9 or higher, respectively. Spearman’s correlation coefficient 
(r) will be performed to evaluate convergent validity. The correlation values for convergent 
validity are classified as follows: r=0, no correlation; r=0.10-0.29 (–0.10 to –0.29), 
negligible correlation; r=0.30-0.49 (–0.30 to –0.49), low positive (negative) correlation; 
r=0.50-0.69 (–0.50 to –0.69), moderate positive (negative) correlation; r=0.70-0.89 (–0.70 to 
–0.89), high positive (negative) correlation; r=0.90-1.00 (–0.90 to –1.00), very high positive 
(negative) correlation.[27] Spearman’s correlation coefficients equal to 0.70 or over are 
desirable. To determine criterion validity, Spearman’s correlation coefficient will be used. 
Concerning the effectiveness diagnostic test, receiver operating characteristic (ROC) curve 
analysis will be performed. The interpretation of the AUC as follows: fail (0.5 ≤ AUC < 
0.6), poor (0.6 ≤ AUC < 0.7), fair (0.7 ≤ AUC < 0.8), good (0.8 ≤ AUC < 0.9), excellent (0.9 
≤ AUC). Youden’s Index will be used to calculate the optimal cut-off value.  Concerning 
the CFA, 2/df for value lower than 5 the fit is acceptable. RMR and SRMR: the lower the 
values, the better the fit. GFI and CFI values over 0.90 are considered a good fit (with a 
maximum value equal to 1). Reference value for the RMSEA between 0.05 to 0.08 mean the 
adjustment is good. Factor loading values above or close to 0.70 are better to explain the 
structure. As for the clinical feasibility, the P-CIN will be considered a practical tool for 
implementation in clinical practice settings if 80% or more of the children completed the 
questionnaire independently. 
Ethical considerations 
This study will not involve any invasive procedure, thus the chance of imposing physical 
harms on subjects is minimal. If the there is any adverse effects that happens during the data 
collection, the registered nurses will immediately stop and ask the participants whether they 
would like to continue or terminate the study. With parental consent, we will pass their 
contact to the head nurses of pediatric oncology ward  (our co-investigators). They will 
further assess the psychological well-being of the participants. If necessary, they will refer 
these participants to relevant medical personnel, e.g. doctors, clinical psychologists and/or 
social workers to follow-up. 
 
References 

 
1. Johnston W, Erdmann F, Newton R, Steliarova-Foucher E, Schüz J, Roman E: 
Childhood cancer: Estimating regional and global incidence. Cancer epidemiology 
2021, 71:101662. 
2. Beijers AJM, Vreugdenhil G, Oerlemans S, Eurelings M, Minnema MC, Eeltink CM, 
van de Poll-Franse LV, Mols F: Chemotherapy-induced neuropathy in multiple 
myeloma: influence on quality of life and development of a questionnaire to 
compose common toxicity criteria grading for use in daily clinical practice. 
Supportive Care in Cancer 2016, 24(6):2411-2420. 
3. Purser M, McMillan H, Johnston D: Chemotherapy-Induced Peripheral Neuropathy 
among Pediatric Oncology Patients. Pediatric Blood & Cancer 2013, 60:S50-S51. 
4. Kandula T, Park SB, Cohn RJ, Krishnan AV, Farrar MA: Pediatric chemotherapy 
induced peripheral neuropathy: A systematic review of current knowledge. Cancer 
Treat Rev 2016, 50:118-128. 
5. Bjornard KL, Gilchrist LS, Inaba H, Diouf B, Hockenberry MJ, Kadan-Lottick NS, 
Bowers DC, Dolan ME, Ullrich NJ, Evans WE, Ness KK: Peripheral neuropathy in 
children and adolescents treated for cancer. The Lancet Child & Adolescent Health 
2018, 2(10):744-754. 
6. Smith E M L , Kuisell C , Cho Y ,et al.Characteristics and patterns of pediatric 
chemotherapy-induced peripheral neuropathy: A systematic review[J].Cancer 
Treatment and Research Communications, 2021:100420. 
DOI:10.1016/j.ctarc.2021.100420. 
7. E.M. Lavoie Smith, L. Li, C. Chiang, et al., Patterns and severity of vincristine- 
induced peripheral neuropathy in children with acute lymphoblastic leukemia, J. 
Peripher. Nerv. Syst. 20 (2015) 37–46.  
8. L. Gilchrist, L. Tanner, Chemotherapy-induced peripheral neuropathy in non-cns 
cancers: comparison between diagnostic groups, Pediatr. Blood Canc. 61 (2014) 
S393.  
9. A.J. Lombardi, M.E. Sutton, G.M. Tiao, J.I. Geller, Vincristine-associated 
neurological morbidity in the treatment of hepatoblastoma, J. Pediatr. Hematol. 
Oncol. 37 (2015) e258–e263.  
10. Salat K, Furgala-Wojas A, Salat R: The Microglial Activation Inhibitor Minocycline, 
Used Alone and in Combination with Duloxetine, Attenuates Pain Caused by 
Oxaliplatin in Mice. Molecules 2021, 26(12). 
11. Triarico S, Romano A, Attina G, Capozza MA, Maurizi P, Mastrangelo S, Ruggiero 
A: Vincristine-Induced Peripheral Neuropathy (VIPN) in Pediatric Tumors: 
Mechanisms, Risk Factors, Strategies of Prevention and Treatment. Int J Mol Sci 
2021, 22(8). 
12. Uittenboogaard A, Neutel CLG, Ket JCF, Njuguna F, Huitema ADR, Kaspers GJL, 
van de Velde ME: Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy 
in Children with Cancer: A Systematic Review and Meta-Analysis. Cancers (Basel) 
2022, 14(3). 
13. Lazzerini M, Martelossi S, Magazzu G, Pellegrino S, Lucanto MC, Barabino A, 
Calvi A, Arrigo S, Lionetti P, Lorusso M et al: Effect of Thalidomide on Clinical 
Remission in Children and Adolescents with Ulcerative Colitis Refractory to Other 
Immunosuppressives: Pilot Randomized Clinical Trial. Inflamm Bowel Dis 2015, 
21(8):1739-1749. 
14. L. Rosca, V. Robert-Boire, J.-.F. Delisle, et al., Carboplatin and vincristine 
neurotoxicity in the treatment of pediatric low-grade gliomas, Pediatr. Blood Canc. 
65 (2018) e27351.  
15. Lin, M.J.; Paul, M.R.; Kuo, D.J. Severe neuropathic pain with concomitant 
administration of Vincristine and Posaconazole. J. Pediatr. Pharmacol. Ther. 2018, 
23, 417–420  
16. S. Dudeja, S. Gupta, S. Sharma, et al., Incidence of vincristine induced neurotoxicity 
in children with acute lymphoblastic leukemia and its correlation with nutritional 
deficiencies, Pediatr. Hematol. Oncol. 36 (2019) 344–351.  
17. P. Jain, S. Gulati, R. Seth, S. Bakhshi, G.S. Toteja, R.M. Pandey, Vincristine-induced 

 
neuropathy in childhood all (acute lymphoblastic leukemia) survivors: prevalence 
and electrophysiological characteristics, J. Child Neurol. 29 (2014) 932–937.  
18. S. Gomber, P. Dewan, D. Chhonker, Vincristine induced neurotoxicity in cancer 
patients, Ind. J. Pediatr. 77 (2010) 97–100.  
19. T.J. ajdyk, F.A. Boyle, K.S. Foran, et al., Obesity as a potential risk factor for 
vincristine-induced peripheral neuropathy, J. Pediatr. Hematol. Oncol. 42 (2020) 
e637–e640, https://doi.org/10.1097/MPH.0000000000001604. 
20. Kandula T, Farrar MA, Kiernan MC, et al. Neurophysiological and clinical outcomes 
in chemotherapy-induced neuropathy in cancer. Clin Neurophysiol 2017; 128: 1166–
75.  
21. F. Brigo, R. Balter, P. Marradi, et al., Vincristine-related neuropathy versus acute 
inflammatory demyelinating polyradiculoneuropathy in children with acute 
lymphoblastic leukemia, J. Child Neurol. 27 (2012) 867–874.  
22. H. Courtemanche, A. Magot, Y. Ollivier, et al., Vincristine-induced neuropathy: 
atypical electrophysiological patterns in children, Muscl. Nerv. 52 (2015) 981–985.  
23. S. Gomber, P. Dewan, D. Chhonker, Vincristine induced neurotoxicity in cancer 
patients, Ind. J. Pediatr. 77 (2010) 97–100.  
24. H. Kayiliog ̆lu, U. Kocak, D. Kan Karaer, et al., Association of cyp3a5 expression 
and vincristine neurotoxicity in pediatric malignancies in turkish population, 
J. Pediatr. Hematol. Oncol. 39 (2017) 458–462.  
25. E.M.L. Smith, L. Li, R.J. Hutchinson, et al., Measuring vincristine-induced 
peripheral neuropathy in children with acute lymphoblastic leukemia, Canc. Nurs. 36 
(2013) E49–E60. 
26. F. Brigo, R. Balter, P. Marradi, et al., Vincristine-related neuropathy versus acute 
inflammatory demyelinating polyradiculoneuropathy in children with acute 
lymphoblastic leukemia, J. Child Neurol. 27 (2012) 867–874.  
27. C.G. Tay, V.W.M. Lee, L.C. Ong, K.J. Goh, H. Ariffin, C.Y. Fong, Vincristine-
induced peripheral neuropathy in survivors of childhood acute lymphoblastic 
leukaemia, Pediatr. Blood Canc. 64 (2017) e26471.  
28. S. Lieber, M. Blankenburg, K. Apel, G. Hirschfeld, P. Herna ́iz Driever, T Reindl, 
Small-fiber neuropathy and pain sensitization in survivors of pediatric acute 
lymphoblastic leukemia, Eur. J. Paediatr. Neurol. 22 (2018) 457–469.  
29. McCrary, J. MattGoldstein, DavidBoyle, FrancesCox, KeithGrimison, PeterKiernan, 
Matthew C.Krishnan, et al., Optimal clinical assessment strategies for chemotherapy-
induced peripheral neuropathy (CIPN): a systematic review and Delphi 
survey[J].Supportive care in cancer. 2017, 25(11). 
30. Cheng H L , Molassiotis A .Longitudinal validation and comparison of the Chinese 
version of the European Organization for Research and Treatment of Cancer Quality 
of Life‐Chemotherapy‐Induced Peripheral Neuropathy Questionnaire (EORTC 
QLQ‐CIPN20) and the Functional Assessment of Cancer‐Gynecologic Oncology 
Group‐Neurotoxicity subscale (FACT/GOG‐Ntx)[J].Asia‐Pacific Journal of 
Clinical Oncology, 2019, 15. 
31. Klafke N, Bossert J, Kröger B, Neuberger P, et al., Prevention and Treatment of 
Chemotherapy-Induced Peripheral Neuropathy (CIPN) with Non-Pharmacological 
Interventions: Clinical Recommendations from a Systematic Scoping Review and an 
Expert Consensus Process. Med Sci (Basel). 2023 Jan 30;11(1):15. 
32. Tamburin S, Park SB, Schenone A, et al. Rehabilitation, exercise, and related non- 
pharmacological interventions for chemotherapy-induced peripheral neurotoxicity: 
systematic review and evidence-based recommendations. Crit Rev Oncol Hematol. 
2022;171, 103575. https://doi.org/10.1016/j.critrevonc.2021.103575.  
33. Toth MJ, Voigt TB, Tourville TW, Prior SM, Guigni BA, Schlosberg AV, Smith IB, 
Forest TJ, Kaufman PA, Wood ME, Rehman H, Dittus K. Effect of neuromuscular 
electrical stimulation on skeletal muscle size and function in patients with breast 
cancer receiving chemotherapy. J Appl Physiol (1985). 2020 Jun 1;128(6):1654-
1665. doi: 10.1152/japplphysiol.00203.2020. Epub 2020 May 7.  

 
34. Yan D, Vassar R. Neuromuscular electrical stimulation for motor recovery in 
pediatric neurological conditions: a scoping review. Dev Med Child Neurol. 2021 
Dec;63(12):1394-1401. doi: 10.1111/dmcn.14974.  
35. Wang TS, Wang SF, Song WD, Tang ZC, Wei W, Wang GK. Neuromuscular 
electrical stimulation for cancer pain in children with osteosarcoma: A protocol of 
systematic review. Medicine (Baltimore). 2020 Jul 24;99(30):e21311.  
36. Kimura T, Kaneko F, Iwamoto E, Saitoh S, Yamada T. Neuromuscular electrical 
stimulation increases serum brain-derived neurotrophic factor in humans. Exp Brain 
Res. 2019 Jan;237(1):47-56. doi: 10.1007/s00221-018-5396-y. Epub 2018 Oct 10. 
PMID: 30306243. 
37. Kandula T, Farrar MA, Cohn RJ, Carey KA, Johnston K, Kiernan MC, Krishnan AV, 
Park SB. Changes in long term peripheral nerve biophysical properties in childhood 
cancer survivors following neurotoxic chemotherapy. Clin Neurophysiol. 2020 
Apr;131(4):783-790. doi: 10.1016/j.clinph.2019.12.411. 
38. Wang J, Jacobs S, Dewalt DA, Stern E, Gross H, Hinds PS. A Longitudinal Study of 
PROMIS Pediatric Symptom Clusters in Children Undergoing Chemotherapy. J Pain 
Symptom Manage. 2018 Feb;55(2):359-367.  
39. Streckmann, F., Kneis, S., Leifert, J.A., Baumann, F.T., Kleber, M., Ihorst, G., et al., 
2014. Exercise program improves therapy-related side-effects and quality of life in 
lymphoma patients undergoing therapy. Ann. Oncol. 25, 493–499.