Efficacy differences of electroacupuncture with single acupoint or matching acupoints for chemotherapy-induced nausea and vomiting: study protocol for a randomized controlled trial
Chen et al. Trials
Efficacy differences of electroacupuncture with single acupoint or matching acupoints for chemotherapy-induced nausea and vomiting: study protocol for a randomized controlled trial
Bo Chen 0 1 3
Yang Guo 0 2
Xue Zhao 0 1 3
Li-li Gao 1 3
Bo Li 1 3
Tian-yi Zhao 1 3
Qi-wen Zhang 1 3
Jin-xing Zou 1 3
Ming-yue Li 4
Yong-ming Guo 1 3
Yi Guo 1 3
Xing-fan Pan 1 3
0 Equal contributors
1 Acu-moxibustion and Tuina Department of Tianjin University of Traditional Chinese Medicine , Tianjin 300193 , China
2 The First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine , Tianjin 300193 , China
3 Acupuncture Research Center of Tianjin University of Traditional Chinese Medicine , 88 Yuquan Road, Nankai District, Tianjin 300193 , China
4 Clinical Practice Teaching Department of Tianjin University of Traditional Chinese Medicine , Tianjin 300193 , China
Background: Previous studies have shown that acupuncture is beneficial for the alleviation of chemotherapy-induced nausea and vomiting. However, there is a lack of clinical evidence concerning the effects of acupoint-matching on chemotherapy-induced nausea and vomiting. Methods/design: This is a parallel randomized controlled trial to evaluate the occurrence of nausea and vomiting after chemotherapy (the incidence of nausea and vomiting, frequency, VAS score, RINVR rating) as the main outcome for cancer. Quality of life, anxiety and depression scores are the secondary outcomes. Quality of life, anxiety and depression scores are the secondary phase. Use of remedy drugs, routine blood examination, and blood biochemical tests are the safety evaluation. We also compare the different effects of ST36 (single acupoint), CV12 (single acupoint), and ST36-CV12 matching groups. Discussion: The results of this trial are expected to explore the effects of matching different acupoints and to offer biologic plausibility for the use of acupuncture in the treatment of chemotherapy-induced nausea and vomiting (CINV). Trial registration: This trial is registered with clinicaltrials.gov NCT02195921, The date of registration was 17 July 2014.
Chemotherapy-induced nausea and vomiting; Acupuncture; Matching acupoints; Randomized controlled trial
Vomiting and nauseas are common side effects of
]. The management of these side effects
is challenging because antiemetic drugs have adverse
effects such as constipation [
]. Acupuncture, a
nonpharmacologic therapy, may be helpful for patients to
manage the side effects of chemotherapy [
]. It has been
shown that acupuncture may reduce the side effects
of chemotherapy such as vomiting, nausea, hot
flashes, and fatigue [
]. Acupuncture treatment has
been recommended since 1997 by the National
Institutes of Health (NIH) to help patients undergoing
chemotherapy deal with severe side effects like
vomiting and nausea [
]. Electroacupuncture has been
recommended on the basis of level 1 evidence for the
prevention of chemotherapy-induced nausea and
vomiting (CINV) [
]. Such evidence has displayed the
efficacy of acupuncture; however, how to match the
acupoints remains a problem for clinical treatment.
Acupoints are the material basis for acupuncture
], and the matching of acupoints is key to
enhancing the effects. For single acupoint use, Zusanli
(ST36) is one of the best acupoints for treatment of
stomach disease, as it is beneficial for regulating the qi
flow and harmonizing the stomach [
]. Zusanli (ST36)
and Zhongwan (CV12) are considered as the most
effective matching acupoints for the stomach qi on the
basis of He-sea and Front-mu acupoint-matching (ST36
is the lower He-sea point of the stomach and CV12 is
the Front-mu acupoint of the stomach) [
This randomized controlled trial evaluates the effects
of acupuncture on CINV after chemotherapy to offer
biologic plausibility for addressing vomiting and nausea.
We will conduct this trial using ST36 single, CV12
single, and ST36-CV12 matching to investigate the
quality of life scores, and depression/anxiety score as a
secondary objective for patients undergoing chemotherapy
as well as to explore the matching rules of acupoints.
This trial will be carried out at the Tianjin Medical
University Cancer Institute and Hospital. All participants
included in this trial are from the wards of integrated
Chinese and western medicine, galactophore, lymphoma,
Random parallel control will be used as the clinical test
design. Participants are randomly assigned to treatment
groups: the ST36 single group (distal), CV12 single
group (local), ST36-CV12 matching group
(proximaldistal), and control group.
Inpatients from Tianjin Medical University Cancer
Hospital who meet the following requirements will be
eligible for enrollment: (1) diagnosed with cancer by
imaging, cytology, pathology, and requiring chemotherapy;
(2) Karnofsky (KPS) score ≥70 points; can take care of
themselves; (3) no gender criteria, aged between 18 to 80;
(4) inpatient or outpatient; (5) can be receiving single or
multiple rounds of chemotherapy, but each patient should
only be included once; (6) cancer patients undergoing
chemotherapy combined with cisplatin (cisplatin ≥75 mg/
m2) or anthracycline therapy (doxorubicin ≥40 mg/m2 or
epirubicin ≥60 mg/m2); (7) expected lifespan longer than
6 months; (8) providing a signed hard copy of the
Participants with any of the following conditions will be
excluded: (1) radiotherapy and chemotherapy used at
the same time; (2) nausea and vomiting due to cancers
of the digestive system, such as gastric cancer; (3)
chemotherapy patients with serious complications or
severe liver/kidney function abnormalities [glutamic
oxaloacetic transaminase (AST), glutamic-pyruvic
transaminase (ALT), total bilirubin (TBIL) triple normal
levels, blood urea nitrogen (BUN) and urine creatinine
(Cr) double normal levels]; (4) fitted with pacemakers or
other implanted medical electronic devices; (5) needle
site with inflammation, scarring or trauma, or other
serious systemic infection; (6) long-term use of opioids
or metabolic imbalance (electrolyte imbalance) which
cause vomiting; (7) a history of mental illness, language
communication disorders; (8) postoperative patients
with gastrointestinal obstruction and other mechanical
risk factors; (9) patients with brain metastases or
symptoms of increased intracranial pressure; (10) pregnancy
or breast feeding.
A basic antiemetic plan (dexamethasone, ramosetron, or
tropisetron) will be used in the control group. The
remaining three groups will be given antiemetics and
receive electroacupuncture at the ST36, CV12, and
ST36-CV12 points. If vomiting cannot be controlled, a
doctor will prescribe medication to relieve the symptoms
according to the disease type.
The control group will receive only a basic antiemetic
regimen. This protocol will be delivered according to the
American Society of Clinical Oncology clinical practice
]. We chose 5-HT3 antagonists (ramosetron
or tropisetron, beginning on day 1 of chemotherapy and
taken continuously for 3–5 days) and dexamethasone.
The acupoints are located according to the WHO
standard acupuncture point locations in the Western
Pacific Region [
]. Zusanli (ST36): below the knee, 3
cun below Dubi (ST35) on the line between Dubi (ST35)
and Jiexi (ST41). Zhongwan (CV12): on the anterior
midline of the abdomen, 4 cun above the umbilicus.
The needles (0.3 cun; Hua Tuo, Jiangsu, China) will be
inserted and manipulated until De Qi (a sensation of
soreness and tingling) is reported by the patient. Then
the needle is connected to a Hua Tuo
electroacupuncture therapy apparatus. Another refined electrode side
will then be attached 1 cm beyond the acupoint. The
frequency used is as in Shen et al. [
]; a bilateral 2-Hz
current under 10 mA. The needles are left in place for
30 minutes. The treatment is delivered 30–60 minutes
prior to commencement of chemotherapy. The therapy
is delivered for 4 consecutive days.
The evaluation of nausea and vomiting is classified by
the incidence of nausea and vomiting. In this trial, we
use the Rhodes Index of Nausea, Vomiting and Retching
] to score the incidence of nausea and vomiting. It
could also be used to evaluate the duration, frequency,
and severity of nausea and vomiting.
The Functional Assessment of Cancer Treatment (FACT)
will be used to explore physical well-being (PWB), social
well-being (SWB), emotional well-being (EWB), and
functional well-being (FWB). The Hospital Anxiety and
Depression Scale (HADS) will be used to identify anxiety
and depression levels in the patients.
Routine blood tests, liver/kidney function, constipation,
diarrhea, and other antiemetic side effects, or adverse
reactions will be assessed.
Sample size calculation
Calculated using the mid-term results of our pilot study,
the mean score for vomiting experience averaged over
5 days was 1.18 [weighted average standard deviation
(SD) 0.53] in the CV12 group and 1.82 (weighted
average SD 0.69) in the control group. At least 27
participants per arm would be required to detect this
pair-wise difference between arms using a t test with
a conservative Bonferroni-adjusted significance level
of 0.05/6 = 0.0083 at a power of 90%. The power was
for a two-tailed test of equal mean change scores at the
5% level of significance. Our study was planned to have
high power to detect a two-unit difference in change
scores. Thus, a total of 160 participants will be included in
this trial with 40 patients in each group.
For the included studies, levels of attrition were noted.
The impact of including studies with high levels of
missing data in the overall assessment of treatment
effect was explored by using sensitivity analysis. For all
outcomes, analyses were carried out, as far as possible,
on an intention-to-treat basis. The denominator for each
outcome in each trial was the number randomly
assigned minus any participants whose outcomes are
known to be missing.
Randomization and allocation concealment
This trial is randomized by a central randomization
system. Eligible participants are randomly assigned to
each group at a ratio of 1:1:1:1. Only the operational
assistants log into
http://www.tcmcec.net:8082/wcr/login.aspx and fill in the basic information of the subjects to
apply a random number and distribution of
constituencies. Stochastic systems are served by an independent
third party, the Clinical Evaluation Center, China
Academy of Traditional Chinese Medicine.
The participants, operational assistants, evaluators, and
statisticians will be blinded to the treatment allocations,
which will not be revealed until the end of the study.
We have described for each included study the methods
used to blind study participants and personnel from
knowledge of which intervention a participant received.
To prevent performance bias, studies are judged at low risk
of bias if they were blinded or if we judged that the lack of
blinding could not have affected the results. Evaluators and
operational assistants will not work together at the same
time. There will be no communication between patients.
The evaluators will not be able to ask whether the patients
receive the acupuncture or not or where the acupoints are.
There will be no opportunities for the statisticians to
become aware of the constituency distributions.
The enrollment will be carried out before the first day of
chemotherapy on day 0. The electroacupuncture
intervention will be given once daily from day 1 to day 4. All
assessments will be scheduled from day 0 to day 5 (Fig. 1)
Fig. 1 The schedule of enrollment, interventions, and assessments
Clinical quality control
Level 1 examination (quality control) is conducted by
the quality inspectors. They are required to develop
quality checklists for all research data sources, data
reporting, and adverse events. During the quality control
process, they will need to take appropriate measures to
assess quality problems and sign on the checklist. In
Level 2 examinations (inspection), audit procedures and
project sheets are in accordance with the progress of the
completion of the test, the subjects in the group, and the
relevant inspection project. The inspectors need to
complete audit reports during the treatment. For the Level
3 examination (audit), case report form (CRF)
management and assessment of the authenticity of the case will
be carried out by the Clinical Evaluation Center, China
Academy of Traditional Chinese Medicine.
Document management and standardization of clinical treatment
To standardize clinical operations and deliver clinical
quality assurance, we developed a series of documents
and standardized clinical management operating
specifications. Developing appropriate standard operating
norms for various stages of clinical research is a way to
ensure homogeneity between various researchers. It is
helpful to use file management and develop a standard
operating procedure (SOP) to ensure the feasibility,
safety, and scientific integrity of clinical research.
Data storage and confidentiality
The Clinical Evaluation Center, China Academy of
Traditional Chinese Medicine provides a central stochastic
system, database development, data entry and cleaning,
data verification, statistical analysis, and other services as
an independent third party. To reduce the risk of
selection bias, the operator, evaluator, and statistician
Statistical analysis will be conducted using SPSS (v.22;
IBM Corp, Armonk, NY, USA). We will express
normally distributed continuous outcomes using mean (SD)
and skewed data with median (range). Dichotomous
outcomes will be expressed as frequency or incidence. If the
data are normally distributed, we will use ANOVA with
Bonferroni-corrected pair-wise comparisons to compare
the primary outcomes among the four treatment groups.
If the data are not normally distributed, we will use a
Kruskal-Wallis test to compare the four treatment
groups and a Wilcoxon rank-sum test for the pair-wise
comparison for the primary outcome. Intergroup
differences in categorical data (Common Terminology Criteria
for Adverse Events) will be assessed using the chi2 test or
Fisher exact tests (two-tailed), as appropriate. Repeated
measures analysis of variance (R-ANOVA) will be used to
assess the frequency of vomiting, and the Visual Analogue
Scale for nausea and nausea and vomiting and retching
among the four study groups. Length of no days of nausea
and vomiting will be calculated using Kaplan-Meier
analysis and compared among the groups using the log-rank
test. Subgroup analysis based on single or multiple
chemotherapy sessions will be performed to compare the
efficacy of basic antiemetic regimens plus
electroacupuncture or an antiemetic regimen only on inducing a
complete response. A p value <0.05 will be considered to
be statistically significant.
The mechanism of CINV is complicated. What we know
at present is that the 5-HT system and SP system may
have an important role in CINV. 5-HT is mainly
involved in the process of acute nausea and vomiting
]. During chemotherapy, enterochromaffin cells (EC)
release 5-HT receptors and vagal afferent nerves have
been shown to be activated by 5-HT receptors. The
signal is passed by the dorsal motor nucleus of the vagal
nerve (vomiting center), which causes severe vomiting
]. The SP system participates in the process, which
prolongs the nausea and vomiting [
longterm chemotherapy, cell apoptosis and inflammation
induce EC to release P substances combined with NK-1
on the chemoreceptor trigger zone by the vagal afferent
nerves. Then the signal reaches the stomach through the
vagal efferent fibers, which delays nausea and vomiting
]. It has been shown that the dopamine system plays
an important role as well in the occurrence of CINV, but
the specific mechanism is unclear [
Electroacupuncture, in particular, has been shown to
inhibit SP and 5-HT release in EC. It may directly
inhibit afferent vagal nerve excitability, or it may inhibit
the solitary tract nucleus or vagal nerve dorsal nucleus
as the acupuncture signals are conducted through the
sensory nerves through the spinal cord upwards to the
central level. Thus, CINV could be reduced. However,
the choice of acupoints may also alter the efficacy of EA
treatment. Clinical studies are still unable to provide
guidance for the prevention of or treatment for CINV.
Further, there is a lack of sufficient clinical evidence as
to how acupoint-matching may improve CINV [
In terms of the risk of bias, derived from the partial
absence of blinding of the interventionists, it is difficult
to implement a fully blind method for the operators
because acupuncture is a physical operation method, and
the interventionists are required to be knowledgeable
Nevertheless, the results of this trial are expected to
explore the effects of the matching of different acupoints
and offer biologic plausibility for the use of acupuncture
in the treatment of CINV.
The trial is currently recruiting patients.
Additional file 1: SPIRIT 2013 Checklist. (DOCX 29 kb)
ALT: Glutamic-pyruvic transaminase; AST: Glutamic oxaloacetic transaminase;
BUN: Blood urea nitrogen; CINV: Chemotherapy-induced nausea and
vomiting; Cr: Urine creatinine; CRF: Case report form; CV12: The Zhongwan
acupoint; FACT-G: Functional Assessment of Cancer Therapy - General;
KPS: Karnofsky score; NIH: National Institutes of Health; ST36: The Zusanli
acupoint; TBIL: Total bilirubin
We acknowledge Tianjin Medical University Cancer Institute and Hospital
for recruiting patients, and The China Academy of Traditional Chinese
Medicine Clinical Evaluation Center for central randomization and clinical
data management. We also appreciate the help and efforts of all research
staff participating in this trial.
This work was supported in part by National Basic Research Program of
China under Grant No. 2014CB543201.
Availability of data and materials
The protocol was registered on ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/
NCT02195921?term=NCT02195921&rank=1. The Central Randomization System for
Clinical Research (web edition) is http://www.tcmcec.net:8082/crivrs/. The clinical
data will be put on the Research Clinical Data Management System (http://
www.tcmcec.net:8082/wcr/login.aspx) (Additional file 1).
BC, YG, and XZ contributed equally to this work. BC, XZ, and XFP conceived
this protocol. BC, YG, and MYL designed the trial. LLG, BL, and TYZ participated
in enrollment and clinical treatment. QWZ and JXZ are the clinical evaluators.
YMG is the clinical data monitors. YG is the project director and responsible for
the top-level design. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Written informed consent will be obtained from each participant. This trial
has been approved by the local institutional ethics committee (Tianjin
University of Traditional Chinese Medicine, Tianjin, China). The approval
number is TJUTCM-EC20140005.
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
1. Hesketh PJ , Grunberg SM , Gralla RJ , et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin-the Aprepitant Protocol 052 Study Group . J Clin Oncol . 2003 ; 21 : 4112 - 9 .
2. Mancini I , Bruera E. Constipation in advanced cancer patients[J] . Support Care Cancer . 1998 ; 6 : 356 - 64 .
3. Lu W. Acupuncture for side effects of chemoradiation therapy in cancer patients Seminars in oncology nursing . WB Saunders . 2005 ; 21 : 190 - 5 .
4. Ezzo J , Streitberger K , Schneider A . Cochrane systematic reviews examine P6 acupuncture-point stimulation for nausea and vomiting . J Altern Complement Med . 2006 ; 12 : 489 - 95 .
5. Lee MS , Kim KH , Choi SM , et al. Acupuncture for treating hot flashes in breast cancer patients: a systematic review . Breast Cancer Res Treat . 2009 ; 115 : 497 - 503 .
6. Posadzki P , Moon TW , Choi TY , et al. Acupuncture for cancer-related fatigue: a systematic review of randomized clinical trials . Support Care Cancer . 2013 ; 21 : 2067 - 73 .
7. Morey SS . NIH issues consensus statement on acupuncture . Am Fam Physician . 1998 ; 57 : 2545 - 6 .
8. Naeim A , Dy SM , Lorenz KA , et al. Evidence-based recommendations for cancer nausea and vomiting . J Clin Oncol . 2008 ; 26 : 3903 - 10 .
9. Pomeranz B , Berman B . Scientific basis of acupuncture . Berlin Heidelberg: Springer; 2003 .
10. Hu S , Du MH , Luo HM , et al. Electroacupuncture at Zusanli (ST36) prevents intestinal barrier and remote organ dysfunction following gut ischemia through activating the cholinergic anti-inflammatory-dependent mechanism . Evid Based Complement Alternat Med . 2013 ; 2013 : 592127 .
11. Dong LL , Liu AG , Wang JY , et al. Effect of acupuncture of Ho (ST 36 ) - plus Mu (CV 12) -acupoints on hypothalamic gonadotropin-releasing hormone mRNA and SP mRNA expression in stress-induced gastric ulcer rats . Acupunct Res . 2013 ; 38 : 291 - 6 .
12. Basch E , Prestrud AA , Hesketh PJ , et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update . J Clin Oncol . 2011 ; 29 : 4189 - 98 .
13. World Health Organization. WHO standard acupuncture point locations in the Western Pacific Region . Geneva: World Health Organization; 2008 . p. 181 .
14. Shen J , Wenger N , Glaspy J , et al. Electroacupuncture for control of myeloablative chemotherapy-Induced emesis: a randomized controlled trial . JAMA . 2000 ; 284 : 2755 - 61 .
15. Fu MR , Rhodes V , Xu B. The Chinese translation of the Index of Nausea, Vomiting, and Retching. Cancer Nurs . 2002 ; 25 ( 2 ): 134 - 40 .
16. Jantunen IT , Kataja VV , Muhonen TT . An overview of randomised studies comparing 5-HT 3 receptor antagonists to conventional anti-emetics in the prophylaxis of acute chemotherapy-induced vomiting . Eur J Cancer . 1997 ; 33 : 66 - 74 .
17. Janelsins MC , Tejani MA , Kamen C , et al. Current pharmacotherapy for chemotherapy-induced nausea and vomiting in cancer patients . Expert Opin Pharmacother . 2013 ; 14 : 757 .
18. Sanger GJ , Andrews PLR . Treatment of nausea and vomiting: gaps in our knowledge . Auton Neurosci . 2006 ; 129 : 3 - 16 .
19. Ariumi H , Saito R , Nago S , et al. The role of tachykinin NK-1 receptors in the area postrema of ferrets in emesis . Neurosci Lett . 2000 ; 286 : 123 - 6 .
20. Murakawa M , Adachi T , Nakao S , et al. Activation of the cortical and medullary dopaminergic systems by nitrous oxide in rats: a possible neurochemical basis for psychotropic effects and postanesthetic nausea and vomiting . Anesth Analg . 1994 ; 78 : 376 - 81 .