The efficacy and safety of acupuncture for alleviating chemotherapy-induced peripheral neuropathy in colorectal cancer patients: study protocol for a pilot single-blinded, randomized sham-controlled trial

Background: Colorectal cancer is the most common cancer in Hong Kong. Oxaliplatin based chemotherapy is a major first-line conventional therapy for advanced and metastatic colorectal cancer. However, oxaliplatin causes chemotherapy induced peripheral neuropathy (CIPN). Acupuncture has been recognized as one of the effective intervention for preventing CIPN. This study aims to examine the efficacy and safety of acupuncture for preventing CIPN in colorectal cancer patients in Hong Kong. Methods/Design: This is a pilot single-blinded, randomized, sham- controlled trial. Eighty-four eligible patients, who are Hong Kong Chinese aged ≥18 years and are diagnosed as colorectal cancer undergoing oxaliplatin based chemotherapy, will be randomized in a ratio of 1:1 to acupuncture group and sham-controlled group. During 12-weektreatment period, patients in acupuncture group will undergo acupuncture once a week from the first cycle of chemotherapy, patients in control group will receive sham-acupuncture, and the patients in both groupswill be followed up for twelve weeks. The primary outcome measure is the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOC-Ntx) questionnaire. The secondary outcome measures include numerical rating scale (NRS), vibration and light touch sense test, quality of life questionnaire-C30 of European Organization for Research and Treatment of Cancer (EQRTC) (EORTC QLQ-C30) and Constitution of Chinese Medicine Questionnaire (CCMQ). Discussion: The study will compare acupuncture with sham acupuncture and will obtain evidence for utilizing acupuncture for chemotherapy induced peripheral neuropathy.

current treatments (included natural products and complementary therapies) were still unknown and only vitamin E may help prevent CIPN 9,10 . The current studies of acupuncture for CIPN was varied in different cancer and anti-cancer drugs such as taxanes for breast cancer 11 , bortezomib and thalidomide for multiple myeloma 12 , and a mix of neurotoxic anticancer drugs 13 . However, studies of acupuncture for oxaliplatin induced peripheral neuropathy are rare and no randomized controlled trial was done 14 . Therefore, we design this single-blinded, randomized controlled clinical trial to explore the efficacy and safety of acupuncture on prevention of CIPN.

Objective
The aim of the study is to assess the efficacy and safety of eletro-acupuncture compared to sham acupuncture on alleviating chemotherapy-induced peripheral neuropathy (CINP) in colorectal cancer patients.
Methods/design chemotherapy and, (4) do not have any pre-existing peripheral neuropathy, will be included in the study. An informed consent will be taken from eligible patients. A total of 84 candidates will be recruited in this study. They will be assigned randomly into either the electro-acupuncture or sham-control group. Both groups will be given a total of 12 sessions of interventions, with 1 session per week. They will be followed up to 12 weeks upon completion of intervention. The Functional Assessment of Cancer Therapy/Gynecology Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire will be used as the primary outcome measured. The questionnaire will be done before start of the study as a baseline score. The score will be obtained on weekly basis during both the intervention and follow-up period, up to 24 weeks. (Fig. 1 are using any pharmaceutical agents e.g. vitamin B6 and vitamin E, or herbal medication for CIPN treatment. All the above medication prescribed by physicians or Chinese medicine practitioners during the study will be recorded. Investigators will determine whether they need to be withdrawn from the study. Candidates will be considered as drop-out from the study if they: withdraw his/her informed consent; stop taking the randomized treatment for any reason; lost to follow-up; develop serious adverse event (SAE) or other safety/ efficacy issues in which suspension will be considered beneficial as suggested by investigators;

becomes pregnant
The date and reason for withdrawal should be noted in the case report form (CRF). All subjects who withdraw from the study should, if all possible, be seen for a final evaluation (Termination Visit). Prematurely discontinued subjects will not be replaced.

Interventions
Eletro-acupuncture treatment Acupuncture intervention will be conducted for one session per week over 12 consecutive weeks. The most frequently used acupuncture points in CIPN are ba feng (EX-LE10), ba xie (EX-UE9), tai chung (LV3), he gu (LI4) 15 . Among them, the traditional effects of the points in hands and feet are regulating Qi and blood circulation and treating localized problems.
With the clinical experience of our principal investigator and co-investigators, eight acupoints are chosen: he gu (LI4), nei guan (PC6), qu chi (LI12), ba xie (EX-UE9), zu san li (ST36), san yin jiao (SP6), tai chung (LV3) and ba feng (EX-LE10). The use of ba xie (EX-UE9) and ba feng (EX-LE10) will be optional if skin lesions of hands and feet occurs due to Capecitabine (Xeloda). The details of acupoints and their functions are listed in Table 2.
The acupuncture treatment will be conducted by a registered Chinese medicine practitioner with more than 5 years of Chinese medicine college education plus at least 5 years of clinical experience.Disposable acupuncture needles (verum acupuncture needles Hwato 0.25×25mm matching the Streiterger sham needles) will be inserted at a depth of 10-25mm into the points. We will deliver electrical stimulation with continuous waves at 2 Hz, at an intensity of each patient's minimum sensation of stimulation through the electrical acupuncture stimulation instrument (KWD808I multi-purpose health device, Ying Di, Chang Zhou, China) to the points. The needles will be retained in position for 25 minutes.

Sham acupuncture
For subjects assigned to the control group, Streitberger's non-invasive acupuncture needles (Gauge 8 × 1.2"/ 0.30 × 30mm) will be applied to serve as a sham control at the same acupoints with the same stimulation modality, except that the needles are only adhered to the skin by a small plastic ring instead of being inserted 16,17 and the stimulation will be a "pseduostimulation", which will be given by connecting the needle to incorrect output socket of the electrical acupuncture stimulation instrument. The credibility and validity of this system has been well demonstrated 18,19 .

Outcome measures
The primary outcome is the validated Functional Assessment of Cancer Therapy/Gynecology Oncology Group/Neurotoxicity (FACT/GOC-Ntx) questionnaire 20,21 .
The questionnaire includes 11 questions covering sensory neuropathy, motor neuropathy, hearing neuropathy, and dysfunction associated with neuropathy. It results in a cumulative score ranging from 0 to 44, with the higher scores reflecting worse neuropathy symptoms. The secondary outcomes include (1) numerical rating scale (NRS) of numbness/pain score in hands and feet 21 , which patients will be asked to rate their average neuropathy symptoms within one week, on an 0 to 10 scale (0 = no symptoms; 10 = worst possible symptoms), those <4 of 10 NRS will be considered as mild CIPN while ≥4 of 10 NRS will be considered as moderate to severe CIPN 22 24,25 , which has 60 items measuring the 9 body constitution types: gentleness, Qi-deficiency, Yang-deficiency, Yin-deficiency, phlegmwetness, wetness-heat, blood-stasis, Qi-depression, and special diathesis; (4) vibration sense test, which It is assessed using the graduated Rydel-Seiffer tuning fork (U.S. Neurologicals, Poulsbo, WA), with printed directions for use and its normative data 26 .
Readings will be averaged and recorded as the vibration value. (5) light touch test, which is assessed with standard 10g monofilaments, contained within the Neuropen (Owen Mumford, Woodstock, UK). During testing, the fiber will be applied perpendicular to the plantar surface of the great toe and the palmar surface of the index finger until the fiber begins to bend and will be held in place for 1 second and removed. This will be repeated 3 times and the patient will be asked to report the ability to feel the fiber when it is applied 26 . The use of the above assessment questionnaires (FACT/GOC-Ntx, QLQ-C30 and CCMQ) will be required authorization from the authors. Besides at baseline (0 week), FACT/GOC-Ntx 11 items subscale, NRS, vibration sense test and light touch test will be assessed every week, EORTC QLQ-C30 will be assessed every 3 weeks, CCMQ will be assessed at the end of treatment (12 th week). The post-trial access by phone or interview will be performed at 15 th , 18 th , 21 st and 24 th week. The schedule of evaluations is presented in Table 3. Adverse events will be noted throughout the study, based on the participants reports and routine laboratory tests (complete blood counts, renal and liver functions) before every chemo-cycle. Subjects will undergo routine laboratory tests before every chemo-cycle for complete blood counts, renal and liver functions in hospitals where they received chemotherapy. Lab reports will be collected and thus any adverse events will be reported and noticed. All clinical adverse events will be recorded according to terms of intensity (mild, moderate or severe), duration, outcome and relationship to the study.

Randomization assignment
All subjects will be assigned to either the intervention or sham-control group randomly. Subjects in intervention group will receive electro-acupuncture treatment, whereas the subjects in the sham-control group will receive the sham treatment. A simple, nonsequential random numbers in a block of four will be generated by a computer program prior to randomization. These numbers will be kept by the principal investigator (PI). A sealed envelope containing the randomization number which corresponds to the group allocation will be provided to the acupuncturist by the PI. Both the clinical assessor and subjects are thus blinded to the group allocation. If there are medical concerns leading to an inevitable review of treatment assignment, the PI will be the responsible person for approval. The date, time and reason for treatment assignment disclosure should be noted in the CRF. Upon disclosure of treatment assignment, the concerned subject must be withdrawn from the study. The data of the concerned subject will be included in the analysis up to the date and time of treatment assignment disclosure.

Sample size calculation
The sample size calculation is based on the change of primary outcome. In this study, the difference in FACT/GOC-Ntx score between the intervention group and the sham-control group accounts for the calculation. As shown in a recent systematic review 14 , there was only one study showing that acupuncture has significantly reduced the FACT GOC-Ntx score (MD = 5.40, SD = 3.91, 95% CI = 0.54-10.26) 27 . In this study, we assume the effect size between eletro-acupuncture and sham acupuncture is 0.3. A minimum sample size of 62 should therefore be provided in order to achieve a significance level of α = 0.05 with power (1-β) of 80%, [number of measurements is 3 and correlation among repeat measures is 0.5]with calculation by Gpower 3.1 (F tests, ANOVA, repeated measures, between factors). After taking 25% of dropout rate into consideration, the number of subjects for this study should raise to 84.

Data processing and analysis
All The efficacy and safety analyses will be based on intention-to-treat (ITT) principle. Any missing values will be imputed by the last-observation-carried -forward method. Statistical Package for the Social Sciences (SPSS) for Windows version 21.0 will be used for the statistical analysis. The statistical significance is defined as two-sided P value of < 0.05.
Baseline characteristics will be reported as mean and standard deviation (SD). The differences in both the normally distributed and non-normally distributed variables between the intervention and the sham-control groups will be assessed through Student's t test and Mann-Whitney U test respectively. The chi-sqaured test or Fisher's exact test will be used for calculating the categorical variables instead. Analysis of covariance (ANCOVA) will be used for the comparisons between the two groups every week, with treatment group as a factor in the model and baseline as the covariate. The difference between the baseline and endpoint score will be tested by using repeated measure analysis of variance (ANOVA). Paired t test and Wilcoxon signed-rank test will be used for analyzing the within-group data which are normally distributed and non-normally distributed respectively. Any deviation from this original statistical plan will be described and justified in the final report. All study files will be archived for 3 years upon completion of the final report. Only the principal investigator, co-investigators, site supervisor, KWC REC and HA Chinese medicine department are the authorized parties to access to these personal data.

Discussion
This single-blinded, randomized controlled clinical trial aims to evaluate the efficacy and safety of acupuncture on chemotherapy induced peripheral neuropathy (CIPN) of colorectal cancer patients in Hong Kong. It will be the first of such study on Hong Kong population and will obtain evidence for utilizing acupuncture in CIPN treatment especially for patients who are receiving chemotherapy. The outcome measures will include the quality of life and body constitution of Chinese medicine which will provide data to us on analysis of the treatment's potential benefit on the above items.
So far there is no such kind of study in Hong Kong and this will provide evidence for largescaled research such as combined therapy on CIPN with Chinese herbal medicine intervention. Further research on the side effects of chemotherapy or integrated medicine can also be developed specifically targeting on different types of cancer patients.
In this clinical trial, the selection of acupoints is standardized and utilized to every subject. It may help easier utilization on the treatment over different individuals but the limitation is that the selection of acupoints is not based on Syndromes differentiation which is the main concern in traditional Chinese acupuncture. Another limitation is the small sample size as the trial was proposed to be a pilot study for later large-scaled clinical trial.
In conclusion, in this pilot study, a single-blinded, randomized controlled clinical trial will be conducted to evaluate the effectiveness, efficacy and safety of acupuncture on CIPN in Hong Kong. This study will obtain the solid evidence for CMPs to utilize acupuncture for CIPN and will also provide a platform to offer research training opportunities for junior CMPs.