This is a pilot single-blinded, randomized, sham-controlled trial on electro-acupuncture for alleviating symptoms of chemotherapy-induced peripheral neuropathy in patients with colorectal cancer. 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 then be followed up regularly for up to 12 weeks after completion of intervention. The Functional Assessment of Cancer Therapy/Gynecology Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire will be used as the primary outcome measure. The questionnaire will be done before the start of the study as a baseline score. The score will be obtained on a weekly basis during the intervention and every three weeks during the follow-up period, up to 24 weeks.(Fig. 1) This study protocol has been approved by Hong Kong Baptist University Ethics Committee on the Use of Human Subjects for Teaching and Research (Approval no. HASC/17-18/C05) and Hospital Authority Kowloon West Custer Research Ethics Committee(KWC REC) (Approval no. KW/FR-18-041(121-01)) and registered in clinicaltrials.gov (NCT03582423). The checklist for items in STRICTA 201013 is given in Table 1.
Participants and setting
Patients with colorectal cancer are planning to receive oxaliplatin-based chemotherapy and do not have any pre-existing peripheral neuropathy will be recruited. The study is conducted in the Yan Chai Hospital cum Hong Kong Baptist University Chinese Medicine Clinic cum Training and Research Centre (Ha Kwai Chung).
Patients will be eligible for the study if they:
- are aged ≥18 years old;
- are newly diagnosed with stage Ⅱto Ⅳcolorectal cancer;
- plan to receive 8 cycles of adjuvant oxaliplatin-based chemotherapy;
- have not received any acupuncture in the previous 3 months; and have a life expectancy ≥ six months
Patients will be excluded from the study if they:
- are not able to comprehend and communicate;
- fail to cooperate with the researcher;
- are not able to read Chinese;
- have prior peripheral neuropathy caused by other diseases including diabetes, stroke, cardiovascular diseases such as arrhythmia, heart failure, myocardial infarction, and patients with cardiac pacemakers;
- have a bleeding tendency;
- are pregnant or breast-feeding;
- have impaired hepatic or renal function;
- 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 dropout from the study if they:
- withdraw his/her informed consent;
- lost during follow-ups;
- develop serious adverse event (SAE) or other safety/ efficacy issues in which suspension will be considered beneficial as suggested by investigators;
- become pregnant;
- stop taking the randomized treatment for any reason;
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, continue to conduct regularly follow up according to the schedule of measurement and be seen for a final evaluation (Termination Visit). Prematurely discontinued subjects will not be replaced.
Subjects will be recruited through either of the following sources: (1) advertisements in newspapers, patients who are interest could contact research staff by phone; or (2) will be identified through clinic lists from the Princess Margaret Hospital (PMH) oncology outpatient department and Yan Chai Hospital cum Hong Kong Baptist University Chinese Medicine Clinic cum Training and Research Centre (Ha Kwai Chung). Potential participants will be approached initially by relevant clinical team and then screened by research staff. An informed consent will be taken from eligible patients.
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)14. 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 occur 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.
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 inserted15,16and the stimulation will be a “pseudo stimulation”, 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 demonstrated17,18.
The primary outcome is the validated Functional Assessment of Cancer Therapy/Gynecology Oncology Group/Neurotoxicity (FACT/GOC-Ntx) questionnaire19,20. 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 lower scores reflecting worse neuropathy symptoms. The secondary outcomes include (1) numerical rating scale (NRS) for numbness/pain score in hands and feet20, 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 CIPN21; (2) the validated European Organization for Research and Treatment of Cancer (EORCTC) quality of life questionnaire QLQ-C3022, which is a 30-items questionnaire assessing five functional scales (physical, role, cognitive, emotional and social), three symptoms scales (fatigue, pain, nausea and vomiting), and other symptoms and problem in cancer patients (dyspnea, appetite loss, insomnia, constipation, diarrhea, and financial difficulties); (3) the validated Constitution of Chinese Medicine Questionnaire (CCMQ)23,24, which has 60 items measuring the 9 body constitution types: gentleness, Qi-deficiency, Yang-deficiency, Yin-deficiency, phlegm-wetness, 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 data25. 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 applied25. 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 (12th week). The post-trial access by phone or face to face interview will be performed at 15th, 18th, 21st and 24th 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. Laboratory 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.
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, non-sequential random numbers will be generated by a computer program prior to randomization. Randomization procedure will be carried out by the research unit of the School of Chinese Medicine, Hong Kong Baptist University. These randomization numbers will be contained in sealed, opaque and sequentially numbered envelopes and those envelops will be stored in a locker where key will be kept by the principal investigator (PI). Those envelops which corresponds to the group allocation will be provided to the acupuncturist by the PI after completion of the subject recruitment procedure. 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 will be retained in the study. However, the number of cases in which randomization assignment is disclosed will be reported and, if necessary, sensitivity analyses may be performed removing these participants.
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 review12, 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)26. In this study, we assume the effect size between electro-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
Descriptive data includes rate of recruitment, dropout and missing intervention will be analyzed and reported as count and percentage. All missing values, efficacy and safety analyses will be based on modified intention-to-treat (ITT) principle. 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 SD for continuous variables and count and percentage for categorical variables. 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-squared 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.
Data management and confidentiality
Personal data will be handled by investigators. Hard copy data will be stored in a locker and electronic data will be stored in a specified computer with encryption. Key of locker and password of database will be kept by investigators only. Personal data will be kept for three years after the study. Hard copies will be discarded as confidential waste while the soft copy would be deleted and unrecoverable after completion of the study.
Data monitoring and trial steering committee
Quarterly monitoring meeting will be held between PI, co-Is, the Hospital Authority Chinese Medicine Department (HACMD) and the School of Chinese Medicine, HKBU. The HACMD would monitor the Chinese Medicine Centre for Training and Research to ensure the quality of the trial and keep track of the study progress and compliance to the required standard and agreement.