- To determine therapeutic efficacy of acupuncture on the recovery of postoperative gastrointestinal function in colorectal cancer patients.
- To provide statistical evidence for the inclusion of acupuncture into ERAS protocols.
The study is a single center, prospective, randomized controlled clinical trial. Recruitment for study subjects began from 16 October 2020, and is estimated to end by June 2021. 160 patients who are scheduled to undergo laparoscopic radical resection for colorectal cancer will be recruited from the Cancer Hospital Chinese Academy of Medical Sciences (CICAMS). Subjects who fulfill inclusion criteria and signed the informed consent form will be randomly assigned to either the Acupuncture group (AG) or Control group (CG) in a 1:1 ratio. CG will receive only ERAS care protocols. AG will receive both acupuncture and ERAS care protocols, with acupuncture sessions conducted once per day over 4 days, beginning on the first day after surgery, with each session lasting 30mins. Assessments are made prior to treatments, and on the 4th day and 1 month after the treatments. Fig. 1 and Fig.2 show the timeline of enrolment, intervention, evaluation, and follow-up assessments.
Randomization and Allocation Concealment
Patients who fulfill inclusion criteria will be randomly allocated to AG or CG in a 1;1 ratio. Randomized allocation sequence will be generated using Statistical Analysis System, SAS 9.3 (SAS Institute Inc. Cary, NC, USA), by an appointed investigator who is not involved in the recruitment or evaluation process. The generated sequences will be placed in serialized, opaque, sealed envelopes (to ensure concealment of allocation from the evaluators). After ensuring patients fulfill inclusion criteria and informed consent forms are obtained from them, the envelopes are opened by the acupuncturist and acupuncture treatment is carried out (the acupuncturist is excluded from assessment and statistical analytic process as blinding of the acupuncturist cannot be achieved).
Throughout the study, the statisticians and evaluators are blinded, so that independent assessments and statistical analysis can be carried out. The subjects in the control group could not be blinded due to their particularity. Acupuncturist were not blinded in this study. Unblinding will only be allowed under emergencies such as incidence of serious adverse effects.
Study Enrolment and Recruitment
Patients are recruited from the Colorectal Surgical In-patient Department of CICMAS through publication and distribution of posters and leaflets containing information of the study.
To enroll in the study, subjects must: 1) be diagnosed with colorectal cancer based on cytological or histopathological features 2) be scheduled to undergo laparoscopic radical resection for colorectal cancer 3) age between 18–80 years old 4) consent to participation and completion of the full treatment process, and be able to sign the informed consent form.
Patients may not participate in the study if they: 1) refuse to undergo laparoscopy treatment 2) have acute intestinal obstruction or intestinal perforation 3) have a history of other malignant neoplasms, or are having other malignant tumors concurrently, 4) have undergone vagotomy or colostomy 5) have preexisting conditions such as severe cardiovascular disease, hepatic, renal, hematopoietic, immune system conditions, psychiatric disorders, hyper- or hypothyroidism, diabetes, spinal cord injury 6) have skin allergies or infections 7) are anxious or fearful of acupuncture treatments 8) have been prescribed adrenergic agonist or antagonist, cholinergic or anticholinergic medications that affect gastrointestinal function for the past 1 month 9) have severe postoperative complications such as anastomotic leak, intra-abdominal infection 10) are pregnant or lactating.
Study subjects from both groups will receive standardized peri-operative care from ERAS protocols (Detailed nursing and care plans will be facilitated by the CICAMS, and would not be intervened by investigators).
Patients in AG will receive acupuncture treatment in addition to ERAS care protocols. Acupuncture treatment will be performed once daily, consecutively over 4 days, starting on the first day after the laparoscopy. Patients will assume supine position for the treatment. Treatment will be carried out by a licensed acupuncturist who holds a China Acupuncturist Certification, with at least 2 years of clinical experience in acupuncture. Site of insertions will be swabbed and disinfected with 75% alcohol prior to needle insertion. Sterile, single-use acupuncture needles with diameter 0.30mm and length 40mm (China Suzhou, Huatuo) are used. Acupuncture points are selected based on Traditional Chinese Medicine (TCM) theory and clinical experience: ST36 Zusanli, ST37 Shangjuxu, PC6 Neiguan, LI4 Hegu (Fig. 3). Exact locations and depth of insertions are referenced from the 2006 National Standards of the People’s Republic of China (GB/T12346-2006) “Nomenclature and Location of Acupuncture Points” (Fig. 4). After insertion of needles, stimulation of acupoints will be performed every 10minutes, through lifting-thrusting and twirling-twisting manipulations, to achieve sensations of deqi. Needles are kept inserted for 30mins.
Figure 4 Locations and manipulations of acupuncture group and control group
Patients in CG will only receive ERAS care with no acupuncture intervention.
Measures of Outcomes
Time of first postoperative flatus, is the study’s primary outcome, and is measured as the time period starting from the patient’s return to ward after the laparoscopy procedure till the first passage of flatus. It is obtained through the assistance of family members and caregivers, via inquiry and record of patient’s status.
Secondary outcomes include time of first postoperative defecation, time of first fluid intake, time of first ambulation, which are obtained through assistance of family members and caregivers, via inquiry and records of patient’s status. Other secondary outcome measures such as gastrointestinal reaction score (postoperative pains, distention, nausea, vomiting), postoperative hospital stay, quality of life, acupuncture sensation evaluation scale, as well as other postoperative complications (fever, pneumonia, wound infection, bleeding etc.) are assessed and evaluated by our investigators.
Postoperative pain: Measured postoperatively from day 1 to 4 at 9.00 in the morning, using Visual Analog Scores (VAS), and tabulated with dosage and frequency of Patient Controlled Analgesia (PCA) and analgesic medication used.
Gastrointestinal reaction score: Extent of distention is recorded using the Likert scale , postoperatively from day 1 to 4 at 9.00 in the morning. Extent of nausea and frequency of vomit is recorded using the VAS, postoperative from day 1 to 4, at 9.00 in the morning.
Postoperative hospital stay: Measured from the day of the laparoscopy procedure till day of discharge. Discharge criteria includes: 1) Controllable pains without use of analgesics 2) Absence of nausea or vomiting 3) Normal passing of flatus or bowels 4) Tolerance towards soft diets 5) Ability to ambulate independently or self-care.
Postoperative complications: Complications are recorded and evaluated using the Clavien Dindo Classification .
Acupuncture Sensation Evaluation Scale: Acupuncture sensations are assessed after every acupuncture treatment session through inquiring about patient’s sensations. Venous blood will also be collected on the day prior to operation, as well as the first and third day after the laparoscopy, to assess safety of acupuncture base on blood examinations and biochemical indicators.
Quality of life: Assessed through Quality of Life Questionnaire (QLQ-c30), provided to patients prior to operation and 1 month after the operation .
All adverse events should be reported by patients proactively, directly observed by clinical physicians, or monitored closely by asking patients of adverse reaction-related incidences. Detailed records of adverse events should be documented in the case report forms (CRFs), and appropriate treatment provided where necessary. If serious adverse events occur, the relevant intervention will be terminated and investigators are to report to the Research Ethics Committee immediately.
Our study estimates that a mean decrease of 8hrs in time of first flatus after application of acupuncture to promote recovery in postoperative gastrointestinal functions is of significant value. Literature review showed standard deviation of time of first flatus between study group and control group to be 12.28 and 14.57 respectively. Using a unilateral test of superiority, PASS.11 software is used to compute sample size. Using α=0.05, β=0.1, Power=0.9, 68 subjects are required in each group, with a total of 136 subjects needed for the study. Estimating a 20% dropout rate, a minimum recruitment of 160 subjects is required.
Guidelines are provided by statistician to the principal investigator, to formulate plans for statistical analysis and database setup, and SPSS software will be used to analyze the collected data. The entire data will be processed by the statistician. Statistical analysis will be carried out using SPSS 22.0, using the Intention-to-Treat (ITT) principle. A one-sided test is applied to the data, with p-value<0.05 considered significant. For descriptive analysis, qualitative variables are described by frequency tables and percentages, quantitative variables are described by mean values and standard deviations. For comparison between two groups, we will use T-test if quantitative variables exhibits normal distribution, homogeneity of variance test will be conducted between groups using p value of 0.05. If variance is unequal, Welch-Satterthwaite T-test is used. Wilcoxon rank-sum test is used if data do not follow normal distribution. Statistical analyses of primary therapeutic efficacy indicators are confirmed by the Statistics department of Bejing University of Chinese Medicine.
Data Collection and Monitoring
Data collection will be carried out by an attending surgeon. Studied variables are assessed daily from day 1 to day 4 after the laparoscopy procedure, and recorded on the CRFs. A month after the operation, a follow-up would be carried out through phone calls, to gather responses for the Quality of Life Questionnaire (QLQ-c30). Data collected will include actual number of participants, excluded case studies, demographics and other baseline variables, compliance rates, safety assessments, incidence of complications from the operation, general treatment outcomes, and therapeutic efficacy. Adverse events will also be documented. Data will be collected over the entire study duration, and managed confidentially and securely. Throughout the study, unless otherwise indicated, study subjects will be addressed using designated serial numbers and not their names. Data will only be accessible to investigators who have signed the confidential disclosure agreement, the organization involved in the study, as well as government auditors. The Research Ethics Committee of Dong Fang Hospital will exercise supervision over the collection and management of patients’ data.
To ensure quality control of the study, our methodologists, acupuncturists, surgeons and anesthetists will discuss and review research protocols continuously. Prior to the start of the study, all research personnel will have to undergo training to familiarize with research plans, experimental timelines, standardized treatment protocols etc. A quality controller appointed by the principal investigator will review CRFs fortnightly. Recorded data on CRFs are not permitted to edits. If any changes are made, a detailed explanation and signature by the modifier must be provided. A meeting will be held every three months to report and provide updates on the progress of the study.
The study has been developed in accordance with the Declaration of Helsinki and principles from the Good Clinical Practice Guide.
The study has been approved by the Research Ethics Committee of Dong Fang Hospital, Beijing University of Chinese Medicine. The trial (ChiCTR2000036351) is registered on the Chinese Clinical Trial Registry (CHiCTR) platform on 22 August 2020.
Consent and Confidentiality
Informed consent forms will be obtained from participating subjects prior to enrolment. Collected data are kept in confidentiality through the entire study.