Using biofeedback and electrical nerve stimulation to treat bowel problems after lower rectal surgery: a plan for a randomized trial

Colorectal cancer (CRC) ranks as the world’s third most prevalent cancer, with the rectum affected in approximately half of the cases [1]. Surgical procedures remain the primary treatment for rectal cancer, offering opportunities for anus-preserving surgeries and improved quality of life using advanced medical technologies such as the Da Vinci robot [2]. However, postoperative complications include low anterior resection syndrome (LARS) that occurs in 25–80% of patients, characterized by fecal incontinence, urgency in bowel movements, and increased frequency of bowel movements [3]. Although these symptoms stabilize within 6 months to 1 year postoperatively, they often tend to persist [4, 5] and may significantly affect the patient’s life, sometimes even necessitating colostomy. Consequently, effective LARS treatments are urgently required.

LARS pathogenesis involves multiple theories, including anal internal sphincter dysfunction, reduced rectal sensitivity, the absence of the rectoanal inhibitory reflex, and reduced rectal compliance [6]. Nerve damage during the low anterior resection process might lead to new rectal innervation, exacerbating the LARS symptoms [7]. Current treatments encompass non-surgical options, such as pharmacotherapy, biofeedback, transanal electrical stimulation, and enema therapy, as well as surgical approaches, such as artificial sphincter replacement, colostomy, and neurostimulation therapy. Oral serotonin receptor antagonists, effective in treating diarrhea-predominant irritable bowel syndrome, are employed to alleviate LARS symptoms such as fecal incontinence and urgency;[8] however, further clinical trials are warranted for validation. Enema therapy effectively manages fecal incontinence but may have potential side effects, including rectal bleeding, perianal pain, anal fissures, abdominal discomfort, and colonic perforation [9]. Although artificial sphincter replacement is suitable for severe anal incontinence, the high cost and postoperative complications limit its application. Colostomy is the last treatment option in cases where other treatments fail; however, it imposes significant psychological stress on patients. Biofeedback may be effective in managing fecal incontinence by using transanal probes to track activity changes in the pelvic floor muscles, guiding patients through Kegel exercises, and delivering precise electrical stimulation for pelvic muscle recovery [10]. However, patients might find it difficult to follow Kegel exercise instructions, which could impede the treatment efficacy. Additionally, surface electromyography (EMG) stimulation via the anus provides an indirect and comparatively weaker therapeutic effect than deeper direct muscle stimulation, potentially offering less favorable outcomes [11].Recently, neural electrical stimulation therapies, such as sacral nerve stimulation and pudendal nerve stimulation, have become focal points in LARS treatment. Multiple clinical studies have affirmed their positive effects in treating fecal incontinence, LARS, and other defecation disorders [12, 13]. However, the implantation of electrodes in the body required in both stimulation methods poses issues, such as battery replacement, high costs, postoperative infections, and surgical failures [14]. Percutaneous electrical pudendal nerve stimulation (PEPNS) is an innovative technique developed by Wang Siyou [15]. It involves the insertion of extended needles through the lower sacral points on the skin confirmed on transverse computed tomography of the coccygeal apex, showing the needle tips located in the ischiorectal fossa proximal to the pudendal nerve within the Alcock canal [16]. The rectum and sphincter are regulated by nerves originating from the pelvic plexus located in the lower abdomen. This plexus includes both sympathetic fibers from the presacral nerves and parasympathetic fibers from the S2–S4 spinal segments, forming the neural basis for controlling functions of the rectum and sphincter muscles. The pudendal nerve is essential for the perineal sensation and voluntary movements of the pelvic floor muscles, especially the control of the external anal sphincter. It originates from the S2–S4 sacral spinal segments and divides into the following three branches in the Alcock canal: the inferior rectal branch, the perineal branch, and the dorsal nerve of the clitoris or penis. The inferior rectal branch innervates the external anal sphincter, levator ani, lower anal canal, and perianal skin [17]. The suggested mechanism involves continual electrical stimulation of the pudendal nerve alongside the merging of incoming nerve fibers from the anorectal region at the common neurons in the S2-S4 spinal segments, which regulate the visceral nerves [18, 19]. Moreover, pudendal nerve electrical stimulation can increase resting pressure in the sphincter, thus enhancing bowel control. [20]

Therefore, the application of PEPNS along with biofeedback could be an effective and economical non-surgical treatment for LARS. This study aims to conduct a randomized controlled trial (RCT) to compare the efficacy and safety of this combined approach with biofeedback alone.

The aim of this study is to evaluate the short-term (1 month) and long-term (6 months) effects of B-PEPNS on alleviating symptoms of LARS and improving the quality of life for patients undergoing rectal cancer surgery.

This is a two-center, randomized controlled, partially blinded superiority study with a two-group parallel design, wherein data from two separate groups will be analyzed over an 8-week treatment period (from February 5, 2023, to January 31, 2025). In total, 242 LARS patients will be randomly allocated to the intervention and control groups in a 1:1 ratio. All procedures are detailed in Fig. 1 according to the Standard Protocol Items: Recommendations for Interventional Trials guidelines. [21]

Patients will be recruited from two tertiary hospitals: Sir Run Run Shaw Hospital (SRRH), affiliated with the Zhejiang University School of Medicine, and the First Affiliated Hospital of Zhejiang Chinese Medical University. Biofeedback sessions will take place at SRRH, while Percutaneous Electrical Pudendal Nerve Stimulation will be administered at the First Affiliated Hospital of Zhejiang Chinese Medical University. Evaluations will be conducted at both institutions.

The fully trained designated researchers (XJZ, FW, DM, LW, XCP) who are present on-site will be responsible for obtaining informed consent from participants.

On the consent form, participants are requested to sign indicating their acknowledgment of having received both written and oral information regarding the purpose, methodology, benefits, and risks associated with participating in the trial, as well as their voluntary agreement to participate. Participants are explicitly informed that they retain the right to withdraw their consent at any time without forfeiting any entitlement to treatment, present or future. Moreover, they are queried about their consent for data utilization in the event of withdrawal from the trial. This trial does not entail the collection of biological specimens for storage.

Both the control group and the intervention group will receive the same duration of biofeedback therapy, but the intervention group will also receive additional PEPNS therapy. This study will demonstrate the synergistic effects of PEPNS in alleviating LARS symptoms and improving patients’ quality of life in conjunction with biofeedback.

(1) Intervention group (B-PEPNS)

If a needlestick infection occurs during PEPNS, the treatment will be delayed, and antibiotics will be administered. If symptoms improve within 1 week, treatment will continue. If symptoms do not improve within 1 week, or if another infection occurs after improvement, treatment will be terminated. Meanwhile, this should be reported as an adverse event. And if any other unforeseen serious side effects occur, the intervention will also be terminated.

Adherence enhancement strategies will be implemented throughout the trial period. After 1 week of treatment, all patients will be directly scheduled for their next week’s treatment session. At the conclusion of each weekly treatment session, we will engage in discussions with patients regarding their treatment experience and remind them of the importance of adhering.

Throughout the trial period, participants with background diseases, regardless of their allocation, are allowed to take relevant medications as needed. However, participants, regardless of their allocation, are prohibited from other treatments related to LARS, such as oral loperamide and enema.

We will provide free medical treatment to intervention-related harms, such as needle-related infections.

Before commencing the treatment regimen, comprehensive patient information will be compiled, including demographic data, tumor metrics, surgical specifics, and any prior radiotherapy or chemotherapy received. Patients will undergo evaluations using the LARS and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Colorectal 29 (EORTC QLQ-CR29) scoring systems along with anorectal manometry (ARM) and pelvic floor EMG assessments. These evaluations will be conducted at the following three key times: baseline, post-intervention (at 1 month), and during follow-up (at 6 months).

The participant timeline is outlined in the SPIRIT figure (Fig. 2).

Based on a prior study [10] involving 45 patients in each group (efficacy rate, 65.6%:46.7%), the required sample size for this study was computed utilizing the Power Analysis and Sample Size 15 software (NCSS Statistical Software, UT, USA). A sample size of 210 patients was determined to achieve a power (1-beta) of 0.80 and an alpha (significance level) of 0.05, with group allocation in a 1:1 ratio. Factoring in potential dropouts (15% of the participants), the total sample size was adjusted to 242 in total (n = 121 in each group).

We aim to recruit 242 patients diagnosed with LARS, who meet eligibility criteria, from the inpatient and outpatient departments of the two hospitals. Our recruitment strategy includes targeted posters displayed in both hospital facilities and dissemination of health education brochures to potential participants. We will leverage mobile applications to disseminate recruitment information efficiently.

Using SAS software (9.3), the Clinical Evaluation and Analysis Centre at SRRH will randomly allocate 242 participants in a 1:1 ratio to the intervention group (undergoing B-PEPNS) or the control group (undergoing biofeedback alone). Professionals overseeing allocation will not be directly involved in the study.

Sequentially numbered opaque envelopes will conceal the random allocation, keeping it confidential from other research staff.

During the post-baseline assessment, an impartial staff member will open the envelope in the participants’ presence, assigning them to the intervention or control group. Simultaneously, the operators will receive information about the participant’s allocation. The recruitment staff and clinical interviewers will remain unaware of the group allotments to uphold study integrity.

Throughout the trial process, data collectors, statisticians, and telephone follow-up personnel will be blinded. However, the operators will be aware of the group allocations but will not be involved in data recording, statistical analysis, or follow-up procedures. They will operate independently without any communication.

If a serious adverse event occurs, the participant’s allocation will be unblinded. The incident will be promptly reported to the Ethics Committee.

Licensed therapists with at least 3 years of experience will conduct biofeedback treatment for both the intervention and control group patients. Acupuncturists conducting PEPNS for the intervention group will have a minimum of 2 years of acupuncture practice. A 2-day training session led by senior research team members will prepare therapists, acupuncturists, and assessors on all aspects of the study from diagnosis to data collection. Inspectors at each center will monitor patient enrollment, treatments, and data quality.

Strategies to enhance participant retention and ensure completion of follow-up: Following each week of treatment, patients will be automatically scheduled for their next session. Additionally, patients will receive a weekly reminder via SMS on their mobile phones regarding their upcoming treatment appointment.

Data will be recorded on paper and entered into a secure electric data management system (developed by an independent data management agency, Linkermed Technology, Beijing, China) for error checks. All records will be stored safely for at least 10 years after the study while ensuring patient privacy. Personal data will be kept separate from the analysis. Both the intervention and control groups will be assigned anonymous numerical codes (1, 2) to blind the individual conducting the statistical analysis. The collected data will only be used for this research.

Personal information will be retained solely by the therapist within a secure electronic data management system. All records will be securely stored for at least 10 years after the study to safeguard patient privacy.

Not applicable, no samples were collected.

This trial is not subject to interim analyses.

Subgroup analysis will be performed for the radiotherapy group. Participants who have undergone pelvic radiotherapy related to rectal cancer will be included in the radiotherapy group.

In cases where the lost-to-follow-up rates are below 20%, we will conduct an intention-to-treat analysis. Missing values will be replaced using single imputation procedures with the group mean.

The datasets analyzed during this trial can be made available from the corresponding author upon reasonable request.

GYC, XJZ, and SC, the lead study coordinators, comprise the trial steering committee. Additionally, three independent members from the Clinical Trials Office of Sir Run Run Shaw Hospital, along with the three lead coordinators, will serve as the coordinating center for this study. These committees will convene monthly to assess the study’s progress and address any financial or technical issues that may arise.

The clinical trial will not incorporate an external data monitoring committee due to the utilization of therapies commonly practiced by pelvic physical therapists and acupuncturist and assessments frequently administered to rectal cancer patients. However, an internal committee will be established to monitor preliminary safety data. This committee will comprise the researchers responsible for assessing the primary outcomes and the principal investigator. They will conduct ongoing preliminary data analyses to assess safety and efficacy. In the event of any reported adverse events, this committee will seek analysis and recommendations from an external surgeon with expertise in treating rectal cancer. The data monitoring group operates independently from the funder and sponsor.

The study will monitor for PEPNS-related adverse events (AEs), such as needle-related infections, and report them to the Ethics Committee. We will document the site, extent, treatment process, and recovery time of each AE, and assess the causality between AEs and the intervention. AEs will be used as safety outcome measures to evaluate the safety of the intervention.

Auditing will be conducted only in case the funder or Ethical Committee requires.

In this trial, important protocol modifications must be approved by the trial registry and the Ethical Committee.

The study findings will be submitted for publication in peer-reviewed journals, irrespective of whether they support or challenge the initial study hypothesis.

This study has been approved by the Medical Ethical Committee of Sir Run Run Shaw Hospital (No. 2022-376-01), and informed consent will be obtained from all participants before commencing the study.

Not applicable. No identifying images or other personal or clinical details of participants are presented here or will be presented in reports of the trial results. The participant information materials and informed consent form are available from the authors upon request.

The authors declare that they have no co mpeting interest s

The datasets generated and/ or analyzed during the study will be available on reasonable request. Data can be obtained by contacting the main researcher. Email for requests: breezehilly@hotmail.com.