Cervical cancer, with almost 0.6 million new cases per year, is globally the 4^th most common cancer among women. Approximately 106,000 cases of cervical cancer occurred in China in 2018 (1). Radical hysterectomy (RH), with bilateral pelvic lymphadenectomy, is currently the gold standard surgical treatment for early-stage cervical cancer. It is the definitive therapy, and associated with an excellent prognosis for most patients (2, 3).

However, many patients may suffer from decreased Qol due to the symptoms following RH. It is reported that 70%-85% of cervical cancer patients undergoing RH had De novo bladder symptoms (4, 5), 76% of them developed lower urinary tract symptoms (LUTS) in the 12 months after surgery (6). The main reason for post-treatment bladder dysfunction is neurovascular injuries including direct cuts, stretching, and thermal injury. Marloes's (7) study indicated that patients undergoing more radical surgery had more significantly urinary dysfunction.

In clinical practice, providers have tried many methods to prevent and manage urinary retention (UR) in patients undergoing RH, among which post-operative bladder training in the early stages was the most commonly applied. However, Fanfani's randomized trial showed that bladder training did not reduce the rate of UR or re-admission for bladder catheterization (8). Some Chinese doctors reported a potential efficacy when using traditional acupuncture to treat UR after RH (9), but due to limited sample size and poor study design in those studies, more studies are needed to prove its effects.

Electrical stimulation (ES) has been used to treat bladder disorders for many years, especially for UR and incontinence, and its efficacy is promising (10, 11). TENS was the most widely used type of ES. Our previous study (12) showed that TENS could cure acute RH in rats by angiogenesis and nerve fiber regeneration in the detrusor and urethral sphincter, and also increased the expression of collagen. It was reported that ES could promote post-operative recovery of bladder function in prostate cancer (13–17), though there have also been some unsupportive findings (18–21). As the complexity is similar to radical prostatectomy, the same questions also exist in regard to ES treatment for cervical cancer patients undergoing RH.

There are a few studies (22) focused on ES-related post-operative rehabilitation of cervical cancer patients that showed that TENS was effective in preventing UR after RH. Since those studies were not prospective randomized control, we designed this prospective, multi-center, randomized-controlled trial (RCT) to investigate if TENS can improve the voiding function after RH with early cervical cancer.

In this study, UDS was performed post-operatively to evaluate lower urinary tract dysfunction, this method being the gold standard to investigate that particular pathology, while the free flow study was essential in the evaluation of voiding patterns and the characteristics of the emptying phase (23), represented by the Qmax, average flow rate, voiding time, and the time to Qmax. The basic electrophysiological indicators of pelvic floor muscle, which mainly comprise strength, duration, and fatigue of the muscle contraction, were used as an evaluated index for pelvic floor dysfunction (24).

Having been registered at www.clinicaltrials.gov (Identifier: NCT02492542), the RCT was conducted from January 2015 to December 2019. The research protocol was designed based on a methodology published by Xiu-li Sun, etc. in 2017 (25) and reviewed and approved by the ethics boards of the following seven Hospitals: Peking University People's Hospital, Peking University First Hospital, Peking University Third Hospital, Beijing Obstetrics and Gynecology Hospital of Capital Medical University, Beijing Chao-yang Hospital of Capital Medical University, Beijing Hospital, Sheng-Jing Hospital of China Medical University, Peking University Shen-zhen Hospital and Gansu Provincial Maternal and Child Health Hospital.

Our results demonstrated that TENS could increase the Qmax in the early post-operative period. However, TENS did not make a significant difference in the improvement of residual urine volume and the urination function and did not have an effect on PFEmF or QoL, indicating that TENS cannot work to improve those post-operative problems.

The mean duration of post-operative catheterization varies in different literatures. In Roh's study, the median period for obtaining a PVR volume of <50 ml among patients from the conventional RH group was 18 days, while that in the nerve-sparing RH group was 11 days (30). In another study, 14 days on average was necessary to achieve a PVR volume of <50 ml after nerve-sparing RH (31). In China, the duration of catheterization is usually between 10 and 14 days after the surgery (32). In our research, we removed the catheter 14 days after the operations.

Chuang's research showed that the residual volume of urine tended to increase at 2 and 6 weeks after RH, the mean and maximal flow rates both showed reduction at 2 weeks, 6 weeks, and 3 mos. after surgery (33). This may be attributed to the surgery impairing the parasympathetic motor innervation in maintaining detrusor contractility. In a neuro-urological study, transient neurological changes were observed after RH: pudendal nerve motor latency was prolonged in the 2 and 6 week checks, but returned to baseline levels in the 3 mos (34). Our study also shows that the application of TENS made no significant difference in residual urine volume and the recovery of urination function, although it increased the Qmax by the 28^th day. This result suggests that recovery of urination function may be related to the time that has passed allowing for post-operative recovery, which is a natural process, but not to the early TENS.

In Huan Li's study (22), 91 patients diagnosed with stage IA2–IB2 cervical cancer, and treated with RH were enrolled and randomized into two groups. The results showed that low-frequency electrical stimulation was more effective than conventional intervention in preventing urinary retention after RH, and it also intensified the recovery of pelvic muscle strength. A prospective random control trial by Yang (35) demonstrated that sacral and transcranial magnetic stimulation improved pelvic floor dysfunction and QoL of gynecological cancer patients. Hwang's (36) research suggested that transcutaneous electrical stimulation (TES) training resulted in a beneficial effect on sexual function in women with stress urinary incontinence, which was evidenced by the significant differences in pelvic floor muscle strength, power, endurance, and Female Sexual Function Index domain scores in both between-group analyses (TES vs. control group) and within-group analyses (pre-TES vs. post-TSE). Research by Yamanishi (16) showed that electrical stimulation could significantly improve the QOL of patients after radical prostatectomy.

However, Laurienzo (20) reported an unsupportive result based on their research, in which they investigated the effect of electrical stimulation and pelvic floor muscle training on muscle strength, urinary incontinence, and erectile function in men with prostate cancer treated by radical prostatectomy and concluded that the muscle strength recovery occurs independently of the therapy employed; electrical stimulation also did not have an impact on the recovery of urinary continence and erectile function. Marloes (7) found that, although some patients were undergoing more radical surgery, their QoL was not different, suggesting that the surgery itself had few effects on QoL, so the effect of TENS on QoL could not be important. In our study, TENS did not make a significant difference in improvement for residual urine volume and the urination function, and showed no effect on PFEmF or QoL.

Although the exact mechanism of action has yet to be fully understood, TENS was believed to restore the balance between excitation and inhibition in bladder function by modulating the signal traffic to and from the bladder through the sacral plexus. Electrical parameters such as the stimulation frequency, intensity, number, and duration of stimulation sessions were highly variable among studies, which reinforces that there was not a universally established regimen for it. Generally, the frequency of TENS ranges from 2 to 75 Hz (16, 17, 19–21, 37–39). Electrical stimulation with low frequency (2–50 HZ) evoked bladder contraction, resulting in increasing voiding efficiency (39). PFM can be activated with frequencies between 35 and 40 Hz, while the effects at 5–10 Hz spread also to the detrusor muscle (40). Huan Li's study compared the treatment frequency of 35 Hz and 1 Hz, and showed that 1 Hz is more effective (22). The stimulation sites of peripheral nerves were different, such as the sacral nerve roots, tibial nerve, pudendal nerve, and dorsal genital nerves. Electrodes could be placed adjacent to the sacral region (S3), tibial region, clitoral or penile region, or into the vagina or rectum. The sacral or tibial region was likely the most logical site since it directly or indirectly targets the medullar root S3, and the latter was often be preferred as a minimally invasive modality due to the poor tolerability of intra-vaginal and intra-anal electrodes resulting from pain or discomfort (37, 41–43). In this study, frequencies of 1/4/1 Hz was selected, and the electrode site was placed in the S3 region.

The indicators observed in this study are related to urination function, PFM, QoL, etc. While the frequency of TENS for different indicators may be different, so the results may be different if the treatment frequency was changed. The treatment period of this study was 2–3 weeks, also, the results may be changed when the treatment time was extended. TENS parameters need to be explored continuously.

In summary, our study showed no sufficient evidence to prove that TENS under the trialed parameters could improve the subject's voiding function, pelvic floor muscle strength, and QoL after RH, which has provided valuable data for rehabilitation after RH.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by 2015PHB050-04. The patients/participants provided their written informed consent to participate in this study.

X-lS and J-lW conceived the study and drafted the study design. X-wL, LG, and QW helped with implementation. X-wL wrote the manuscript. J-lW helped to revise the manuscript. H-bW designed the statistical analysis of the study and undertook power calculation. Others are responsible for recruiting patients, performing surgery, collecting data and completing follow-up. YL is responsible for the establishment of medical database. All authors approved the final manuscript.

This work was supported by the National Key R&D Program of China (nos. 2018YFC2002204), Clinical Trials.gov (NCT02492542) on June 25, 2015 and Chinese Preventive Medicine Association (nos. 2020-Z-23).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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