Introduction

Transurethral resection of the prostate (TURP) is currently the standard surgical treatment for men with prostate (30–80 mL) and moderate-to-severe lower urinary tract symptoms (LUTS) secondary of benign prostatic obstruction (BPO) [1]. However, when evaluating urodynamic parameters, recurrence rate and surgical revision, TURP is evidently inferior to open prostatectomy (OP) [2,3,4]. In addition, TURP is still associated with significant morbidity, including perioperative bleeding requiring blood transfusion (2%) and TUR syndrome (0.8%) [5]. To address these problems, a variety of endoscopic procedures have been developed. For example, endoscopic enucleation of the prostate (EEP) using bipolar circuitry has been shown to be comparable to OP regarding the efficacy and durability by four randomized-controlled trials (RCTs) and confirmed as an anatomical enucleation technique [6,7,8,9]. Furthermore, together with holmium laser enucleation of the prostate, EEP such as bipolar enucleation have demonstrated comparable efficacy but lower morbidity in comparison to OP by two meta-analysis [10, 11], and were recommended by the 2016 EAU guidelines as the first choice of surgical treatment in men with a substantially enlarged prostate and moderate-to-severe LUTS.

Over the recent years, EEP with various other energy sources has been also developed [12], including diode laser enucleation of the prostate (DiLEP), which has been recognized as a safe and effective procedure, and also considered as an anatomical EEP technique [13,14,15]; However, the relevant RCT remains limited. Therefore, the present aimed to evaluate the overall efficacy and safety of a modified DiLEP and also to compare DiLEP versus BEEP in a dual-center RCT.

Patients and methods

Patients

The study protocol was approved by the Ethics Committee of the two participating hospitals. All subjects signed written informed consent prior to the study. Preoperative assessment included complete medical history, physical examination, prostate volume (PV) by transrectal ultrasound, post-void residual urine (PVR), uroflowmetry, International Prostate Symptom Score (IPSS), quality of life (QoL), International Index of Erectile Function (IIEF-5), prostate-specific antigen (PSA), hemoglobin and electrolytes assay, urine analysis, and urine culture. Consecutive patients (age 50–80) with LUTS due to BPO (prostate size 20–160 mL) were assessed for eligibility. The inclusion criteria were IPSS ≥ 12 and the QoL ≥ 4, maximum urinary flow rate (Qmax) ≤ 15 mL/s, and/or The Schafer grade ≥ 2, and/or failed medical therapy of BPO, and/or recurrent urinary retention. Exclusion criteria were previous urethral/prostatic surgery, known prostate cancer or urethral strictures, and neurogenic bladder or other neurologic disorder that may affect micturition.

Study design

This is a dual-centre, open-label, parallel-design non-inferiority RCT (Trial registration: http://www.who.int/ictrp/en/, Identifier: ChiCTR-IPR-15006717). The primary outcomes were Qmax, IPSS at 12 months. The secondary outcomes included operation time, tissue removal ratio, morcellation efficiency, total retrieve efficiency, energy delivery, laser fibers and bipolar loops used, decrease in serum hemoglobin and sodium, duration of bladder irrigation, indwelling catheterization, hospital stay, and complication rate. The follow-up was conducted at 1 week, 1, 3, 6, and 12 months postoperatively, and included Qmax, IPSS, QoL, PSA, IIEF-5, and adverse events. The PV and PVR were recorded only at 3, 12 months.

The assessment was made by researchers blinded to treatment allocation. AEs related to treatments were recorded according to the modified Clavien classification system [16] and reviewed by an independent clinical events committee consisting of three urologists blinded to treatment. The process of clinical trials and the original results were monitored by a clinical research organization authorized by China Food and Drug Administration.

Sample size, randomization, and statistical analysis

The sample size was estimated using nQuery Advisor 7.0 based on expected no difference in Qmax and IPSS between the two arms at 12-month, and non-inferiority limit of − 5 mL/s for Qmax and 3 points for IPSS [17]. Estimated standard deviation was 9 mL/s and 5 points for Qmax and IPSS, respectively [18,19,20]. Significant level was 2.5% (one-sided) and power was 80%. The estimation yielded 52 and 45 subjects in each arm based on Qmax and IPSS, respectively. Anticipating a drop out of 10%, we planned to enroll 57 subjects in each arm.

The randomization was stratified based on centres. The randomization sequence (1:1 ratio) was developed using the proc plan process of SAS 9.2. Allocation concealment was conducted using sealed opaque envelopes, distributed by the Clinical Research Associate upon the enrollment of each subject.

The analysis was carried out using the SAS statistical package (version 9.2, SAS Institute, Cary, NC, USA). Normally distributed continuous variables were expressed as mean ± standard deviation, and were compared by t tests. Non-normally distributed continuous variables were presented as median and interquartile range, and were analyzed with Mann–Whitney U test or Wilcoxon rank-sum test. Categorical variables were expressed as percentages and were compared with the Pearson Chi-square or Fisher’s exact test. For Qmax and IPSS, the missing data were imputed by last observation carried forward method, and the analyses were conducted following the intention-to-treat principle.

Surgical procedures

All ten surgeons were licensed urologists trained and experienced with DiLEP and BEEP more than 50 cases.

DiLEP

Patients were placed in a lithotomy position under general or spinal anesthesia. A 26F continuous-flow resectoscope equipped with a reusable end-firing 980-nm diode laser fiber was used. Normal saline was used for irrigation. The diode laser (INTERmedic, Spain) was set at 120 W for cutting and 30 W for coagulation. A 26F offset nephroscope, along with a soft-tissue morcellator (HAWK, YSB-III, China), was used.


Step #1: identification of surgical capsule plane (SCP).


Landmarks were identified close to the verumontanum using diode laser, and the urethra mucosa between the median lobe and verumontanum was incised. The beak of resectoscope was used to squeeze the left lobe to the right from the landmark (Fig. 1a), and the SCP of the left lobe would be identified naturally (Fig. 1b). Similarly, the SCP of median and right lobe could be also identified when the beak of resectoscope was squeezed to the right from the SCP of the left lobe (Fig. 1c). Then, the SCP of three lobes were identified around the distal prostatic (Fig. 1d).

Fig. 1
figure 1

Modified DiLEP. V verumontanum, LL left lobe, RL right lobe, ML median lobe, SC surgical capsule, BC bladder cavity, BN bladder neck, U urethra, UMF urethral mucosa flap, PF prostatic fossa, ES external sphincter

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Step #2: enucleation of the three lobes.


Starting from the SCP of the median lobe, the beak of resectoscope was used to detach the median lobe retrogradely, and detach the left lobe off pseudocapsule toward bladder neck clockwise from 6 to 12 o’clock (Fig. 1e). The diode laser was used to coagulate all the hemorrhage spots during procedure when need, and to cut off the connection between lobes and bladder neck. Similarly, the right lobe could be also detached off pseudocapsule counter-clockwise. At this time, the whole adenoma would be separated from pseudocapsule, with the urethral mucosa flap connected with distal prostatic apex (Fig. 1f). Cut off the urethral mucosa flap in an inverted resectoscope (Fig. 1f) and push the adenomas into bladder cavity. Then, a smooth prostatic fossa would be discovered, no transition zone tissue residue (Fig. 1g).


Step #3: morcellation of the enucleated adenoma.


A nephroscope was placed to distend the bladder with continuous flushing. A downward technique was used to improve the safety of morcellation (Fig. 1h). Extracted tissue was kept in a container to perform pathological analysis. A standard 22F three-way catheter was inserted for flushing using normal saline.

BEEP

The procedure of BEEP was performed using a previously described technique [18], which is similar to DiLEP exception of the supply vessels and hemorrhage spots were coagulated by the bipolar loop. Identical tissue morcellation technique was carried out in both procedures. The bipolar plasmakinetic system (ScanMed, China) was set at 160 W for cutting and 100 W for coagulation.

Results

Study subjects

From May 2015 to October 2015, 142 patients were screened for eligibility; 28 were deemed ineligible. The remaining 114 subjects were enrolled (57 patients in each arm). Three patients were excluded from analysis (Fig. 2). The baseline characteristics are shown in Table 1.

Fig. 2
figure 2

Flow diagram of the participants through the study

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Table 1 Baseline patient characteristics
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Perioperative results

All operations were successful. The total retrieval efficiency of DiLEP was inferior to than BEEP (1.1 ± 0.32 vs. 1.3 ± 0.43 g/min, P = 0.045), while there were no difference regarding operation time (41.4 ± 18.1 vs. 38.8 ± 16.9 min, P = 0.430) including enucleation time and morcellation time. The two arms were also comparable in tissue removal ratio, morcellation efficiency, sodium decrease, hemoglobin decrease, length of bladder irrigation, catheterization time, and hospital stay (Table 2).

Table 2 Perioperative data
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Non-inferiority outcomes

The criterion for non-inferiority was met for both Qmax (95% confidence interval of mean difference: − 2.86 to 2.50) and IPSS (95% confidence interval of mean difference: − 0.79 to 1.02) (Table 3). There was a consistent improvement in Qmax during the first 6 months after DiLEP and during the first 3 months after BEEP, with sustained increase throughout the 12-month period in both arms (Fig. 3a). There was also a consistent improvement in IPSS during the first 3 months postoperatively, with sustained improvement during the 12-month period in both arms (Fig. 3b). Neither Qmax nor IPSS differed between DiLEP and BEEP at any time points.

Table 3 Non-inferiority of DiLEP to BEEP
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Fig. 3
figure 3

Outcomes following treatment with the DiLEP or BEEP. a Qmax, b IPSS, c QoL, d PSA, e PVR, f PV, g IIEF-5

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Functional results

QoL, PVR, IIEF-5, PSA, and PV were comparable between the two arms (P > 0.05 for all). Both QoL (Fig. 3c) and PVR (Fig. 3e) improved substantially over 12-month in both arms. PSA decreased from 6.8 ± 7.5 to 0.6 ± 0.3 ng/mL (fell by 91.5%) in the DiLEP and from 7.7 ± 8.5 to 0.6 ± 0.2 ng/mL (fell by 92.6%) in the BEEP over the first 6 months, the decreases were sustained until 12 months (Fig. 3d). PV decreased from 59.5 ± 28.8 to 22.6 ± 3.9 mL in DiLEP and from 63.4 ± 36.4 to 22.2 ± 4.3 mL in the BEEP at 3 months (Fig. 3f). IIEF-5 improved from 11.2 ± 7.6 to 14.2 ± 8.8 in DiLEP and from 10.2 ± 8.0 to 14.1 ± 8.3 in BEEP during the first 6 months; effects were sustained throughout the 12-month period (Fig. 3g).

Adverse events

Common AEs in DiLEP and BEEP were discomfort symptoms (19.3 vs. 21.1%) and retrograde ejaculation (45.6 vs. 42.1%). 8.8% patients in each group have been confirmed urinary incontinence and relieved through pelvic floor exercises within 3 months. Three patients in DiLEP (5.3%) vs. one patient (1.8%) in BEEP underwent incision of bladder neck for bladder neck contracture, respectively. There were no capsule perforation, morcellation injuries, TUR syndrome, blood transfusion, and reoperation for residual gland occurred, and no significant difference in AEs between two procedures (Table 4).

Table 4 Adverse events (AEs) assessed by modified Clavien classification
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Discussion

Bipolar-plasmakinetic transurethral enucleation and resection of the prostate (TUERP/PKEP) was designed and has been routinely performed in clinical practice at our department since January 2001 [21]. In TUERP, the adenoma was completely dissected along the SCP in a similar way as a surgeon’s index finger does during OP, which is comparable to HoLEP, and also considered as anatomical enucleation technique [18]. Moreover, in HoLEP, the adenoma was enucleated by the blasting expansion power due to the pulsed nature of holmium laser during HoLEP, and the tissue was retrieved using morcellator, whereas, in TUERP, the adenoma was enucleated by applying the blunt power using the beak of resectoscope and resected with a bipolar loop. Recently, this enucleation technique had been improved and applied into DiLEP. Notably, our preliminary experiences demonstrated that DiLEP associated with better hemostatic properties than HoLEP when the diode laser was used in a non-connected manner. Consequently, this dual-centre randomized-controlled non-inferiority trial was undertaken to compare DiLEP with BEEP for the first time.

Currently, various EEP procedures have been developed and introduced [22]; However, there was an obvious discrepancy between these objectively parameters in those mentioned literatures, including the mean Qmax change (varied from 8.3 to 23.9 mL/s), and mean PSA reduction (67–93%). These discrepancies might be attributed to the different EEP techniques employed, which could be divided into three categories based on retrieved tissue: (1) similar enucleation (the adenoma was partly removed close to SCP), (2) partial enucleation (a part of the adenoma was dissected along SCP), and (3) anatomical enucleation (the entire adenoma dissected along SCP).

DiLEP should be considered as an anatomical EEP. The SCP identification is the crucial step for DiLEP. In the previous studies, SCP was identified by making an incision to the verumontanum-proximal urethral mucous [18] or from an incision of bladder neck [23]. In the present study, the SCP was simply identified with the ‘blunt squeezing technique’ by squeezing the right or left lobe approximate to verumontanum using the beak of the resectoscope. According to our experiences, this “blunt squeezing technique” is a simple and rapid method for the identification of SCP, which also ensures the anatomical enucleation of the adenoma at the apex, and avoids the sharp cutting injury or thermal damage to the sphincter caused by energy sources. In addition, the entire adenoma was dissected along the SCP during procedures; some intractable adenomas during OP could also be removed by diode laser under endoscopic vision. Thus, hypothetically DiLEP may be considered superior to OP regarding urodynamic parameters and reoperation rates. This is confirmed by the fact that the change in the mean Qmax, 21.0 mL/s in DiLEP was not significantly different to the change in OP (11.0–21.4 mL/s) [6,7,8,9]. The mean tissue retrieval rate was 71.8%, and the percentage reduction in PSA was up to 91.5% in DiLEP, which appeared to higher than PSA reduction (78.6–90.1%) for OP [7, 8]. Furthermore, no reoperation was required due to residual adenoma at 12-month follow-up. Taken together, these findings suggested that the adenoma was removed entirely, leading to significantly improved functional outcomes, including IPSS, QoL, PVR, and IIEF.

Bleeding and TUR syndrome remain major challenges for TURP, particularly in patients with larger prostates, due to a continuous bleeding and water absorption during TURP. However, the blood vessels of adenoma were blocked immediately and usually only once at SCP during EEP, which minimized the bleeding and water absorption compared to TURP. This was reflected by the minimal estimated blood loss and water absorption, in the current study and available literature [24]. Furthermore, diode laser has been associated with excellent hemostatic properties [25], It has also been demonstrated that DiLEP (1380 nm) was also associated with less blood loss compared to TURP in an RCT [15] and as compared to laparoscopic adenomectomy in control study [26], the hemoglobin decrease of DiLEP (0.24–0.71 g/dL) in the two studies was consistent with this trial (0.356 g/dL). Furthermore, the two RCTs also showed that DiLEP was superior to BEEP regarding hemoglobin decrease [14, 27]. However, the current dual-centre RCT demonstrated that there was no significant difference in terms of blood loss and water absorption, which may be attributed to the constant intravenous fluid management in all patients or the tissue morcellator was used in the both groups, while these biases were not controlled in the previous trials.

The previous studies have showed longer operate time with EEP compared to TURP [28]. Nevertheless, tissue morcellation significantly promoted the development of EEP. The efficiency of 12.5 g/min of tissue morcellation in the present study was responsible for a higher retrieval efficiency (1.12 g/min) and a shorter operation time (40 min) than TURP (0.8 g/min and 55.3 min, respectively) [19]. Moreover, we also believed that bleeding and water absorption could be further reduced with the advances in the equipment and technique concerning morcellation. Taken together, these findings suggested that with tissue morcellator, DiLEP could significantly eliminate the TUR syndrome and blood transfusion. For these reasons, men with the mild-to-medium prostate (20–80 mL) and substantially enlarged prostate (80–160 mL) were included in this RCT. Indeed, in our department, men with prostate volume over 280 mL were successfully treated with DiLEP and BEEP.

Of note, both the groups had 8.8% transient incontinence postoperatively which were insignificant as compared to that of TURP (0–5%) [5]; However, when the men with a prostate size of ≤ 80 mL were only considered, the transient incontinence decreased to 2%. We speculated that urinary incontinence was possibly correlated with larger prostate volume which was consistent with previously reported [29].

Besides, three patients (5.3%) in DiLEP and one patient (1.8%) in BEEP have been confirmed as bladder neck contracture at 12-month postoperatively; However, the difference between the two groups was not statistically significant. Furthermore, the higher complication rate of the Clavien III complications in DiLEP should not be ignored due to a low sample seize of the study and lower statistical power to detect their difference, this may be considered the limitation of this study. Other limitations are the shorter follow-up period and the unevaluated learning curve. Further defined and large RCTs comparing DiLEP with TURP or HoLEP are needed.

Conclusion

The modified DiLEP was comparable with BEEP in terms of safety and efficacy at 12-month postoperatively. Both are size-independent procedure providing complete removal of the transition zone, satisfied micturition improvement, and low morbidity for men with moderate-to-severe LUTS/BPO. However, our experiences need to be confirmed and the long-term follow-up is needed.