Efficacy and Safety of Enucleation vs. Resection of Prostate for Treatment of Benign Prostatic Hyperplasia: A Meta-analysis of Randomized Controlled Trials - Full Text Article

The purpose of this study is to compare the efficacy and safety of transurethral enucleation and resection of the prostate for treatment of benign prostatic hyperplasia (BPH). 

This meta-analysis was conducted through a systematic search before 1 September 2018. All included publications were randomized controlled trials (RCTs). Efficacy was evaluated based on International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax), and quality of life (QoL). Perioperative data and complications postoperatively were also assessed. The quality assessment of included studies and results was performed by using the Cochrane System and GRADE (grading of recommendation assessment, development, and evaluation) System. 

Thirty-one publications involving 26 RCTs with 3283 patients were assessed in this review. The differences between enucleation and resection in IPSS, Qmax, and QoL at 1, 3, and 6 months postoperative were not significant. At 12 months postoperatively, IPSS and Qmax in the enucleation group were significantly better than those in the resection group. The results also suggested a benefit of enucleation over resection in-hospital stay, hemoglobin loss, serum sodium decrease, blood transfusion rate, grade II, grade III complications, and early complications. However, resection exhibited a better operative time. 

Compared with resection, enucleation showed better efficacy and safety postoperatively with less hematological changes and severe complications, except for longer operative time.

Introduction
For surgical therapy of benign prostatic hyperplasia (BPH), monopolar transurethral resection of the prostate (TURP) has been the gold standard for many years.1 Despite its promising efficacy in treating BPH, TURP is associated with a risk of significant complications and clinical limitations,2 including life-threatening events such as transurethral resection (TUR) syndrome, as well as high cost due to long hospital stay and difficulty in management of large-sized glands; thus, alternative therapeutic approaches have been explored.3 Various minimally invasive therapies have been investigated to reduce the morbidities in surgical management of BPH. Bipolar transurethral resection (B-TURP) in the plasma kinetic (PK) system (Gyrus-PK), or transurethral resection in saline (TURis) system (Olympus), could be performed using saline as irrigant; these approaches avoid the possibility of TUR syndrome and require a shorter duration of hospital stay.4 In both TURP and B-TURP, resection is the key procedure of the operation. Technological advances in recent years has led to the emergence of enucleations for BPH, involving various laser and plasma approaches. Holmium laser enucleation of the prostate (HoLEP) was first described in 1995;5 its efficacy and safety have been demonstrated especially for large prostates. Thulium laser enucleation of the prostate (ThuLEP) was introduced in 2010;6 its blunt enucleation was proven safe and effective, with favorable results compared with other treatment modalities.7 In addition, the diode laser, which was approved in the USA in 2007, has been widely used due to its high vaporization capacities and excellent coagulation properties;8 diode laser enucleation of the prostate (DiLEP) is also a promising technique for BPH. In addition to the above techniques for enucleation of the prostate, a PK system was developed that enables anatomic enucleation of entire lobes of the prostate 9 via PK enucleation of the prostate (PKEP). A previous study demonstrated that PKEP is safe and technically feasible for the treatment of BPH.10

In general, enucleations such as HoLEP, ThuLEP, and PKEP, as well as monopolar or bipolar resections, comprise the major contemporary surgical techniques for BPH. Thus, it is necessary to determine which technique is better for surgical therapy in patients with BPH. Importantly, numerous clinical studies and reviews have compared and analyzed the outcomes of specific approaches such as HoLEP vs. TURP for the treatment of prostate with different follow-up periods, but overall effects of enucleation vs. resection of prostate were not noted. This is the first study to compare enucleation and resection of prostate for treatment of BPH in seven subgroups involved in various enucleative and resective techniques.

The objective of this review was to determine the contemporary status of the above techniques for enucleation and resection of prostate, and to quantitatively analyze their efficacy and safety via meta-analysis of randomized controlled trials (RCTs). Treatment-specific efficacy and safety profiles were generated to aid in medical decision making for patients and doctors.

Materials and Methods
Data sources and searches: The meta-analysis was conducted based on systematic searches of MEDLINE, Web of Science, EMBASE, and the Cochrane Library using the search terms of “prostate,” “resection,” and “enucleation,” before 1 September 2018. After the removal of duplicates and the exclusion of conference abstracts, the initial selection was made based on the titles and abstracts of the articles. Papers reporting the results of RCTs that compared enucleation with resection of the prostate in patients with BPH were identified through full-text review. An additional manual search of references from identified studies was performed. After selection, relevant information was gathered from the articles. After the authors of this meta-analysis reached consensus, the reference lists of all identified articles and general reviews of this topic were examined manually by two independent reviewers. The quality assessment of included studies in the meta-analysis was measured by using the Cochrane System.

Study selection: Inclusion and exclusion criteria were defined pre-article search. Studies were included if met the following criteria: RCTs comparing the efficacy and safety of enucleation and resection, patients with lower urinary tract symptoms (LUTS) caused by BPH, patients with International Prostate Symptom Score (IPSS) ≥ 8, and maximum urinary flow rate (Qmax) ≤ 15 mL/s. Exclusion criteria included the following: prostate cancer, previous urethral, prostate, and bladder surgeries, and neurogenic bladder.

Data abstraction: Parameters assessed in this analysis were as follows: IPSS, Qmax, and quality of life (QoL) during the follow-up period served as efficacy outcomes; hemoglobin loss, operative time, hospital stay, and blood transfusion served as perioperative outcomes; International Index of Erectile Function5 (IIEF-5); early and late complications according to the Clavien classification system, as well as some other specific complications such as urge incontinence, stress incontinence, dysuria, hematuria, blood transfusion, and bladder neck contracture, served as safety outcomes.

Data synthesis and analysis: The mean difference and risk ratio were used for continuous variables and binary outcomes such as specific complications, which were calculated by dividing the total number of specific outcomes by the total number of patients treated by each respective procedure; 95% confidence intervals were also determined. The Cochrane χ2 - test and Inconsistency (I 2 ) were used to assess the heterogeneity among studies. p < 0.10 indicated the present of heterogeneity and I 2 < 50% indicated that the heterogeneity was acceptable, such that a fixed-effects model was used; otherwise, a random-effects model was used. The overall effects were determined by the Z-test and p < 0.05 was considered statistically significant. Subgroup analysis was conducted while comparing different operative methods. All tests were performed using Review Manager Software (RevMan 5.3) and GraphPad Prism 6. Results are shown as forest plots, tables, and funnel plots. Quality of evidence is assessed by GRADE (grading of recommendation assessment, development, and evaluation) System using GRADE profile 3.6.1, in which grades of evidence include high quality, moderate quality, low quality, and very low quality. They mean “Further research is very unlikely to change our confidence in the estimate of effect.”, “Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.”, “Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.”, and “We are very uncertain about the estimate.”, respectively.11

Results
Study characteristics: There were 31 publications involving 26 RCTs with a total of 3283 patients who were treated by enucleation (n = 1652) or resection (n = 1631) of the prostate, with an evidence level of 1b (Fig. 1).12-42 The results of the quality assessment of included studies in the meta-analysis by using the Cochrane System are shown in Fig. 2. Because of the use of different techniques, seven types of comparable studies were assessed as subgroups. Three RCTs with 460 patients reported HoLEP vs. B-TURP (230/230), 5 RCTs with 666 patients reported PKEP vs. B-TURP (332/334), and 2 RCTs with 366 patients reported ThuLEP vs. B-TURP (181/185). One RCT with 126 patients reported DiLEP vs. TURP (74/ 52), 12 RCTs with 1296 patients reported HoLEP vs. TURP (650/646), 1 RCT with 204 patients reported PKEP vs. TURP (102/102), and 2 RCTs with 165 patients reported ThuLEP vs. TURP (83/82). Table 1 provides an overview of the composite baseline characteristics of all included studies.

PCAN_flow_diagram.png

PCAN_risk_of_bias.png

Quantitative Data Synthesis

Efficacy outcomes:
International Prostate Symptom Score - Twenty-one studies reported IPSS. Figure 3 and Supplementary Figures 1–5 show the IPSS at 1, 3, 6, 12, and 24 months after the operation. Overall, IPSS at 1 (− 0.28 [− 0.93, 0.37], p = 0.40), 3 (− 0.26 [− 0.90, 0.37], p = 0.42), 6 (− 0.31 [− 0.89, 0.28], p = 0.30), and 24 months (− 0.48 [− 1.33, 0.37], p = 0.27) were not significantly different between enucleation and resection of prostate. However, at 12 months postoperatively, enucleation showed lower IPSS than resection (− 0.84 [− 1.32, − 0.35], p = 0.0007). For specific subgroups, IPSS in ThuLEP was significantly better than that in B-TURP at 1 (− 0.50 [− 0.94, − 0.06], p = 0.03) and 6 months (− 0.80 [− 1.27, − 0.33], p = 0.0008), whereas it was worse at 3 months (0.45 [0.03, 0.88], p = 0.03). IPSS in HoLEP was lower than in B-TURP at 1 month (− 1.04 [− 1.75, − 0.33], p = 0.004). Similar results were noted between PKEP and TURP groups at 12 and 24 months; IPSS was better in PKEP (− 1.70 [− 2.67, − 0.73], p = 0.0006 and − 2.20 [− 2.89, − 1.51], p < 0.00001, respectively). In addition, IPSS in HoLEP was superior to that in TURP at 12 months postoperatively (− 1.17 [− 1.93, − 0.41], p = 0.003).

Qmax - The data were acquired from 19 studies. For Qmax at 1, 3, and 6 months postoperatively, there were no significant differences between enucleation and resection of prostate (0.58 ml/s [− 0.22, 1.37], p = 0.15; 0.62 ml/s [− 1.09, 2.34], p = 0.48, and 1.25 ml/s [− 0.04, 2.55], p = 0.06, respectively). At 12 months, Qmax was greater in the enucleation group than in the resection group (0.83 ml/s [0.26, 1.40], p = 0.004). For specific groups at specific follow-up time points, Qmax was greater in PKEP than in B-TURP at 1 month (0.78 ml/s [0.05, 1.52], p = 0.04); Qmax was greater in PKEP than in TURP at 6 months (4.70 ml/s [2.71, 6.69], p < 0.00001). Besides, better results were noted in HoLEP than in B-TURP (0.42 ml/s [0.04, 0.80], p = 0.03) or TURP (1.09 ml/s [0.13, 2.06], p = 0.03) at 12 months postoperatively (Fig. 4 and Supplementary Figure 6-9).

Quality of life - Eleven studies reported the data. Figure 5 and Supplementary Figures 10-13 show the QoL at 1, 3, 6, and 12 months after the operation. Overall, QoL at 1 (0.04 [− 0.27, 0.36], p = 0.78), 3 (− 0.07 [− 0.16, 0.03], p = 0.18), 6 (− 0.14 [− 0.40, 0.12], p = 0.28), and 12 months (− 0.14 [− 0.37, 0.09], p = 0.24) were not significantly different in the enucleation and resection groups. For specific subgroups, QoL was better in PKEP than in TURP at 6 (− 1.00 [− 1.38, − 0.62], p < 0.00001) and 12 months (−0.60 [−0.95, −0.25], p = 0.0007), and in B-TURP at 3 months (− 0.22 [− 0.42, − 0.03], p = 0.02) postoperatively. QoL was better in HoLEP than in B-TURP at 6 (− 0.28 [− 0.44, − 0.12], p = 0.0006) and 12 months (− 0.24 [− 0.39, − 0.09], p = 0.001) postoperatively. However, better result was noted in ThuLEP than in B-TURP at 1 month (0.10 [0.04, 0.16], p = 0.002) postoperatively.

International Index of Erectile Function-5 - Data regarding IIEF-5, which reflects erection function, were collected from seven studies postoperatively. In a comparison of IIEF-5 between enucleation and resection of prostate (Table 2 and Supplementary Figure 14-16), the overall effect did not statistically differ between enucleation and resection of prostate at 6 (0.16 [− 0.31, 0.62], p = 0.51), 12 (− 0.02 [− 0.50, 0.47], p = 0.94) and 24 months (0.02 [− 0.05, 0.09], p = 0.54). Furthermore, regardless of the type of enucleation or resection of prostate at 6, 12, or 24 months, no significant difference was noted.

Safety outcomes:
Perioperative data - Perioperative data included operative time, hospital stay, hemoglobin loss, and serum sodium decrease. Detailed results are shown in Table 3

Operative time - Twenty-two studies with 2842 patients reported analyses of operative time. The enucleation group exhibited longer operation time than the resection group (11.14 min [5.51, 16.78], p = 0.0001). In subgroups analyses, HoLEP (15.51 min [9.29, 21.72], p < 0.00001), PKEP (12.60 min [8.70, 16.50], p < 0.00001), and ThuLEP (27.70 min [15.66, 39.74], p < 0.00001) groups were inferior, compared with TURP. In addition, the HoLEP group exhibited a longer operation time, compared with B-TURP (24.13 min [14.11, 34.16], p < 0.00001) (Supplementary Figure 17).

Hospital stay - Twenty studies with 2629 patients reported analyses of hospital stay. Different from operative time, the duration of hospital stay was shorter in the enucleation group than in the resection group (− 22.11 h [− 28.87, − 15.36], p < 0.00001). For subgroup comparisons, HoLEP (− 24.34 h [− 35.81, − 12.86], p < 0.0001), DiLEP (− 16.80 h [− 27.01, − 6.59], p = 0.001), and PKEP (− 35.80 h [− 43.08, − 28.52], p < 0.00001) groups exhibited shorter hospital time, compared with TURP group. Significant differences were also noted in the ThuLEP (− 65.72 h [− 98.52, − 32.92], p < 0.0001) and PKEP (− 16.22 h [− 29.53, − 2.91], p = 0.02) groups, compared with B-TURP (Supplementary Figure 18).

PCAN enucleation vs. resection of prostate
PCAN favoursEPRP
Fig. 3 Forest plot of IPSS at 1, 3, 6, 12, and 24 months postoperatively. B-TURP, bipolar transurethral resection of the prostate, CI, confidence interval; EP, enucleation of prostate; GRADE, grading of recommendation assessment, development, and evaluation system; HoLEP, holmium laser enucleation of the prostate; IPSS, International Prostate Symptom Score; PKEP, plasma kinetic enucleation of prostate; RP, resection of prostate; TURP, transurethral resection of the prostate; ThuLEP, thulium laser enucleation of the prostate


Hemoglobin loss - Twenty studies with 2399 patients in 6 subgroups reported analyses of hemoglobin loss. Overall, the enucleation group exhibited lower hemoglobin loss than was observed in the resection group (− 0.62 g/dl [− 0.81, − 0.43], p < 0.00001). Lower hemoglobin loss was noted in HoLEP (− 0.46 g/dl [− 0.85, − 0.07], p = 0.02) and PKEP (− 0.59 g/dl [− 0.80, − 0.39], p < 0.00001) groups, compared with B-TURP. Similar results were observed in HoLEP (− 0.46 g/dl [− 0.76, − 0.17], p = 0.002) and PKEP (− 1.14 g/dl [− 1.36, − 0.92], p < 0.00001) groups, compared with TURP group (Supplementary Figure 19).

Serum sodium decrease - Twelve studies with 1729 patients in 6 subgroups reported analyses of serum sodium decrease. Overall, the enucleation group exhibited lower serum sodium loss (− 0.68 mmol/L [− 1.15, − 0.22], p = 0.004). Compared with the TURP group, lower serum sodium loss was noted in HoLEP (− 1.45 mmol/L [− 2.37, − 0.54], p = 0.002), PKEP (− 0.31 mmol/L [− 0.56, − 0.06], p = 0.02), and ThuLEP (− 1.30 mmol/L [− 2.43, − 0.17], p = 0.02) groups (Supplementary Figure 20).

Complication classification - To evaluate the severity of complications after enucleation or resection of the prostate, we classified complication data into different groups, in accordance with the Clavien classification system.43 The results are shown in Table 2 and Supplementary Figure 21-24. Twenty-one studies with 2587 patients, 21 studies with 2687 patients, 18 studies with 2442 patients, and 2 studies with 304 patients reported complications of grades I, II, III, and IV, respectively. Overall, the frequencies of grade I and IV complications did not significantly differ between enucleation and resection groups (0.94 [0.80, 1.10], p = 0.42 and 0.24 [0.03, 2.15], p = 0.20, respectively). HoLEP was associated with a higher rate of grade I complications than B-TURP (2.63 [1.17, 5.87], p = 0.02). However, complications of grades II and III occurred less frequently in the enucleation group (0.61 [0.38, 0.97], p = 0.04 and 0.54 [0.35, 0.83], p = 0.005, respectively) than in the resection group. No statistical difference existed in any subgroup comparisons.

PCAN favoursEPRP2
Fig. 4 Forest plot of Qmax at 1, 3, 6, and 12 months postoperatively.  B-TURP, bipolar transurethral resection of the prostate; CI, confidence interval; EP, enucleation of prostate; GRADE, grading of recommendation assessment, development, and evaluation system; HoLEP, holmium laser enucleation of the prostate; PKEP, plasma kinetic enucleation of prostate; Qmax, maximum urinary flow rate; RP, resection of prostate; ThuLEP, thulium laser enucleation of the prostate; TURP, transurethral resection of the prostate


Early and late complications postoperatively - The results are shown in Figs. 6 and 7. For early complications, less occurred in the enucleation than in the resection groups (0.74 [0.62, 0.90], p = 0.002). Of them, better results were noted in urinary retention (0.68 [0.48, 0.97], p = 0.03), hematuria (0.37 [0.17, 0.82], p = 0.01), blood transfusion (0.26 [0.15, 0.46], p < 0.00001), and urinary tract infection (0.52 [0.30, 0.93], p = 0.03) in the enucleation than in the resection groups significantly. For late complications, there was no statistic difference between enucleation and resection (0.92 [0.78, 1.09], p = 0.34) as a whole. Urethral stricture occurred less in the enucleation than in the resection groups (0.50 [0.30, 0.84], p = 0.009). For specific complications in subgroups, urge incontinence, stress incontinence, dysuria, hematuria, blood transfusion, and bladder neck contracture were illustrated in detail.

Urge incontinence - The data were obtained from 15 studies with 2026 patients. The overall effect did not significantly differ between enucleation and resection groups (1.24 [0.94, 1.65], p = 0.13). Urge incontinence occurred more frequently in PKEP than in B-TURP groups (1.64 [1.02, 2.64], p = 0.04).

Stress incontinence - Seven studies with 666 patients reported analyses of stress incontinence. No significant difference was noted between enucleation and resection groups (0.87 [0.38, 2.02], p = 0.75). Similarly, the outcomes of three subgroup analyses did not show significant differences: HoLEP vs. TURP (0.87 [0.33, 2.28], p = 0.78), ThuLEP vs. TURP (0.24 [0.03, 2.08], p = 0.20), and HoLEP vs. B-TURP (9.00 [0.50, 163.58], p = 0.14).

Dysuria - Similar to the analyses of stress incontinence, eight studies with 1009 patients reported no overall difference between enucleation and resection groups (0.48 [0.13, 1.71], p = 0.26). A similar lack of difference was noted in comparisons of specific subgroups (HoLEP vs. TURP, 0.80 (0.12, 5.48, p = 0.82), PKEP vs. B-TURP, 0.40 (0.05, 3.13, p = 0.38), and PKEP vs. TURP, 0.20 (0.01, 4.11, p = 0.30).

Hematuria - Seven studies with 700 patients showed an outcome favoring the enucleation group (0.37 [0.17, 0.82], p = 0.01). However, no significant differences were noted in subgroup analyses.

Blood transfusion - Nineteen studies with 2315 patients reported analyses of blood transfusion rate. Overall, blood transfusion rate was significantly lower in the enucleation group than in the resection group (0.26 [0.15, 0.46], p < 0.00001); blood transfusion was rare in the HoLEP (0.18 [0.07, 0.47], p = 0.0004) group, compared with the TURP group. In addition, the PKEP group exhibited a lower blood transfusion rate than the B-TURP group (0.16 (0.03, 0.89), p = 0.04).

PCAN favoursEPRP3
Fig. 5 Forest plot of QoL at 1, 3, 6, and 12 months postoperatively. B-TURP, bipolar transurethral resection of the prostate; CI, confidence interval; EP, enucleation of the prostate; GRADE, grading of recommendation assessment development, and evaluation system; HoLEP, holmium laser enucleation of the prostate; PKEP, plasma kinetic enucleation of prostate; QoL, quality of life; RP, resection of prostate; ThuLEP, thulium laser enucleation of the prostate; TURP, transurethral resection of the prostate


Bladder neck contracture - Seven studies with 1276 patients reported analyses of bladder neck contracture. There was no difference between enucleation and resection groups (0.82 [0.35, 1.92], p = 0.64). Similarly, no differences were found within subgroup analysis.

Discussion
BPH is a common disease in urology, the morbidity of which increases with age; notably, 50% of men at 50 years of age develop the disease, and after 80 years of age 80% of patients exhibit LUTS.44 In this meta-analysis, we assessed differences in efficacy and safety between the two primary transurethral therapies in surgery, enucleation, and resection. We divided the included studies into seven subgroups. We selected IPSS, Qmax, and QoL as efficacy outcomes. Perioperative outcomes and complications (as safety outcomes) were also assessed.

The present meta-analysis compared the efficacy profile of enucleation and resection of prostate for BPH. There was no difference between the two groups in Qmax, IPSS, and QoL at 1, 3, and 6 months postoperatively. Higher Qmax values and lower IPSS were observed in the enucleation group at 12 months postoperatively. No difference was noted at 24 months postoperatively. With regard to longerterm results, unfortunately we failed to make assessments due to the lack of data. In fact, most of the treatments of enucleation lacked the longer-term follow-up data comparing with resection. Among all the trials included in this meta-analysis, Gu et al.22 presented a 6-year follow-up outcome. IPSS were significantly better at 72 months (8.79 vs. 10.03, p < 0.001) in the HoLEP group than in the BTURP group. Qmax was significantly better at 60 months (19.26 vs. 17.50, p < 0.01) in the HoLEP group. Zhu et al. 42 reported 5-year follow-up outcomes: IPSS was significantly better at 48 (3.26 vs. 4.31, p = 0.031) and 60 months (3.32 vs. 4.90, p = 0.001) in the PKEP group, compared with the B-TURP group. Qmax was significantly better at 48 (26.97 vs. 23.11, p = 0.045) and 60 months (26.45 vs. 22.07, p = 0.03) in the PKEP group. Yang et al. 38 reported 5-year follow-up outcomes between ThuLEP and B-TURP. IPSS and Qmax were not significantly different at 36 months (5.4 vs. 6.1, p = 0.066; 22.9 vs. 22.3, p = 0.315) and 60 months (6.5 vs. 6.9, p = 0.179; 19.4 vs. 18.9, p = 0.631).

PCAN_IIEF.png

Differences in the results between enucleation and resection were due to essential techniques and methods during the operation. This may be attributed to the technique of enucleation we used to separate the adenoma from the capsule, which combined both the power of the endfiring laser fiber and the mechanical peeling effect of the sheath leading to a more radical removal of the adenoma as compared with the resection technique. In fact, during the process of enucleation, such as HoLEP, ThuLEP, and PKEP procedures, the tip of the fiber or resectoscope sheath mimicked the tip of the surgeon’s index finger during open prostatectomy, thus producing an anatomical plane between the surgical capsule and the tissue. Here, the surgical capsule could be completely peeled off and a large, open cavity was created with tissue removal. However, with the electric loop back and forth, resection often did not extend down to the fibers of the capsule for fear of capsular perforation and bleeding. Therefore, it could not remove more tissue than enucleation, which was conducted in the “peeling-effect” way. A larger amount of removed tissue was noted in enucleation procedures than in resection procedures (Supplementary Figure 25).

PCAN_B-TURP.png
PCAN Forest plot of early complications
Fig. 6 Forest plot of early complications including urinary retention, hematuria, blood transfusion, urge incontinence, urinary tract infection, and dysuria. B-TURP, bipolar transurethral resection of the prostate; CI, confidence interval; EP, enucleation of prostate; GRADE, grading of recommendation assessment, development, and evaluation system; HoLEP, holmium laser enucleation of the prostate; PKEP, plasma kinetic enucleation of prostate; RP, resection of prostate; ThuLEP, thulium laser enucleation of the prostate; TURP, transurethral resection of the prostate.

PCAN Forest plot of late complications including bladder neck contractureFig. 7 Forest plot of late complications including bladder neck contracture, stress incontinence, retrograde ejaculation, urethral stricture, and reoperation. B-TURP, bipolar transurethral resection of the prostate; CI, confidence interval; EP, enucleation of prostate; HoLEP, holmium laser enucleation of the prostate; GRADE, grading of recommendation assessment, development, and evaluation system; PKEP, plasma kinetic enucleation of prostate; RP, resection of prostate; ThuLEP, thulium laser enucleation of the prostate; TURP, transurethral resection of the prostate.

Overall, operative time was shorter in resection than in enucleation. Operative time was determined by several factors. First, enucleation during operation occurred at the level of the capsule; the technique of retrograde resection of the apical tissue in HoLEP and PKEP required additional time at the region of the sphincter, which received additional attention during enucleation. The second was the time required for morcellation of the enucleated tissue.20 Thus, the total time in the enucleation group included enucleation and morcellation, whereas that in the resection group only included resection time.12 Besides, more attention was paid during morcellation, for fear of the injury of the bladder mucosa, which was usually caused during morcellation of enucleated tissue by incidental aspiration of the bladder wall. Furthermore, corresponding additional tissue was removed with time in enucleation.35 The process of enucleation was more complex, requiring a longer “learning curve”.45 Unskilled surgeons might have contributed to this increased time requirement. 

The learning curve, as mentioned above, is a very important issue for various techniques. Montorsi et al.31 held the point that it was difficult to compare learning curves between enucleations and resections because surgeons performing new techniques had had previous endoscopic experience with TURP. However, a few trials involved in this study mentioned the long learning curve of HoLEP with the use of the morcellator and due to the procedure. It requires substantial skill in endoscopic techniques as well as precise knowledge of the anatomy and morphology of the bladder neck and prostatic urethra. Beginning with small prostates, the learning curve should be accomplished rapidly.26 Hemendra et al.46 reported an endourologist inexperienced with holmium laser prostate enucleation can perform the procedure with reasonable efficiency after about 50 cases with an outcome comparable to that of experts and the learning curve can be minimized with appropriate case selection and a short period of structured supervision.47 Yang et al.37 reported the learning curve of DiLEP performed by a single surgeon; the operator had gained quite good experience after the first 20 cases. As the experience of the surgeon increased, the overall efficiency of the procedure increased, except for HoLEP and DiLEP; others could not be taken into account, because very few papers display adequate details about the level of training of the surgeons. 

Regarding hospital stay, the enucleation group exhibited significantly shorter hospitalization time than the resection group. Hospitalization time was determined by the overall physiological status of patients, occurrence of complications, and recovery condition. Moreover, the difference might be partly caused by the standard for discharge at the involved hospitals. A notable confounding factor might be that many studies did not include a specific definition of hospitalization time.

Loss of hemoglobin and subsequent blood transfusion were determined by the characteristics of enucleation and resection. Lourenco et al.48 reported similar results. In this meta-analysis, enucleation was superior, with reduced loss of hemoglobin and a lower blood transfusion rate. Enucleation provides sufficient hemostasis during the operation. During enucleation, which is performed at the level of the capsule, the blood vessel can be opened only once; it is then sealed by the root on the capsule.40 In contrast, during resection, the loop is used to cut tissues in multiple directions until the blood vessel is sealed, which increases the risk of bleeding, especially in large prostates. In addition, extraction of separated tissue may cause a dramatic change of pressure in the prostate during resection; conversely, morcellation smashes and removes the tissue with a slight change of pressure, which may contribute to a lower bleeding rate.17 With regard to specific lasers, in ThuLEP, the wavelength of the laser matches that of the water absorption peak in tissue (1.92 mm in continuous-wave mode), which likely results in sufficient hemostasis.16

Serum sodium decrease was also significantly lower in enucleation than in resection. Compared with traditional TURP, a primary advantage of the bipolar device was that it used physiologic saline (NaCl 0.9%) as irrigating fluid. The use of saline irrigation resulted in minimal sodium shifts. Ho et al.4 in an RCT of resection technique, showed a significant advantage over the bipolar approach with regard to the occurrence of TUR syndrome. Enucleation techniques such as HoLEP, ThuLEP, and PKEP are conducted in similar manners. TURP is reported to exhibit an increased risk of TUR syndrome, particularly when treating a larger prostate.49 Of all RCTs involved in this meta-analysis, two reported TUR syndrome in three cases, all of which were in TURP groups.31, 40

In previous studies, the intraoperative and postoperative complications exhibited a wide range of damage and severity.50 We used the Clavien classification system to report and analyze the complications according to treatment.43, 51 We found that there were no differences in grade I and IV complications between enucleation and resection groups. Considering grade II and III complications, although no subgroup exhibited significant differences, enucleation exhibited overall superiority in that it resulted in fewer grade II and III complications. Notably, HoLEP has significantly associated with a higher rate of grade I complications than B-TURP; this may be partly explained by a greater incidence of bladder mucosa injury during morcellation in enucleation.32 Data regarding bladder mucosa injury supported this conclusion. Besides, we analyzed early and late complications as a whole. Early complications occurred less in enucleation than in resection significantly. For late complications, slightly better results were noted in enucleation, although with no statistic difference. In general, we concluded that enucleation had better safe profile than resection, at least not worse than the latter.

In addition, to clearly evaluate safety, some complications were analyzed separately. Incontinence after the operation was one of the possible complications for BPH. The cause of this was mostly associated with bladder overactivity, the healing process of the operation wound in prostate, or with the infection that occurred in some cases. There were no significant differences in the incidence of urge incontinence or stress incontinence between the two groups. Interestingly, the incidence of urgency incontinence after the operation was higher in the PKEP group than in the B-TURP group; this conflicted with the result reported by Liao et al.52 This increased incidence was probably due to the high energy applied to the capsule during the procedure.31 Indeed, the surgical technique was an important factor in the risk of stress urinary incontinence.53 Greater caution is required when treating the apical tissue to avoid injuring the sphincter, particularly during the process of enucleation. There was no significant difference between enucleation and resection groups with respect to dysuria and bladder neck contracture. Regarding hematuria, due to sufficient hemostasis and lower rates of urinary tract infection in enucleation, the hematuria rate was lower in enucleation than in resection.

Sexual dysfunction is highly prevalent in patients with BPH and in those surgically treated for this condition.54, 55 There was no statistical difference between enucleation and resection groups in IIEF-5 at 6, 12, and 24 months postoperatively. A similar result was noted with regard to retrograde ejaculation (Fig. 7). Moreover, three RCTs in our meta-analysis reported other sexual functions, such as intercourse satisfaction, orgasmic function, sexual desire, and overall satisfaction.15, 31, 35 None of them was statistically different between enucleation and resection. However, these results may be affected by other factors, such as age and cardiovascular disease,55 and insufficient data. Moreover, the erection function cannot fully represent sexual function, which also includes satisfaction, orgasm, desire, etc. Therefore, more precise trials and data are needed.

Funnel plots were applied for the assessment of publication bias. The results are shown in Supplementary Figure 26. Regarding operative time, the data of Zhang et al.40 were not in accordance with those of other RCTs. This may be because part of the prostate tissue was vaporized by the distinct button electrode during the enucleating process, such that less residual tissue required resection. Therefore, enucleation exhibited shorter operative time than resection. Regarding hospital stay, Bozzini et al.14 reported a dramatic mean difference between ThuLEP and B-TURP, because the duration of hospital stay was determined by various factors. In that RCT, the presence of clots and the requirement for a longer catheterization time in B-TURP (due to the subsequent hematuria) could have led to longer hospital stay. Regarding hemoglobin loss, bias was noted in the publication by Bozzini et al.14 As hemoglobin loss is a perioperative outcome, many studies include an assessment at the end of the operation. In contrast, in that publication, hemoglobin loss was recorded 24 h after operation, which likely caused a difference. Moreover, due to the small sample size, the results of publications by Tan et al.35 and Dragoslav et al.18 caused deviation in hemoglobin loss, as well as IPSS and Qmax at 1, 3, 6, and 12 months postoperatively. Furthermore, the deviation was noted in the funnel plot of grade I complications, which could be explained that we did not precisely classify the complications because of the lack of exact treatments of some complications in several publications, which varied with severity. Therefore, the deviation was caused by reviewers’ predispositions. Except for the outcomes above, funnel plots of other outcomes showed symmetry, which indicated little bias.

In addition, several limitations must be noted in this meta-analysis. First, the overall results were primarily determined by HoLEP vs. TURP, because this subgroup constituted the largest portion of all studies. Second, the follow-up time was different among studies; most studies were followed up to 12 m, which caused that the long-term efficacy and safety of enucleation vs. resection cannot be evaluated due to a lack of sufficient data. Third, although the prostate size was considered a critical factor for perioperative morbidity and postoperative outcomes,31 it was not included in the article. Fourth, in this meta-analysis, we classified resection of the prostate into conventional TURP and B-TURP. However, B-TURP included a few subtypes on the basis of different systems. Our article primarily involved the PK (Gyrus-PK) and saline (TURis) systems (Olympus), and thus could be separated into further subgroups. Finally, great heterogeneity existed among the included studies. However, we did not perform a meta-regression to further investigate the cause of this heterogeneity. Instead, a random-effects model was used to analyze these data.

Conclusions
Although the operative time favored the resection group, the technique of enucleation was more preferable due to its more favorable profile, defined by the statistically relevant differences detected regarding better IPSS and Qmax at 12 m postoperatively. In addition, shorter hospital stay, less hemoglobin and serum sodium decrease, and less blood transfusion rate were noted in the enucleation group. Enucleation group also had less severity of adverse events and early complications. In general, enucleation had better efficacy and safety compared with resection for treatment of BPH.


Authors: Yucong Zhang,1,2 Penghui Yuan,1,2 Delin Ma,3 Xintao Gao,1,2 Chao Wei,1,2 Zhuo Liu,1,2 Rui Li,1,2 Shaogang Wang,1,2 Jihong Liu,1,2 Xiaming Liu,1,2
Author Affiliations: 
1. Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China 
2. Hubei Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 
3. Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

References:
1. Reich O, Seitz M, Gratzke C, Schlenker B, Walther S, Stief C. [Benign prostatic hyperplasia (BPH): surgical therapy options]. Urol A. 2010;49:113–26. 
2. Reich O, Gratzke C, Bachmann A, Seitz M, Schlenker B, Hermanek P, et al. Morbidity, mortality and early outcome of transurethral resection of the prostate: a prospective multicenter evaluation of 10,654 patients. J Urol. 2008;180:246–9. 
3. Rassweiler J, Teber D, Kuntz R, Hofmann R. Complications of transurethral resection of the prostate (TURP)--incidence, management, and prevention. Eur Urol. 2006;50:969–79. Discussion 980 
4. Ho HS, Yip SK, Lim KB, Fook S, Foo KT, Cheng CW. A prospective randomized study comparing monopolar and bipolar transurethral resection of prostate using transurethral resection in saline (TURIS) system. Eur Urol. 2007;52:517–22. 
5. Gilling CC, Cass CB, Malcolm AR, Fraundorfer MR. Combination holmium and Nd:YAG laser ablation of the prostate: initial clinical experience. J Endourol. 1995;9:151–3. 
6. Herrmann TR, Bach T, Imkamp F, Georgiou A, Burchardt M, Oelke M, et al. Thulium laser enucleation of the prostate (ThuLEP): transurethral anatomical prostatectomy with laser support. Introduction of a novel technique for the treatment of benign prostatic obstruction. World J Urol. 2010;28:45–51. 
7. Kyriazis I, Swiniarski PP, Jutzi S, Wolters M, Netsch C, Burchardt M, et al. Transurethral anatomical enucleation of the prostate with Tm:YAG support (ThuLEP): review of the literature on a novel surgical approach in the management of benign prostatic enlargement. World J Urol. 2015;33:525–30. 
8. Wendt-Nordahl G, Huckele S, Honeck P, Alken P, Knoll T, Michel MS, et al. 980-nm Diode laser: a novel laser technology for vaporization of the prostate. Eur Urol. 2007;52:1723–8. 
9. Neill MG, Gilling PJ, Kennett KM, Frampton CM, Westenberg AM, Fraundorfer MR, et al. Randomized trial comparing holmium laser enucleation of prostate with plasmakinetic enucleation of prostate for treatment of benign prostatic hyperplasia. Urology. 2006;68:1020–4. 
10. Rao JM, Yang JR, Ren YX, He J, Ding P, Yang JH. Plasmakinetic enucleation of the prostate versus transvesical open prostatectomy for benign prostatic hyperplasia>80 mL: 12-month follow-up results of a randomized clinical trial. Urology. 2013;82:176–81. 
11. Balshem H, Helfand M, Schunemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64:401–6. 
12. Ahyai SA, Chun FK, Lehrich K, Dahlem R, Zacharias MS, Fisch MM, et al. Transurethral holmium laser enucleation versus transurethral resection of the prostate and simple open prostatectomy--which procedure is faster? J Urol. 2012;187:1608–13. 
13. Ahyai SA, Lehrich K, Kuntz RM. Holmium laser enucleation versus transurethral resection of the prostate: 3-year follow-up results of a randomized clinical trial. Eur Urol. 2007; 52:1456–63. 
14. Bozzini G, Seveso M, Melegari S, de Francesco O, Buffi NM, Guazzoni G, et al. Thulium laser enucleation (ThuLEP) versus transurethral resection of the prostate in saline (TURis): a randomized prospective trial to compare intra and early postoperative outcomes. Actas Urol Esp (Engl Ed). 2017;41:309–15. 
15. Briganti A, Naspro R, Gallina A, Salonia A, Vavassori I, Hurle R, et al. Impact on sexual function of holmium laser enucleation versus transurethral resection of the prostate: results of a prospective, 2-center, randomized trial. J Urol. 2006;175:1817–21.
16. Chang CH, Lin TP, Chang YH, Huang WJ, Lin AT, Chen KK. Vapoenucleation of the prostate using a high-power thulium laser: a one-year follow-up study. BMC Urol. 2015;15:40. 
17. Chen YB, Chen Q, Wang Z, Peng YB, Ma LM, Zheng DC, et al. A prospective, randomized clinical trial comparing plasmakinetic resection of the prostate with holmium laser enucleation of the prostate based on a 2-year followup. J Urol. 2013;189:217–22. 
18. Dragoslav Bašic JS, Potic Milan, Ignjatovic Ivan. Holmium laser enucleation versus transurethral resection of the prostate: a comparison of clinical results. Acta Chir Iugosl. 2013;60:15–20. 
19. Fayad AS, Elsheikh MG, Zakaria T, Elfottoh HA, Alsergany R, Elshenoufy A, et al. Holmium laser enucleation of the prostate versus bipolar resection of the prostate: a prospective randomized study. “Pros and Cons”. Urology. 2015;86:1037–41. 
20. Fayad AS, Sheikh MG, Zakaria T, Elfottoh HA, Alsergany R. Holmium laser enucleation versus bipolar resection of the prostate: a prospective randomized study. Which to choose? J Endourol. 2011;25:1347–52. 
21. Gilling PJ, Wilson LC, King CJ, Westenberg AM, Frampton CM, Fraundorfer MR. Long-term results of a randomized trial comparing holmium laser enucleation of the prostate and transurethral resection of the prostate: results at 7 years. BJU Int. 2012;109:408–11. 
22. Gu M, Chen YB, Liu C, Wan X, Cai ZK, Chen Q, et al. Comparison of holmium laser enucleation and plasmakinetic resection of prostate: a randomized trial with 72-month follow-up. J Endourol. 2018;32:139–43. 
23. Gupta N, Sivaramakrishna, Kumar R, Dogra PN, Seth A. Comparison of standard transurethral resection, transurethral vapour resection and holmium laser enucleation of the prostate for managing benign prostatic hyperplasia of > 40 g. BJU Int. 2006;97:85–9. 
24. Hamouda A, Morsi G, Habib E, Hamouda H, Emam AB, Etafy M. A comparative study between holmium laser enucleation of the prostate and transurethral resection of the prostate: 12-month follow-up. J Clin Urol. 2016;7:99–104. 
25. Jhanwar A, Sinha RJ, Bansal A, Prakash G, Singh K, Singh V. Outcomes of transurethral resection and holmium laser enucleation in more than 60 g of prostate: a prospective randomized study. Urol Ann. 2017;9:45–50. 
26. Kuntz RM, Ahyai S, Lehrich K, Fayad A. Transurethral holmium laser enucleation of the prostate versus transurethral electrocautery resection of the prostate: a randomized prospective trial in 200 patients. J Urol. 2004;172:1012–6. 
27. Li K, Wang D, Hu C, Mao Y, Li M, Si-Tu J, et al. A novel modification of transurethral enucleation and resection of the prostate in patients with prostate glands larger than 80 mL: surgical procedures and clinical outcomes. Urology. 2018;113:153–9. 
28. Luo YH, Shen JH, Guan RY, Li H, Wang J. Plasmakinetic enucleation of the prostate vs plasmakinetic resection of the prostate for benign prostatic hyperplasia: comparison of outcomes according to prostate size in 310 patients. Urology. 2014;84:904–10. 
29. A.Eltabey M, Sherif H, A.Hussein A. Holmium laser enucleation versus transurethral resection of the prostate. Can J Urol. 2010;17:5447–52. 
30. Mavuduru RM, Mandal AK, Singh SK, Acharya N, Agarwal M, Garg S, et al. Comparison of HoLEP and TURP in terms of efficacy in the early postoperative period and perioperative morbidity. Urol Int. 2009;82:130–5. 
31. Montorsi F, Naspro R, Salonia A, Suardi N, Briganti A, Zanoni M, et al. Holmium laser enucleation versus transurethral resection of the prostate: results from a 2-center, prospective, randomized trial in patients with obstructive benign prostatic hyperplasia. J Urol. 2004;172:1926–9.
32. Świniarski Piotrpaweł, S S, Dudzic waldemar, kęsy Stanisław. Thulium laser enucleation of the prostate (TmLEP)vs. transurethral resection of the prostate (TURP):evaluation of early results. Cent Eur J Urol. 2012;65:130–4. 
33. Ran L, He W, Zhu X, Zhou Q, Gou X. Comparison of fluid absorption between transurethral enucleation and transurethral resection for benign prostate hyperplasia. Urol Int. 2013;91:26–30. 
34. Sun N, Fu Y, Tian T, Gao J, Wang Y, Wang S, et al. Holmium laser enucleation of the prostate versus transurethral resection of the prostate: a randomized clinical trial. Int Urol Nephrol. 2014;46:1277–82. 
35. Tan AH, Gilling PJ, Kennett KM, Frampton C, Westenberg AM, Fraundorfer MR. A randomized trial comparing holmium laser enucleation of the prostate with transurethral resection of the prostate for the treatment of bladder outlet obstruction secondary to benign prostatic hyperplasia in large glands (40 to 200 grams). J Urol. 2003;170:1270–4. 
36. Wilson LC, Gilling PJ, Williams A, Kennett KM, Frampton CM, Westenberg AM, et al. A randomised trial comparing holmium laser enucleation versus transurethral resection in the treatment of prostates larger than 40 grams: results at 2 years. Eur Urol. 2006;50:569–73. 
37. Yang SS, Hsieh CH, Lee YS, Chang SJ. Diode laser (980 nm) enucleation of the prostate: a promising alternative to transurethral resection of the prostate. Lasers Med Sci. 2013;28:353–60. 
38. Yang Z, Liu T, Wang X. Comparison of thulium laser enucleation and plasmakinetic resection of the prostate in a randomized prospective trial with 5-year follow-up. Lasers Med Sci. 2016;31:1797–802. 
39. Yang Z, Wang X, Liu T. Thulium laser enucleation versus plasmakinetic resection of the prostate: a randomized prospective trial with 18-month follow-up. Urology. 2013;81:396–400. 
40. Zhang K, Sun D, Zhang H, Cao Q, Fu Q. Plasmakinetic vapor enucleation of the prostate with button electrode versus plasmakinetic resection of the prostate for benign prostatic enlargement>90 ml: perioperative and 3-month follow-up results of a prospective, randomized clinical trial. Urol Int. 2015;95:260–4. 
41. Zhao Z, Zeng G, Zhong W, Mai Z, Zeng S, Tao X. A prospective, randomised trial comparing plasmakinetic enucleation to standard transurethral resection of the prostate for symptomatic benign prostatic hyperplasia: three-year follow-up results. Eur Urol. 2010;58:752–8. 
42. Zhu L, Chen S, Yang S, Wu M, Ge R, Wu W, et al. Electrosurgical enucleation versus bipolar transurethral resection for prostates larger than 70 ml: a prospective, randomized trial with 5- year followup. J Urol. 2013;189:1427–31.
43. Clavien PA, Barkun J, de Oliveira ML, Vauthey JN, Dindo D, Schulick RD, et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg. 2009;250:187–96. 
44. Vuichoud C, Loughlin KR. Benign prostatic hyperplasia:epidemiology, economics and evaluation. Can J Urol. 2015;22(Suppl 1):1–6. 
45. Rasch A, Gruber S, Perleth M. Learning curve in laser treatment of benign prostatic syndrome: a systematic review. Z Evid Fortbild Qual Gesund. 2013;107:335–43. 
46. Shah HN, Mahajan AP, Sodha HS, Hegde S, Mohile PD, Bansal MB. Prospective evaluation of the learning curve for holmium laser enucleation of the prostate. J Urol. 2007;177:1468–74. 
47. EL-HAKIM A, ELHILALI MM. Holmium laser enucleation of the prostate can be taught: the first learning experience. BJU Int. 2002;90:863–9. 
48. Lourenco T, Armstrong N, N’Dow J, Nabi G, Deverill M, Pickard R, et al. Systematic review and economic modelling of effectiveness and cost utility of surgical treatments for men with benign prostatic enlargement. Health Technol Assess. 2008;12:iii, ix–x. 1-146, 169-515 
49. Mebust WK, Holtgrewe HL, Cockett, Peters ATK, Transurethral PC. prostatectomy: Immediate and postoperative complications. A cooperative study of 13 participating institutions evaluating 3,885 patients. J Urol. 1989;141:243–7. 
50. Krambeck AE, Handa SE, Lingeman JE. Experience with more than 1,000 holmium laser prostate enucleations for benign prostatic hyperplasia. J Urol. 2010;183:1105–9. 
51. Smith RD, Patel A. Transurethral resection of the prostate revisited and updated. Curr Opin Urol. 2011;21:36–41. 
52. Liao N, Yu J. A study comparing plasmakinetic enucleation with bipolar plasmakinetic resection of the prostate for benign prostatic hyperplasia. J Endourol. 2012;26:884–8. 
53. Lerner LB, Tyson MD, Mendoza PJ. Stress Incontinence during the learning curve of holmium laser enucleation of the prostate. J Endourol. 2010;24:1655–58. 54. Kuntz RM, Lehrich K. Transurethral holmium laser enucleation versus transvesical open enucleation for prostate adenoma greater than 100 gm.: a randomized prospective trial of 120 patients. J Urol. 2002;168:1465–9. 
55. Leliefeld HHJ, Stoevelaar HJ, McDonnell J. Sexual function before and after various treatments for symptomatic benign prostatic hyperplasia. BJU Int. 2002;89:208–13.

Zhang, Y., Yuan, P., Ma, D., Gao, X., Wei, C., Liu, Z., Li, R., Wang, S., Liu, J. and Liu, X. (2019). Efficacy and safety of enucleation vs. resection of prostate for treatment of benign prostatic hyperplasia: a meta-analysis of randomized controlled trials. Prostate Cancer and Prostatic Diseases. Received: 29 November 2018 / Revised: 14 January 2019 / Accepted: 17 January 2019 © Springer Nature America, Inc. 2019 https://doi.org/10.1038/s41391-019-0135-4

Read More: A Commentary from the Associate Editor of PCAN
E-Newsletters

Newsletter subscription

Free Daily and Weekly newsletters offered by content of interest

The fields of GU Oncology and Urology are rapidly advancing. Sign up today for articles, videos, conference highlights and abstracts from peer-review publications by disease and condition delivered to your inbox and read on the go.

Subscribe