State of the Art of Thulium Laser Enucleation and Vapoenucleation of the Prostate: A Systematic Review

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State of the art of Thulium laser enucleation and vapoenucleation of the prostate: a systematic review Daniele Castellani , Giacomo Maria Pirola , Andrea Pacchetti , Giovanni Saredi , Marco Dellabella PII: DOI: Reference:

S0090-4295(19)30968-9 https://doi.org/10.1016/j.urology.2019.10.022 URL 21840

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Urology

Received date: Revised date: Accepted date:

9 August 2019 28 October 2019 30 October 2019

Please cite this article as: Daniele Castellani , Giacomo Maria Pirola , Andrea Pacchetti , Giovanni Saredi , Marco Dellabella , State of the art of Thulium laser enucleation and vapoenucleation of the prostate: a systematic review, Urology (2019), doi: https://doi.org/10.1016/j.urology.2019.10.022

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Title: State of the art of Thulium laser enucleation and vapoenucleation of the prostate: a systematic review Authors: Daniele Castellania, Giacomo Maria Pirolab, Andrea Pacchettic, Giovanni Saredid, Marco Dellabellaa Author affiliations: a

Department of Urology, IRCCS INRCA, Ancona, Italy

b

Department of Urology, Usl Toscana Sud Est, San Donato Hospital, Arezzo, Italy

c

Department of Urology, University of Genoa, Genoa, Italy

Department of Urology, Ospedale di Circolo e Fondazione Macchi, Varese, Italy Corresponding author: Daniele Castellani. Addresses: Department of Urology, IRCCS-INRCA, via della Montagnola 81, 60127 Ancona, Italy. Phone: +393471814691. Fax: +39718003643. ORCID: 1-7354-9190; E-mail: d

[email protected] World count: abstract 92; main text 7233 Key words: prostatic, hyperplasia; laser therapy; complications; patient outcome assessment; ThuLEP; ThuVEP. Declaration of interest: Giovanni Saredi does surgical tutorship for Quanta System and receives honoraria for his tutorship. Daniele Castellani, Giacomo Maria Pirola, Andrea Pacchetti and Marco Dellabella have no conflict of interest with any institution or product that could have affected their manuscript. Financial disclosures: none. Acknowledgements: none

ABSTRACT Tm:YAG laser operates at a wavelength of 1940-2013 nm in a continuous wave mode, which enables smooth incision and rapid vaporization of prostatic tissue, with a shallow penetration of only 0.2 mm. These characteristics make Tm:YAG a versatile laser, allowing the surgeon to perform resection, vaporization, and vapoenucleation. This systematic review aims to summarize the current evidence of safety and efficacy, long-term durability, impact on sexual function following Tm:YAG laser enucleation and vapoenucleation of the prostate and to compare the outcomes of these procedures versus other surgical treatments of benign prostatic hyperplasia.

INTRODUCTION Lasers have been made available for clinical use in benign prostatic hyperplasia (BPH) surgery as minimally invasive procedures to overcome morbidity (severe bleeding, TUR-syndrome, prolonged recovery) of open prostatectomy (OP) and transurethral resection of the prostate (TURP). The use of laser technology in surgery relies on its physical characteristics and effects on tissue. The effect of the laser radiation on tissue depends on its wavelength, which determines how much energy is absorbed by the chromophores present in the tissue itself. 1 The prostatic chromophores are hemoglobin and water, and their absorption coefficient changes according to the laser wavelength, with different energy absorption between the laser types.1 The interaction between the laser beam and prostate leads to energy absorption by the prostatic tissue, which causes intracellular temperature increases. The speed and consequent temperature increase (below or above the boiling) can achieve incision, coagulation, vaporization, or carbonization of the prostate.1 Another important laser characteristic is optical depth penetration into tissue, which is determined by laser wavelength and power output.2 The optical penetration led the notion of extinction length, defined as the depth until which 90% of laser radiation is absorbed and converted into heat.2 Laser with shorter length transfers more energy per unit area and allows, at the same power level, a more focused delivering of energy with immediate tissue vaporization.2 Depending on the above characteristics, the current generation of lasers for the treatment of BPH are used for coagulation, resection, vaporization, and vaporesection. Among lasers, Thulium:yttrium-aluminium-garnet laser (TL) is the last introduced in clinical practice. Xia et al. published the first report on TL resection of the prostate in 2005, showing good early outcomes.3 Since then, TL has been applied in several techniques: vaporesection (ThuVaRP), vaporization, vapoenucleation (ThuVEP), and enucleation (ThuLEP).4 However, transurethral endoscopic enucleation of the prostate (EEP) is increasingly becoming the new standard of care for surgical treatment of BPH, being a size-independent procedure, and ensuring complete adenoma removal (virtually no reoperation due to recurrent adenoma). This systematic review aims to summarize the current evidence of safety and efficacy, long-term durability, impact on sexual function following ThuVEP and ThuLEP, and to compare the outcomes of these procedures versus other surgical treatments of BPH.

MATERIAL AND METHODS Search strategy A Web literature search was performed on 10th July 2019 in MEDLINE via PubMed, Web of Science, Scopus, and Embase. The search strategy included the following terms and boolean operators: Thulium laser AND prostate AND enucleation OR vapoenucleation. No date limit was used. Study selection Two authors (D.C. and G.M.P.) screened all retrieved records to identify the full text of the papers relevant to the topic of this review. Discrepancies were solved by the senior authors (G.S and M.D.). Non-English language papers, editorials, letters to editors, and case reports were excluded. The search was further implemented by manual search based on the references of the full-text relevant papers. Overall, 104 articles were selected for review. A total of 71 papers were accepted based on the relation to the topic and quality of information. The evidence acquisition is presented according to PRISMA diagram in Supplemental Figure 1.

EVIDENCE

Physical and Technical aspects TL operates in 0.9% sodium chloride solution at 1940-2013 nm wavelength, in a continuous wave mode, which enables accurate cutting of the tissue. The target chromophore in the prostate is water. Optical penetration is only 0.2 mm, which allows high energy density, leading to smooth incision and rapid tissue vaporization.1 The shallow penetration also results in a smaller zone of thermal damage in remaining prostatic tissue, which may turn in a low rate of postoperative storage symptoms.5 In 2005, Fried and Murray demonstrated in ex vivo porcine tissues that TL was capable of precise incision of the ureter and bladder, and

rapid vaporization and coagulation of the prostate.6 Four types of TL are currently available for the treatment of BPH: 2 μm Revolix® (2013 nm Tm:YAG laser, LISA Laser products, Katlenburg, Germany), 2 μm Cyber™ (2010 nm Tm:YAG laser, Quanta System, Sobiate Olona, Italy), 1.9 μm Vela® XL (1940 nm Tm:fiber laser Starmedtec, Starnberg, Germany) and Urolase® (1940 nm Tm:fiber laser NTO, IRE-Polus, Russia). The use of TL with front-firing fiber is employed in two techniques in EEP: ThuVEP and ThuLEP.4 First described in 2009, ThuVEP consists in a continuous use of the laser for dissecting the adenoma from the surgical pseudocapsule (vapoenucleation) in 3-lobe fashion (median lobe first, lateral lobes afterwards. Supplemental Figure 2), similar to classical technique in holmium laser enucleation of the prostate (HoLEP).7 Herrmann et al. introduced ThuLEP in 2010.8 In this technique, TL is used to incise the mucosa and to coagulate the vessels, while the adenoma is bluntly dissected off the pseudocapsule using the beak of the endoscope. 8 After an inverted U incision in front of the veru montanum, two incisions are performed at the level of the bladder neck at 5 and 7-o’clock position, permitting the retrograde enucleation of the middle lobe. Afterward, the distal margin of the adenoma is incised at 12-o'clock position, and the lateral lobes are dissected separately. The left lobe is bluntly enucleated toward the bladder neck from the 12 to 4 o’clock and, finally, from the 6 to 4 o’clock position. The right lobe is enucleated in the same way.8 Both procedures require at the end mechanical morcellation to retrieve the enucleated adenoma. Once the tissue is extracted, an adequate histological diagnosis can be made. Carmignani et al. analyzed 450 tissue specimens from patients who underwent ThuVEP and TURP.9 They showed that ThuVEP with morcellation provided satisfactory samples for histopathology diagnosis, with analogous thermal damage in histological preparations and a similar rate of incidental cancer compared to TURP.

ThuVEP Series The group from Hamburg reported the first feasibility study of 70-W ThuVEP in 2009.10 The procedure was completed in all 88 cases, with a mean surgical time of 72±26.6 minutes. In 2013, this group published the early postoperative outcomes in a series of 1080 patients with median prostate volume (PV) of 51 ml.11 Median postoperative catheterization time and hospital stay were 2 and 4 days respectively, with no

difference among the three groups. The extended postoperative stay was mainly correlated to the German health system reimbursement, requiring a minimum of 2 nights overstay. The overall immediate morbidity rate was 16.9%. Acute urinary retention (4.7%), urinary tract infection (1.5%), blood transfusion (1.7%) and reoperation for bleeding control, residual tissue and secondary morcellation (4.7%) were the most frequent complications, with no difference among different PV groups (<40 ml, 40-79 ml and >80 ml). Only one patient was admitted to intensive care unit due to acute myocardial infarction. No patient died. The immediate improvement of micturition proved to be satisfactory. One-year follow-up in 79 patients showed persistent relief of lower urinary tract symptoms (LUTS) and bladder outlet obstruction (BOO).12 Postoperative storage urinary symptoms were present in 27% of the patients and lasted one month after surgery. Three percent of patients suffered from urge-incontinence, which usually lasted two months.13 Stress incontinence rate was slightly higher (6.28%), resolved in 3 three months in most of the patients, and was persistent at 1-year follow-up in 1.45%. At 2-year follow-up, functional outcomes still differed significantly compared to baseline.14 One-hundred-thirty-one patients completed five years follow-up.15 The long-term complications were present in 17.5% of the patients. Two-percent of patients required TURP for recurrent adenoma between 4 and 5 years after ThuVEP. Surgery for bladder neck sclerosis/urethral stricture was necessary in 2% in patients with PV >60ml and in 8.8% in those with PV <60 ml. Relief of BOO and LUTS was durable despite baseline PV. The PSA reduction was 77.1%, showing complete removal of prostatic adenoma. The long-term durability of ThuVEP of this series was in line with recent series of HoLEP, but better than photo-vaporization (PVP) series.16 Tiburtius et al. tested the difference between the TL with different wavelengths (1940 nm and 2013 nm) in the same setting (90-W) and demonstrated that both lasers were comparable in terms of immediate voiding improvements and perioperative complications.17 Regarding outcomes of 120-W compared to 200-W machine, Netsch et al. demonstrated that complication rate and functional results were similar.18 The only difference was found in resected tissue, which was lower in the 200-W group because of the higher rate of vaporized tissue (58.48 vs. 72.93%, p=0.047), although a trend to shorter laser and operative time was notable in the 200-W ThuVEP.

The high coagulation efficiency of TL allowed Carmignani et al. to perform ThuVEP in one-day surgery in 53 patients.19 The average postoperative catheterization time was 14.8 hours. All patients were discharged after one overnight. No patients required readmission, neither post-operatory blood transfusion nor bleeding control. The current literature shows that ThuVEP is a safe and effective procedure, with excellent long-term durability and a valid option in the modern treatment of BPH.

ThuLEP series ThuLEP has been less extensively studied since it is a younger procedure. However, the available data shows similar outcomes compared to ThuVEP. Raber et al. published early outcomes of ThuLEP in 139 patients with confirmed BOO at flowpressure study (mean PV 66.9 ml).20 Two patients required blood transfusion and one cystoscopy for bleeding control. At 1-month follow-up, 99% of patients had significant improvement in voiding parameters and symptoms. Urethral stricture/bladder neck contracture occurred in 2 patients. Iacono et al. reported their experience in 148 patients with large prostates (mean PV 108.08±24.23 ml).21 Surgery was completed in all cases and showed a good safety profile, with 12.8% urinary tract infection, 6.7% re-catheterization, and 2.7% blood transfusion rate. One-year follow-up showed significant improvement in micturition and IPSS. Two patients required urethrotomy for stricture. Rausch et al. confirmed in 234 patients that ThuLEP was an efficient and safe procedure.22 However, they found that prostate size <80 was associated with 9% of re-operation rate or chronic indwelling catheterization. This rate of treatment failure was probably due to surgical limitations with regards to anatomical landmarks for blunt enucleation, which led to capsular perforation with subsequent bleeding and incompleteness of enucleation. Ketan et al. analyzed a series of 236 cases treated between 2010 and 2014.23 Catheter was removed in the first postoperative day in 94%, and re-catheterization was necessary for 1.2% of the patients. Four

patients required delayed morcellation. The excellent hemostatic feature of TL translated into 92.3% of patients discharged 24-hour after surgery. After 6-week, International Prostatic Symptoms Score (IPSS) and maximum flow rate (Qmax) improved significantly compared to baseline. Reoperation rate for urethral stricture/bladder neck contracture was 5.1% Another large series of 222 patients was recently published by Vazirian-Zadeh et al.24 Only one patient required blood transfusion and reoperation for bleeding control. The mean improvement in Qmax was 171.40%. Carmignani et al. further demonstrated the favorable outcomes of ThuLEP in a prospective study focused on 93 patients in chronic urinary retention (PVR >300 ml) o with an indwelling catheter.25 Catheter was successfully removed in the first postoperative day in half of the patient, and only 13% developed acute urinary retention during the first week. At 3-month follow-up, no patient required further catheterization. The mainstay of ThuLEP is finding the correct plane between the adenoma and the surgical capsule to perform a safe and accurate enucleation. One could argue that finding this plane might be tricky in patients who previously underwent prostatic surgery. Becker et al. demonstrated the feasibility of ThuLEP in men with recurrent BPH after initial treatment.26 The correct plane was identified and secondary ThuLEP completed in all cases. Although young, ThuLEP has already been proved to be a safe and effective procedure in treating clinical BPH.

Outcomes in large volume prostates (Table 1). Treating patients with a large prostate is challenging, with long operative time in resection procedures and relevant morbidity, prolonged postoperative catheterization, and hospital stay in OP, even in recent series.27 Netsch et al. compared early morbidity of ThuVEP in 687 patients, who were divided into three groups according to their PV (group A <40 ml, group B 40-79 ml, group C >80 ml).28 The median

catheterization time was 2 days in all groups. Four, seven, and three men required blood transfusion in groups A, B and C, respectively. Surgical revision was not statistical different among the groups, regarding bleeding control (1,4,1), secondary morcellation (5,6,1), left tissue (5,8,7), and stent positioning because of ureteral orifice injury (5,6,1). Functional outcomes were similar in all groups at discharge. Bach et al. reported the early complication rate in 90 patients with PV >80 ml who underwent ThuVEP (range 80-200 ml).29 Mean total operative time was 100.26±39.06 minutes. Mean postoperative catheter dwelling time was 2.23 days. Two patients required blood transfusion, 4 recatheterization, 1 double J stent position for ureteral orifice injury, and 1 cystoscopy for bleeding control. Considering the proportion of vaporized tissue, ThuVEP showed excellent enucleation efficiency, with 86% of median volume reduction and 88% PSA decrease 12 months after surgery. Four-year follow-up visit showed significant and persistent functional improvement and only 2 patients required redo surgery for residual adenoma and urethral stricture.30 Netsch et al. explored the efficiency of high power ThuVEP, comparing 120-W vs. 70-W lasers in 84 men with PV ≥60 ml. 31 The main advantage of 120-W ThuVEP was higher enucleation efficiency, with better-resected weight/laser time (2.16±1.21 g/min1 vs. 1.23±0.60 g/min1), resected weight/total operation time (0.76±0.35 g min1 vs. 0.42±0.27 g min1) and percentage of resected tissue (66.93%±22.79% vs. 45.41%±23.33%). However, the median PV reduction was similar at 12-month follow up (81.7% in 70-W vs. 82.19% in 120-W), with no difference between the groups in complications rate and functional improvement. Pearce et al. confirmed these results in a series of 25 patients with very large prostates who underwent 80-W ThuVEP.32 The mean PV was 163±62 ml. They reported 2 bladder wall injuries during morcellation, and one patient required blood transfusion. All patients were discharged home with an indwelling catheter, 28% were treated as outpatient, and 52% were discharged on the first postoperative day. The one-year visit showed excellent improvement in micturition and LUTS, and no patients required reoperation. Chang et al. reported results in a ThuVEP series of 125 patients with a mean PV of 106.80±45.77.33 Complications rate was slightly worse than the previous series, with one death due to stroke, 11.6%

recatheterization (blood clots/failure to void) and 3.2% transfusion rate. The late reoperation rate due to bladder neck contracture/urethral stricture was 4.8%. Enucleation efficiency was excellent, with a PSA reduction of 85.5%. One year after surgery, functional outcomes were in line with previous reports. The literature data analyzed above confirms that ThuVEP appears to be a size-independent procedure, with low postoperative morbidity and improvement in patient-reported outcomes and objective voiding parameters.28,29,31–33 Furthermore, perioperative morbidity, postoperative catheterization time and functional outcomes did not depend on PV.28,29,31–33 These results are comparable to recent HoLEP series.16

Impact on sexual function Induced neuropraxia by laser energy could raise the concern of a possible erectile dysfunction after laser EEP. Six studies on EEP with TL focused on this aspect (Table 2).21,34–38 Iacono et al. assessed erectile function (EF) by the International Index of Erectile Function (IIEF-5) score in a series of 148 men who underwent ThuLEP.21 They showed a non-statistically significant increase of IIEF-5 score at 12-month follow-up compared to baseline (19,3±8,23 vs. 20,3±8,16). Wang et al. retrospectively evaluated the impact of ThuVEP on sexual function in 63 patients compared to 59 patients treated by TURP.34 At 12-month follow-up, IIEF-5 score showed a marginal but not significant increase compared to baseline in both groups, with no difference between the two surgical procedures. Half percent of the patients complained retrograde ejaculation (RE) and 8% mild painful ejaculation in both groups. Interestingly, the authors found a positive linear correlation between mean IPSS, quality of life (QoL), Qmax, and IIEF-EF domain score improvement after surgery, suggesting a potential role of improvement of postoperative LUTS and QoL on patient’ EF. Tiburtius et al. reported a prospective series of 72 ThuVEP cases in which patients were divided into two subgroups according to preoperative IIEF-5 score (more or less than 19).35 Again, a slight but nonsignificant increase in the median IIEF-5 score at 12-months was reported in this study in both subgroups.

Carmignani et al. prospectively analyzed the impact of ThuLEP on EF in 110 patients.36 Six-month follow-up showed that 52.7% of men preserved antegrade ejaculation, and 12.1% of these patients presented painful ejaculation. Analysis of postoperative IIEF-5 showed a 79.1% rate of conserved erection compared to baseline. Saredi et al. showed similar results on erectile and ejaculatory functions in a study on 177 sexually active men (IIEF-5 score ≥17).37 They showed no IIEF-5 score variation eight months after ThuLEP. Conversely, the ejaculatory function was severely affected, and only 21/120 (11.86%) patients with conserved ejaculation before surgery reported antegrade ejaculation after. Enikeev et al. presented the impact of Thulium fiber laser enucleation of the prostate (ThuFLEP) on EF.38 They prospectively compared 211 patients to a control group of 258 treated by monopolar TURP. EF remained unchanged in 43% and 56% of patients in TURP and ThuFLEP groups, respectively. About a quarter of men reported improved EF after surgery in both groups. De novo erectile dysfunction was found only in the TURP group (2%). The actual evidence shows excellent results of TL EEP on EF, with a stable/slight increase of postoperative IIEF-5 score. The shallow penetration depth of TL devices might be the reason for preventing thermal damage beyond the prostatic capsule. Unfortunately, ejaculation is severely impacted, with a low rate of postoperative antegrade ejaculation. Compared to other BPH surgical treatments, TL EEP shows similar good outcomes in preserving EF, except PVP, which has a higher rate of early erectile dysfunction.39 TURP and the laser procedures have the same proportion of ejaculatory dysfunction, occurring in almost three out of four to five men.40

Morbidity in patients with increased risk of hemorrhage (Table Supplemental 1) Urologists have always questioned about performing transurethral surgery of patients on ongoing anticoagulants (AC). The choice of stopping or continuing AC should be balanced between the risk of severe bleeding and stroke, myocardial infarction, and thromboembolic events. The withdrawal of AC is a hot topic

in BPH surgery considering the continuous aging of the population, the increasing prescription of AC worldwide, and the risk of thromboembolic events in case of AC withdrawal.41 Hauser et al. were the first to focus on morbidity of men at high risk of hemorrhage (AC and acquired/congenital impaired coagulation).42 They retrospectively reviewed 39 men who underwent ThuVEP with small-to-medium size prostate. Mean catheterization time and hospital stay were 4.8 and 5 days, respectively. No patients required reoperation for bleeding control. Only one patient needed blood transfusion. Netsch et al. reported their experience with ThuVEP in 56 men in two centers.43 Although catheterization time (2 days) and hospital stay (4 days) were lower than in Hauser’s study, the complication rate was higher. Eighteen-percent of patients required catheter insertion due to blood clots, 7.1% blood transfusion, 7.1% reoperation for bleeding control, and 1.7% for residual adenoma. Carmignani et al. compared 42 patients on anti-platelet therapy versus 50 patients not in AC, who underwent ThuLEP.44 No data regarding PV, catheterization time and hospital stay were available. Only one patient required reoperation for bleeding control and blood transfusion in each group. To our best knowledge, no randomized trials compared the different lasers in treating patients on AC. However, Green-Light PVP is the one with the lowest rate of transfusion (<1%).41 ThuLEP and ThuVEP have a lower transfusion rate compared to TURP (20-30%) and similar to HOLEP (8%).41 Even if there are only limited data in men with small-to-medium size prostate, ThuLEP and ThuVEP can be considered safe procedures in patients with impaired coagulation.

Outcomes in older men (Table Supplemental 2) BPH is an aging process, and BPH related LUTS have a significant impact on QoL in older men. Indeed, men in their 70s were 4.6 times more likely as younger to seek medical attention for LUTS treatment.45 TURP and OP have increased and significant morbidity in this population.46,47

Chun-Ming et al. retrospectively analyzed 303 men who underwent ThuLEP.48 Thirty-eight patients were older than 80-year. No patients required blood transfusion and re-catheterization. The improvement of Qmax and reduction in PSA and PV was similar in older men compared to younger. Castellani et al. showed that en bloc ThuLEP was a safe and effective procedure in older men.49 Early and late postoperative complications, and functional outcomes were not statistical different in patients aged ≥75-year compared to youngers. Mean postoperative catheterization and hospital stay were similar in both groups (2 and 3 days, respectively). The transfusion rate was 1.9% in each group. The incidence of Clavien grade 3-4 complications was low and comparable between the groups (3.8% in the group aged <75year, 1% in the group aged ≥75-year). Three patients underwent cystoscopy for bleeding control (1 in the group aged ≥75-year). The difference in IPSS was statistically significantly better in men aged <75-year at 1month, but older patients had more considerable difference in IPSS at 6 six and 12-months. Overall, QoL improved progressively over time, with no difference between the two groups. Younger patients had a statistically significant greater improvement in Qmax at all follow-up visits. Rausch et al. showed conversely that age >80 years and ASA score were significant predictors of early complications and functional treatment failure after ThuLEP.22 The authors explained this circumstance with incremented comorbidity and detrusor underactivity in aging males. Further studies are needed to better explore the role of ThuLEP in older men, especially in frail patients.

Learning curve The learning curve is always a crucial issue when comparing different BPH surgical procedures, particularly EEP techniques. Gross et al. analyzed the impact of the learning curve of ThuVEP on complication rate in their series of 1080 patients.11 The overall complication rate decreased significantly over time, reflecting the institutional learning curve of 11 surgeons (41.7% within the first 216 cases vs. 19.4% within the last 216 cases, p<0.001). This change resulted from decreasing low-grade complications (Clavien ≤2), mainly

transfusion rate and acute postoperative retention. The differences in severe complications were less relevant. The same authors evaluated the ThuVEP learning curve using a mentor-based approach.50 The mentor was a urologist with >300 ThuVEP procedures performed (surgeon C). The trainees were a resident with minimal transurethral skill (surgeon A) and a consultant urologist with >500 TURP previously performed. Both trainees were familiar with the technique by intensive studies of ThuVEP videos. PV was limited to 75 ml in the first 15 cases of surgeon A and B, while surgeon C had no limitations in prostate size. The authors analyzed the results of 96 patients, equally distributed among the three surgeons. ThuVEP was successfully performed in all patients, and the mentor had not taken over the ThuVEP procedure in any of surgeries in the trainees. The enucleation efficiency was statistically different among the three operators, but the complication rate, postoperative catheterization, and hospital stay were similar. After 8-16 procedures, the effectiveness of enucleation and morcellation was reasonable for both laser naïve surgeons. The authors, therefore, concluded that ThuVEP can be performed with acceptable outcomes even during the learning curve if the operator is closely mentored. Saredi et al. reported the ThuLEP learning curve of 2 laser naïve but experienced endourologists.51 The authors started performing ThuLEP after visiting experienced laser centers and after practicing the surgical steps of the procedure for 2 weeks on a dedicated simulator (CyberSim; Quanta System, Sobiate Olona, Italy). Surgery on humans had no mentor tutoring. Intraoperative complications occurred in 3/100 patients: 2 bladder perforations and 1 secondary morcellation. Postoperative complications occurred in 4 other patients: 1 endoscopic hemostatic procedure, 1 secondary morcellation, 1 TURP for residual adenoma, and 1 urethrotomy. All complications occurred during the first 60 cases, and the authors concluded that ThuLEP can be performed well and safely after 30 procedures. Conversely, Krombach et al. showed that a novice surgeon, with no transurethral experience, needed about 50 mentored cases to develop stable skills in performing ThuLEP.52 ThuVEP and ThuLEP seem to have a more favorable learning curve compared to HoLEP. Indeed, it has been demonstrated that HoLEP has a steep learning curve of at least 30 cases and needs at least 50 cases to have reasonable outcomes.53 If not mentored, 50% of laser naïve surgeons abandoned this technique

before finishing their learning curve.53 To assess the difference in the learning curve of different EEP, Enikeev et al. randomized 90 patients with PV ≤80 ml to ThuFLEP, HoLEP, or monopolar enucleation of the prostate (MEP).54 Patients were assigned to 3 three EEP naïve surgeons with expertise in TURP (30 patients to each, one surgeon for each EEP). The surgeons started performing EEP after watching training videos, and the first ten procedures were mentored. Enucleation rates of all three techniques improved progressively 10-by-10 procedures, but ThuFLEP was superior to in the first 20 cases. MEP was always inferior to either laser techniques. Catheterization time and hospital stay were shorter and similar in laser techniques (1-3 and 3-5 days, respectively) and more prolonged in MEP (2-4 and 4-6 days, respectively). Only one patient required blood transfusion (MEP group). Secondary morcellation was necessary for two patients in HoLEP and MEP groups and for one in ThuFLEP group. One patient in the HoLEP group required cystoscopy for bleeding control. At 3-month IPSS, QoL and voiding parameters showed significant improvement in all groups, with no difference among the groups. The authors concluded that 30 procedures were sufficient to perform safety and efficient EEPs. Similar outcomes were outlined by the same authors in a retrospective analysis of 551 patients who underwent those three procedures in their center.55 Even without a high level of evidence, it seems that ThuLEP/ThuVEP learning curve is shorter than HoLEP, even in surgeons with low endoscopic skills. This finding might be correlated to the intrinsic physic of the lasers. Holmium laser does not alter the appearance of tissue during enucleation, because it achieves tissue separation with pulsed and steam generated bubbles.1 Consequently, Holmium laser allows the surgeon to well distinguish the surgical plane between the adenoma and the surgical capsule. However, the steam due to water vaporization, which appears between the laser pulses, generates tissue rupture. Tissue disruption may cause difficulty in regaining the enucleation layer in case of enucleation plane loss. Conversely, TL works in continuous wave mode, allowing the beam to precisely cut and vaporize the tissue. 1 The carbonized effect of TL may pose a problem in finding the surgical capsule and the enucleation plane at the beginning of the procedure. Once found the plane, the blunt dissection during ThuLEP or the smooth tissue incisions during ThuVEP allow comfortable correction of the layer during enucleation.50,51 This feature enables also changing from enucleation to vaporization or vaporesection in case of trouble, which is beneficial mostly during the learning curve.

As far as we know, ThuLEP and ThuVEP have a short learning curve and can be performed safely from the very first stages.

En bloc techniques The original technique described by Herrmann remains the standard of reference for ThuLEP.8 However, raising attention has recently been given to en bloc enucleation techniques. The main objective of these alternative approaches is to improve some potentially technical pitfalls of the classical three-lobe technique, mainly the correct identification and development of the surgical capsule during all the steps of the enucleation. Three-lobe enucleation can lead to the risk of developing “false planes” by mismatching incisions, mostly anteriorly. The loss of the correct enucleation plane may cause capsular perforation, which determines significant bleeding and impairs the completeness of the enucleation itself. Conversely, the en bloc enucleation concept consists in the identification of the capsular plane as the first step, which is then followed towards all prostatic boundaries until the adenoma is completely enucleated. Kim et al. introduced the first en bloc ThuLEP, the “All-in-One” technique.56 The dissection starts at the apex, as an “inverted-U” incision at the veru montanum and an anterior incision at 12 o’clock and carries on joining the two incisions circumferentially (video clip online http://youtu.be/ShJ6GLAR2MY). Progressive circumferential enucleation of the adenoma towards the bladder neck completes the procedure. Forty-seven patients underwent this procedure, which was completed in all cases. Postoperative complications were low grade, with no capsular perforation or ureteral orifice injury. No patients required blood transfusion. Three-month follow-up showed good relief of LUTS and micturition improvement. Saredi et al. described a different en bloc technique, in which the enucleation starts with a single mucosal incision from the bladder neck to the veru montanum at 5-o’ clock.57,58 Once the capsular plane is identified, the left lobe is enucleated counterclockwise from 5 to 11-o’clock; the right lobe, together with the median lobe, is enucleated clockwise from the apex to the prostatic base at 11-o’clock. Enucleation finishes with an anterior apical incision from 10 to 2-o’clock of the remaining fan-shaped mucosa (Supplemental Figure 3). The authors showed in a comparative study that the en bloc approach allowed an easier

enucleation of the adenoma, a significant reduction in total operating time, and the amount of laser energy delivered per adenoma gram.58 A significant reduction of IPSS compared to the classical 3-lobe technique was also demonstrated.58 They further showed that the overall operative time of en bloc approach was not influenced by experience, but the increasing experience permitted a significant reduction in the total amount of delivered energy.59 Dellabella and Castellani described a 2-lobe enucleation technique: the median lobe is enucleated first and the lateral lobes are dissected and enucleated en bloc.60 Once the medial lobe is moved into the bladder lumen, the dissection is carried out at 4-o’clock position toward the bladder neck, enucleating the left lobe in an anticlockwise direction. At the 12-o’clock position, dissection keeps going beneath the right lobe toward the 9-o’clock position. At this point, an incision is made at 8-o’clock position, and enucleation is completed in a clockwise direction toward the 9-o’clock position (Supplemental Figure 4). The latter authors compared their en bloc approaches in 164 men.61 They demonstrated that both procedures had similar complications and outcomes and could be considered surgeon-independent techniques. In this series, extraperitoneal fluid collection, bladder injury due to morcellation, capsular perforation, bladder neck false passage, and ureteral orifice injury did not occur. These complications may, of course, be explained by the expertise of the surgeons, but also by a better vision of the surgical field, which is determined by optimal control of the capsule allowed by en bloc enucleation. From that literature evidence, en bloc techniques appear safe and effective. The absence of comparative studies about the learning curve of 3-lobe versus en bloc doesn't allow stating clear advice for laser naïve surgeons facing ThuLEP.

Comparative studies This paragraph analyzes all comparative studies of ThuVEP or ThuLEP versus other surgical procedures for treating BPH (Table 3).

Comparison versus monopolar/bipolar TURP During EEP major vessels are opened only once at the level of the surgical capsule, which is reached early and followed afterward. In contrast, the same vessels are opened and re-opened several times until the surgical capsule is reached during TURP. At this level, the final coagulation can be performed. This difference theoretically leads to major bleeding and more tissue left behind in case impaired vision during TURP, especially in large glands. Furthermore, this might translate into major complications and reoperation rates. Świniarski et al. assessed in randomized trial complications and outcomes of 70-W ThuLEP (54 patients) vs. monopolar TURP (52 patients).62 Resected tissue weight and percent of tissue resected were larger in TURP group (34.8±14.1 vs. 24.8±14.8 g; 51.9±11.2 vs. 37.8±14.2%, respectively). The postoperative decrease in hemoglobin level was approximately twice as low in ThuLEP group. Two patients required blood transfusion in the TURP group, no patients in ThuLEP group. Postoperative indwelling catheter time and hospital stay were similar and not statistically different between groups. Three-month after surgery, micturition and LUTS improved significantly in both groups, with no statistical difference among the groups. Two patients required reoperation due to residual tissue in ThuLEP group. Chang et al. were the first to compare ThuVEP vs. monopolar TURP (29 and 30 patients, respectively).63 The resected tissue was higher in the TURP group than in the ThuVEP group (37.4±23.0 vs. 21.3±14.3 g, p=0.024), but the estimated residual PV ratio was the same (0.47±0.17 vs. 0.47±0.20, p=0.449). These findings were correlated to the amount of tissue vaporized during ThuVEP. Postoperative catheterization time and hospital stay were in favor of ThuVEP (1.8±0.5 vs. 2.3±0.5 days, p = 0.001 and 3.0±0.9 vs. 3.4±0.7 days, p = 0.032, respectively). Early complications were low grade and similar, with 4 patients required blood transfusion in ThuVEP group and 8 in TURP group. Twelve months after surgery, functional outcomes were not statically different among the groups. Two prospective and randomized trials compared ThuLEP versus plasmakinetic resection of the prostate (PKRP).64,65 Yang et al. enrolled 79 patients in each arm.64 ThuLEP required longer operation time (65.4 vs 47.4 minutes, p=0.022). A significantly lower mean postoperative hemoglobin drop was in favor of ThuLEP (0.15 vs. 0.3 g/dL, p<0.05). However, no patients required blood transfusion. The superior

coagulation of TL translated in a shorter catheterization time (2.1 vs. 3.5 days, p=0.031), irrigation volume (12.4 vs. 27.2 L, p=0.022), and hospital stay (2.5 vs. 4.6 days, p=0.026) in favor of ThuLEP. At 18-month follow-up, both procedures showed significant improvement in IPSS, QoL, Qmax and post-void residual (PVR), with comparable results. Five years follow-up in 80 patients showed maintained improvements in LUTS and micturition compared to baseline, and no statistical difference was demonstrated between the groups.66 Bozzini et al. confirmed Yang’s results in a randomized trial in 208 men.65 There was no statistically significant difference between both groups regarding the urodynamic data and symptom improvement. ThuLEP was superior to PKRP in blood loss, catheterization time, irrigation volume, and hospital stay. The provided literature demonstrated that compared to monopolar/bipolar TURP, ThuVEP and ThuLEP need longer operative time, but offer lower blood loss, and shorter catheterization time, irrigation volume and hospital stay, with comparable functional outcomes.

Comparison versus TL resection ThuVaRP consists of simultaneous resection and vaporization of prostatic adenoma in small TURP-like chips; the chips are evacuated through the resectoscope sheath at the end of the procedure. ThuLEP and ThuVEP should be theoretically “more radical” than ThuVaRP in removing prostatic tissue through a complete enucleation of the adenoma peeling it off the surgical capsule. Using a 1:1 propensity score match analysis, Chung et al. compared 150 patients.67 ThuVaRP required longer operation (72.8 vs. 61.0 minutes, p=0.023) and laser time (24.5 vs. 19.9 minutes, p=0.037) and resulted in lower resected tissue than ThuVEP (9.0 vs. 18.2 g, p =0.029). The average reduction of PV was 55.5% in the ThuVaRP group and 64.0% in the ThuVEP group. Early complications were mostly low grade, with only one blood transfusion in ThuVEP group. Three patients in the ThuVaRP group and one in ThuVEP group required transurethral coagulation for bleeding control. IPSS, QoL, Qmax, and PVR showed no statically difference at 12-month. PSA reduction was slightly better in ThuVEP group (55.3±23.8% vs.

50.0±19.7%, p=0.093). Three patients in the ThuVaRP group required secondary surgery for urethral stricture/bladder neck stenosis. Netsch et al. compared the two procedures in 52 patients on AC using a match pair comparison according to PV.68 Hemoglobin decrease was higher after ThuVEP (1.5 vs. 0.3 g/dl, p<0.001). Catheterization time was shorter for ThuVaRP (1 vs. 2 days). No patients in the ThuVaRP group underwent clot retention and required blood transfusion or secondary coagulation. Transfusion rate and secondary hemostasis in ThuVEP group were 3.9% and 7.7%, respectively. Qmax was significantly higher after ThuVEP at 6-month follow-up, whereas IPSS, QoL, and PVR were similar. Twenty-four-month follow-up of this study with a larger population (160 patients) was published in 2017.69 The early complication rate was again in favor of ThuVaRP, with no blood transfusion and reoperation for bleeding control. Despite the similar improvement in IPSS and QoL, the ThuVaRP group showed a statistically significant better Qmax (21.5 vs. 18.2 ml/sec, p<0.001) in contrast with Chung’s study.67 PSA reduction favored the ThuVEP (78.93 vs. 23.39%, p<0.006). Late reoperation for urethral stricture/bladder neck stenosis was required only in ThuVEP group (3.8%). Regarding ThuLEP vs. ThuVaRP, two papers were retrieved. 70,71 In a retrospective study on 400 patients, Yuan et al. showed that ThuLEP required shorter operation time in patients with PV>60 ml.70 Postoperative catheterization and hospital stay were similar. A significant lower hemoglobin drop was found in ThuVaRP group (0.23±0.18 vs. 0.37±0.10 g/dl, p<0.01). However, no patients required blood transfusion. No statically difference was found between the groups regarding IPSS, QoL, Qmax, and PVR at 12-month follow-up. Three patients (1.4%) in the ThuVaRP group and two (1.1%) in the ThuLEP group developed urethral strictures, which were treated with dilatation. Sun et al. randomized 115 patients with small prostate (PV<30 ml) to ThuLEP (n=56) or ThuVaRP (n=59).71 Total operative time, postoperative catheterization, and hospital stay were similar. ThuLEP retrieved more tissue compared to ThuVaRP (4.1±1.9 vs. 2.2 ± 1.2 g, p < 0.001). At 12-month follow-up, IPSS, QoL, Qmax, and PVR improved significantly, with no difference between the two groups. Interestingly, the authors found a lower rate of bladder neck contracture in ThuLEP group (1.8% vs. 13.6%, p=0.045), probably due to the thermal damage of ThuVaRP at this level.

The presented data shows that ThuVaRP and ThuVEP/ThuLEP had equal efficiency in relieving BOO and improving LUTS, with no reoperations for re-growth of adenoma 2-year after surgery. However, longer follow-up might show a significantly higher re-operation rate after ThuVaRP due to the lower PSA reduction rate after this procedure. ThuVaRP should not be performed in small prostates, due to its high rate of bladder neck stenosis.

Comparison versus HoLEP Despite the technical differences of Thulium and Holmium lasers (pulsed vs. continuous energy emission), the surgical principle of complete removal of the adenoma remains identical, and one could expect no differences regarding functional outcomes. A recent meta-analysis by Xiao et al. compared the efficacy and safety of ThuVEP/ThuLEP compared to those of HoLEP.72 ThuVEP and ThuLEP were considered similar techniques, as the difference between them is quite negligible. The authors identified five studies, including two randomized controlled trials and three case-control trials with a total of 1010 patients.55,73–76 The meta-analysis showed significant differences in enucleation time between TL EEP and HoLEP, in favor of the first one (weighted mean difference= -7.73, 95% CI − 14.39-1.07, p=0.02). These findings could be correlated with the continuous pulse of TL, which might provide a faster enucleation. However, total surgical time was analogous. This might be explained with different criteria of operation time among the studies, laser settings, and diverse surgeon expertise, but also to the technical difference of lasers. Coagulation depth is 2 mm in TL and 4 mm in Holmium laser. ThuVEP/ThuLEP may require more time for the final coagulation compared with HoLEP. Hemoglobin decrease was lower in TL EEP compared to HoLEP, even if this finding was not statistically and clinically significant. Indeed, no differences in blood transfusion rate occurred in any study. Catheterization time and hospital stay were similar. Early complications were low grade in both procedures with no difference between them. IPSS, QoL, voiding parameters and urinary incontinence did not differ between the two techniques, showing complete relief of LUTS and BOO at 12-month follow-up. We retrieved one more paper comparing the two procedures.77 Its findings confirmed the results of

Xiao’s meta-analysis.

Comparison versus OP OP is still the standard approach worldwide in many centers in case of PV >80-100 ml. However, it is an invasive procedure, with substantial perioperative morbidity, long catheterization time, and prolonged hospital stay.27 Therefore, new minimally invasive transurethral procedures have recently been pursued to overcome morbidity of OP, mostly HoLEP and plasmakinetic enucleation of the prostate (PKEP).78 Carmignani et al. randomized 61 patients with PV≥80 ml to ThuLEP or OP.79 Hemoglobin loss was significantly less, and catheterization time and hospital stay were significantly shorter in ThuLEP group. No patients required blood transfusion in ThuLEP group, in contrast to 20% in the OP group. Enikeev et al. retrospectively compared 40 patients who underwent Millin’s OP to 90 who underwent ThuFLEP.80 Mean operative time and mean tissue removed were similar in both groups. Postoperative hemoglobin reduction was significantly higher in the OP group. Catheter indwelling time and hospital stay were significantly longer in the OP group (6.4±1.5 vs. 1.4±0.6 days, p<0.001; 9.0±2.4 vs. 3.3±0.6 days, p<0.001, respectively). Two patients required blood transfusion in the OP group. Delayed morcellation was performed in three cases. Re-catheterization due to blood clots was necessary for two patients in each group. After 6 months, very low mean PSA was present in both groups (0.84±0.5 in ThuFLEP group vs. 0.9±0.5 ng/ml in OP group), signifying that both procedures were equally efficient in completeness adenoma removal. Micturition and LUTS improved significantly compared to baseline, without difference between the two groups. ThuLEP appears to be a promising minimally invasive option in very large prostate as an alternative to OP, but further comparative studies are required to confirm these initial results.

Comparison versus other techniques

Castellani et al. retrospectively compared the safety and efficacy of ThuVEP and 180-W GreenLight PVP.81 The propensity score analysis of 90 patients showed similar postoperative catheterization and hospital stay. Hemoglobin drop was statically significant lower in the PVP group, but only one patient required blood transfusion in both groups. Most of the complications were mild-to-moderate and comparable among groups. Twelve-month after surgery, 96.4% of all patients had an improvement of their symptoms, with no difference between groups. However, the PVP group had a better improvement in Qmax. Bach et al. prospectively compared the perioperative outcomes of 2648 patients who underwent TURP (30.1%), ThuVEP (52.2%), and Green-light PVP (17.7%) in 4 centers.82 The TURP group had the lowest baseline PV (average 40.7 ml vs. 56.4 ml in PVP and 64.5 ml in ThuVEP). ThuVEP was more efficient in tissue removal compared to TURP. The median postoperative stay was longer in the TURP group (4 days) compared to ThuVEP (3 days) and PVP (2 days). PVP had the lowest rate of Clavien ≥3 complication score. Blood transfusion was required in 0.6% after PVP, 2% after TURP, and 3.3% after ThuVEP, mostly in men on AC. The high rate of transfusion after ThuVEP only occurred in patients with very large prostates. After a mean follow-up of 3.2 years, laser treatments were associated with a better continence rate and re-operation rate due to significantly less residual tissue in the ThuVEP group (0.71% vs. 18.4% in PVP vs. 7.59% in TURP).83 Feng et al. randomized 127 patients to PKEP or ThuLEP, both with mushroom technique.84 Surgical time was similar. The hemoglobin drop and catheterization time were significantly lower in ThuLEP group, whereas hospital stay was not. Blood transfusion with secondary bleeding control was necessary for one patient in PKEP group. There was a significant improvement in micturition parameters and symptoms at 12month follow-up compared with preoperative values, with no difference between the two groups.

CONCLUSION Through a comprehensive literature review, this paper presented the “state of the art” of the surgical twins ThuVEP and ThuLEP. Taken as a whole, the reviewed studies suggest that TL EEPs are safe and size-

independent procedures, with low perioperative morbidity even in highly comorbid patients, including those who are on AC and in patients with large volume prostates. Moreover, ThuLEP and ThuVEP produce effective and long-term improvement in patient-reported outcomes and objective voiding parameters, with no detrimental impact on EF. Their short learning curve may attract laser naïve surgeons to master the procedure easily.

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Table 1. Safety and effectiveness of ThuVEP/ThuLEP in large prostates.

Stud y (yea r)

Surg ery

Stud y desi gn

Numb er of patie nts

Me an age , yea rs

Mea n PV, ml±S D

Mean catheteriza tion time, days

Mean hospitaliza tion time, days

Early Complicatio ns (Clavien grade)

12month functio nal outcom es, (mean value±S D)

Bach (201 1)

ThuV EP (90 W)

P

90

71. 3

108. 59 ±26. 46

2.24±0.74

NA

Recatheteriz ation 2.22% (1)

IPSS*: 4.74±3. 44

- Blood transfusion 2.22% (2) - UTI 7.1 %(2) Reoperation for bleeding control 1.1% (3b)

QoL*: 1.04±0. 92 Qmax*: 26.2±11 .29 ml/sec

- Stenting for superficial ureteral orifice lesion 1.11% (3b) Pear ce (201 6)

ThuV EP (80 W)

R

25

70

163± 62

6.5±2.7

1.2±1.2**

- Long catheterizati on due to bladder injury during morcellation

IPSS: 4.7±4.6 QoL: 1.2±1.3 Qmax:

8% (1) Catheterizati on due urinary retention 12% (1)

20.1±10 .4 ml/sec

- Cather insertion due to blood clots 4% (1) - Positive urine culture 20% (1) - Blood transfusion 4% (2)

Cha ng (201 9)

ThuV EP (150 W)

R

125

71. 85 ± 8.8 9

106. 80 ± 45.7 7

NA

NA

-Cather insertion due to blood clots 1.6% (1) Recatheteriz ation 9.6% (1)

IPSS: 7.35 ± 5.89 QoL: NA Qmax: 19.00 ± 18.30 ml/sec

- Blood transfusion 3.2% (2) - Death 0.8% (5) UTI: urinary tract infection *: data on 56 patients available IPSS: International Prostate Symptoms Score. QoL: quality of life. Qmax: maximum flow rate. ** Discharged home with indwelling catheter

Table 2. Impact of ThuLEP/ThuVEP on erectile function.

Study (year)

Surgery

Iacono (2012)

ThuLEP

Wang

ThuVEP

Power Watt

BE

Study design

P

Number of patients

148

Mean PV, ml±SD

68.2±

108.08±2 4.23

19.3±8.23

62.3±15. 8

22.5±5.8

48

25

NA

NA

26

NA

60

6

NA

NA

8

NA

67.83±

75.46±

16.84±4.45

NA

43.75

18.10±3.8 1

NA

7.74

16.47±3.1 8

5.03 120

R

63

(2014) Tiburtius

Age mean years±S D

65.8± 6.3

ThuVEP

90

P

72*

(2014)

Group A

Baseline IIEF-5 score

3 months IIEF-5 score

6 months IIEF-5 score

12 months IIEF-5

p-value

score NA

NA

20.3±

NA

8.16 NA

NA

24.2±

0.064

4.3

68 Group B 73

Carmignani

ThuLEP

BE

P

110

(2015) Saredi

ThuLEP

BE

P

177

70±7.66

64.55± 28.24

22.49±1.8

22.14±3.1

22.18±3.2 **

NA

0.195

ThuFLEP

60

R

211

67±7.4

90±42.9

11.1±5

NA

11.7±4.7

NA

0.08

(2016) Enikeev (2018)

R: Retrospective P: prospective PV: prostate volume. NA: not available. BE: blunt enucleation. IIEF-5: International Index of Erectile Function * Patients divided in two subgroups according to preoperative IIEF ≥19 (Group A) or <19 (Group B) ** 8-month follow-up

Table 3. Comparative studies of ThuVEP/ThuLEP versus other surgical procedures for BPH

Study (year)

Surgery

Stu dy desi gn

Num ber of patie nts

Age mean years± SD, (pvalue)

Mean PV, ml±SD (pvalue)

Mean catheteri zation time, days

Mean hospitali zation time, days

(p-value)

(p-value)

Early Complicat ions (Clavien grade)

Functi onal outco mes, mean value± SD (pvalue)

Świni arski (2012 )

ThuLEP vs. mTURP

P-r

54 vs. 52

68.3±6 .8 vs. 69.3±7 .2

(0.458 9)

62.03± 23.7 vs. 66.5±2 2

2.1±0.8 vs. 2.0±0.9

3.6±0.9 vs. 3.6±0.8

Recathete rization 0 vs. 5.77% (1)

IPSS*: 6.57±4. 46 vs. 7.04±3. 19

(0.6154)

(0.9446)

- Blood transfusio n 0 vs. 3.85% (2)

(0.2385 )

(0.3336 )

- UTI 3.7 vs. 7.69 % (2)

QoL*: 1.5 ±1.1 vs. 1.3±0.9 (0.2488 ) Qmax* : 23.0±8. 30 vs. 26.04± 8.52 ml/sec (0.6491 )

Chan g (2015 )

ThuVEP vs. mTURP

P

29 vs. 30

76.1±9 .4

57.2±2 5.1

vs. 72.6±7 .4

vs. 64.7±3 2.5

1.8±0.5

3.0±0.9

vs.

vs.

2.3±0.5

3.4±0.7

Hematuria with clot retention 0 vs. 3.3% (1) -

IPSS and Qol**: (0.551) Qmax* **: not

(0.001) (0.280 )

(0.032)

(0.758)

Catheteriz ation due urinary retention 6.9 vs. 0% (1)

differen t

- Blood transfusio n 13.8 vs. 28.6% (2) Yang (2016 )

ThuLEP

P-r

vs. PKRP

79 vs. 79

62.4±7 .2

72.4±2 1.2

vs. 61.4±6 .9

vs.

2.1±0.8

2.5±1.4

vs.

vs.

3.5±1.2

4.6±1.4

NA

69.2±2 3.1

6.9±3.2 vs. 6.5±2.7

(0.031) (0.322 )

IPSS§:

(0.179)

(0.026)

QoL§: (0.081)

1.4 ± 0.8 vs.1.5± 1.1 (0.431) Qmax§: 19.4±1 5.3 vs. 18.9±1 3.7 ml/sec (0.631)

Bozzi ni (2016 )

ThuLEP vs. PKRP

P-r

102 vs. 106

72.5±1 7.54

89.7±4 5.1

vs.

vs.

70.7±1 6.09

81.9±3 9.4

1.3±2.55

1.7±2.73

vs.

vs.

4.8±3.81

5.2±3.98

(0.011) (>0.05 )

(>0.05)

(0.016)

Recathete rization 6.8 vs. 11.3% (1) - Blood transfusio n 0 vs. 2.8% (2)

IPSS*: 5.85±4. 23 vs. 5.78±5. 2 (>0.05)

QoL*°: 41.8±1 2.33 vs. 39.9±1 7.87 (>0.05) Qmax* : 22.14± 10.23 vs. 19.87± 9.70 ml/sec (>0.05) Chun g (2014 )

ThuVEP vs. ThuVaR P

R

75 vs. 75

67.7±7 .9

55.5±2 0.2

vs.

vs.

67.3±7 .3

51.2±2 2.1

2.4±1.1 vs. 2.2±0.5

(0.798) (0.631 )

(0.118)

NA

Recathete rization 6.7 vs. 5.4% (1) - Blood transfusio n 1.3 vs. 0% (2) - UTI 0.8 vs. 0.7 %(2) Reoperati on for bleeding control 1.3 vs. 2.7%(3b) Conversio n to TURP 4 vs. 2.7% (3b)

Not specifie d. No statistic ally differen t.

Becke r (2017 )♯

ThuVEP vs. ThuVaR P

R

80 vs. 80

69.5 vs. 69¶

(0. 863)

Yuan (2019 )

ThuLEP vs. ThuVaR P

R

188 vs. 212

65 vs. 65¶

2 vs. 2¶

4 vs. 2¶

(0. 982)

- Blood transfusio n 1.3 vs. 1.3% (2)

57.1±5 .5

53.7±2 2.5

52.3±5.3 hours

vs.

vs.

vs.

54.2±5 .2

56.2±2 4.3

56.7±6.3 hours

5.8±1.3 vs. 6.4±1.2

(0.144)

Sun (2019 )

ThuLEP vs. ThuVaR P (PV≤30 ml)

P

56 vs. 59

Recathete rization 5 vs. 2.5% (1)

(0.334 )

(0.332)

(0.093)

69.2±1 3.4

26.4±3. 5

44.6±16. 3 hours

45.8±16. 3 hours

vs.

vs.

vs.

vs.

67.7±9 .9

25.1±4. 7

44.2±19. 4 hours

48.7±19. 9 hours

IPSS×: 5 vs. 5 (0.812) QoL×: 1 vs. 1 (0.471)

Reoperati on for bleeding control 2.5 vs. 0%(3b)

Qmax× : 18.2 vs. 21.5 ml/sec

Recathete rization 0.5 vs. 2.3% (1)

Not specifie d. No statistic ally differen t

- UTI 7.9 vs. 15.1% (2)

(<0.001 )

IPSS: 6.9±3.7 vs. 7.1±3.8 (0.776) QoL:

(0.363 )

(0.097)

(0.905)

(0.396)

2 vs. 2 (0.813) Qmax: 25.1±7. 2 vs. 24.3±8. 1 ml/sec

(0.577) Enike ev (2109 )

ThuFLE P

R

Vs.

90 vs. 40

Open prostate ctomy

67.4±7 .7 vs.

127.8± 40.2

67.0±1 .0

vs.

(0.771 )

1.4±0.6

3.3±0.6

vs.

vs.

6.4±1.5

9.0±2.4

114.1± 38.9 (<0.001)

(<0.001)

- Blood transfusio n 0 vs. 5% (2) - Delayed morcellatio n 3.3 vs. 0%

IPSS≠: 10.7±2. 6 vs. 10.6±3. 4 (0.996) QoL≠:

(0.071) 1.6±0.7 vs. 1.5±0.7 (0.432) Qmax≠: 17.7±2. 3 vs. 17.2±2. 7 ml/sec (0.23)

Caste llani (2108 )

ThuVEP vs. Greenlight PVP

R

90 vs. 90

69.8±7 .2

56 vs. 50

vs. 68.6±8 .8

2 vs. 2

3 vs. 2 (0.88)

(0.120) (0.389)

- Clavien 1:

ΔIPSS >20:

6.7 vs. 68.9%

68.9 vs. 37.8% (0.003)

- Clavien 2: 2.2 vs. 0%

(0.466 )

- Clavien 3a: 6.7 vs. 2.2%

ΔQma x >12: 33.3 vs. 64.4% (0.003) PPI: 97.8 vs. 93.3% (0.306)

Feng

ThuLEP

P-r

61

66.66±

69.02±

1.85±0.9

2.64±1.0

-

IPSS:

(2016 )

vs. PKEP

vs. 66

8.99

22.29

4

8

vs.

vs.

vs.

vs.

70.03± 7.84

67.05± 16.28

2.28±1.3 4

3.02±1.4 5

(0.568)

(0.042)

(0.101)

(0.114 )

Recathete rization 1.6 vs. 1.5% (1)

6.87±2. 54 vs. 7.03±2. 38

- Blood transfusio n 0 vs. 1.5% (2)

(0.712)

Reoperati on for bleeding control 0 vs. 1.5%(3b)

QoL: 1.32±0. 47 vs. 1.38±0. 49 (0.490) Qmax: 21.46± 4.05 vs. 21.09± 3.29 ml/sec (0.574)

Zhan g (2012 )

70 W ThuLEP vs. 90 W HoLEP

P-r

71 vs. 62

(Both with mushroo m techniqu e)

Hong (2015 )

120 W ThuVEP vs. 100 W HOLEP

76.2±9 .7

46.6±2 5.2

vs.

vs.

73.4±1 0.3

43.5±2 3.0

2.4±1.0

NA

vs. 2.5±1.0

Sovrapubi c drainage for capsular perforation 1.4 vs. 1.6% (3b)

(0.118) (0.108 )

R

42 vs. 46

(0.74)

72.1±4 .1

54.7±1 1.7

vs.

vs.

70.3 ± 5.3

56.1±1 3.6

Recathete rization 1.4 vs. 1.6% (1)

2.7±1.2

3.7±1.0

vs.

vs.

2.9±1.0

3.8±1.0

(0.668)

(0.422)

Catheteriz ation due to prolonged hematuria 7.1 vs. 6.5% (1)

IPSS≈: 5 vs. 6 QoL≈: 1.8 vs. 1.7 Qmax≈: 23 vs. 24 ml/sec IPSS: 8.1±2.0 vs. 8.3±1.7 (0.555) QoL:

(0.075

- UTI 7.1

)

(0.609)

vs. 4.3% (2)

0.8±0.8 vs. 0.8±0.8 (0.947) Qmax: 21.4±3. 8 vs. 21.1±3. 2 ml/sec (0.699)

Becke r (2018 )

90 W ThuVEP vs. 39.6 W HOLEP

P-r

48 vs. 46

74 vs. 71.5¶

82.5 vs. 77.5¶

2 vs. 2¶

(0.966) (0.207 )

(0.826)

2 vs. 2¶

(0.809)

Recathete rization 8.4 vs. 19.5% (1) - UTI 2.1 vs. 2.1% (2)

IPSS≠¶: 5 vs. 5 (0.730) QoL≠¶: 1 vs. 1 (0.824)

- Blood transfusio n 0 vs. 2.2% (2) - Removal of enucleate d tissue in local anesthesia 0 vs. 2.2% (3a) - Double J insertion 0 vs. 2.2% (3a) Secondary morcellatio n 0 vs.

Qmax≠ ¶ : 25.9 vs. 25 ml/sec (0.616)

2.2% (3b) Cistoscop y for bleeding control 2.1 vs. 4.3% (3b) Pirola (2018 )

110 W ThuLEP

R

vs. 100 W HOLEP

117 vs. 117

70 vs. 71¶

75 vs. 75¶

1 vs 1¶

(0.142) (0.587 )

1 vs 2¶

(0.068)

(0.715)

- Blood transfusio n 0.85 vs. 0.85% (2)

IPSS¶:

Cystoscop y for bleeding control 1.71 vs. 0.85% (3b)

(0.0580 )

Secondary morcellatio n 1.71 vs. 1.71% (3b) Secondary enucleatio n 0.85 vs. 1.71% (3b) Gu (2018 )

ThuLEP vs. HOLEP

R

60 vs. 56

73.87± 8.6 vs. 72.14± 0.95

(0.24)

NA

Resect ed weight: 48.10± 0.44 46.63± 6.33

3.63±1.1 0 vs. 3.89±1.1 1

NA

NA

3.5 vs. 5

QoL¶: 0 vs. 1 (0.164) Qmax¶: 25.9 vs. 25 ml/sec (0.8715 )

IPSS¶: 6 vs. 6 (NA) QoL¶: 1.8

(0.21)

vs. 1.6 (NA)

(0.22)

Qmax¶: 22 vs. 22 ml/sec (NA)

mTURP: monopolar transurethral resection of the prostate. PVP: photo-vaporization of the prostate. PKRP: plasmakinetic resection of the prostate. PKEP: plasmakintic enucleation of the prostate P: prospective. P-r= prospective and randomized R: retrospective. PV: prostate volume. *: 3-month follow-up. P-r: prospective and randomized. **: 1-year follow-up, only p-value available. ***: 1-year follow-up, data and p-value not-reported. §: 5-years follow-up in 80 patients. ≠: 6month follow-up. °: questionnaire used not reported. NA: not available. ThuVaRP: thulium laser vaporesection of the prostate. HOLEP: Holmium Enucleation of the Prostate. ♯: all patients on oral anticoagulants. ¶: value presented as median. ×: 24-month follow-up. ≈: 18-month follow-up IPSS: International Prostate Symptoms Score. QoL: quality of life. Qmax: maximum flow rate. Δ: difference vs. baseline. PPI: patient perception of improvement