Thulium fiber laser in BPH surgery: Bench to bedside - a systematic review on behalf of YAU Urotechnology Working Group

Introduction The Thulium fiber laser (TFL) is a new device that in contrast to the other solid-state YAG-based lasers takes a different approach to pulse formation allowing for two different modes: in the QCW (quasi-continuous wave) function, TFL is convenient for soft tissue surgery and in the SP (Superpulsed) mode it is highly effective in lithotripsy. Thus, unlike the other thulium lasers (Tm : YAG), TFL can be used in a wide range of surgical procedures. Materials and Methods We conducted a systematic search in 3 databases: Medline, Scopus and Cochrane library. All original articles (both preclinical and clinical) on TFL application in soft tissue surgery were included in data analysis. Results In terms of its cutting properties, QCW TFL is not inferior to the other thulium lasers, and in fact allows for decreased carbonization (due to lower heat production) compared to continuous lasers (e.g. Tm : YAG). It has been used successfully in endoscopic enucleation of the prostate (EEP) and in en bloc resection of bladder tumors (ERBT). The efficacy and safety of this laser is comparable to TURP and simple prostatectomy, but the recovery period is shorter and the learning curve is slightly superior to other endoscopic procedures. There are no significant differences between TFL and Ho : YAG in terms of efficacy and safety during EEP. Unfortunately, there are no clinical studies that analyse the efficacy and safety of SP TFL in EEP or ERBT. Conclusion TFL is a safe and effective tool for BPH surgery. In terms of parameters, it is in no way inferior to Tm : YAG or Ho : YAG during EEP. However, TFL surpasses these lasers in terms of usability and serviceability. These advantages are likely to render it more popular over time.


Introduction
Lasers are now unquestionably an integral part of endoscopic surgery. Laser based techniques have become the standard modalities of choice in BPH surgery, NMIBC treatment and of course in lithotripsy procedures (1)(2)(3)(4)(5). This spectrum of capabilities is linked to the specific properties of the laser such as wavelength, pulse power and pulse duration (6). Whilst some types of lasers are better applied to soft tissue surgery others lend themselves more to lithotripsy. The most significant determining factor for a laser's efficiency is its wavelength. The laser affects only molecules whose absorption spectrum is as close as possible to the wavelength of the laser. They are called chromophores. Water and hemoglobin molecules are the most prevalent chromophores in the human body; their peak of absorption happens at 1910 nm and 532 nm respectively (7). Chromophores absorb the laser energy which leads to the heating of tissues containing those chromophores (8). If the laser wavelength is close to the chromophore absorption peak (high absorption coefficient), the majority of energy affects directly the chromophore without resulting in energy dispersion in the surrounding tissues. This means that collateral damage can be minimized by using lasers with a high absorption coefficient (9).
Since the late 1990s, the Holmium : YAG laser (Ho : YAG) has become the most frequently used device in endoscopy. Thanks to its wavelength, Ho : YAG is highly absorbed by water which leads to vaporization without deep coagulative necrosis with the depth of tissue penetration being 0.4-0.7 mm (10). The main feature of this laser is its high peak power (2-10 kW) and its ability to rapidly increase its power. This titanic outburst of power creates a large stream of vapor bubbles which can be a factor in soft tissue surgery, when it is not only the laser radiation which cuts the tissue, but the stream of vapor.
Thulium based lasers stepped into the limelight with the introduction of the solid-state Tm : YAG laser. This laser is a continuous, water-targeted laser with a wavelength of 2010 nm. Its theoretical penetration depth is approximately 0.2 mm, and its firing regimen is different to that of the Ho : YAG. Tm : YAG is a continuous wave device and is therefore characterized by effective hemostasis, and so we would expect it to become a suitable tool for soft tissue cutting (10). It can be used for prostate vaporization, vaporesection, vapoenucleation and for mostly mechanical enucleation (11)(12)(13). Also, it has turned out to be a highly effective, safe and convenient tool for en bloc resection of NMIBC (14,15). In summary, one could say that this laser is a good option for the cutting of soft tissues but you could say that its advantage is also its limitationbeing a continuous wave device it is not effective for lithotripsy.
TFL construction substantially differs from Tm : YAG. Firstly, the YAG laser medium was replaced with thulium doped silica fiber (16,17). Thulium was chosen because the wavelength it creates is the closest to the water absorption peak (TFL -1940(TFL - nm, water -1910. For this reason, its theoretical penetration depth is only 0.15 mm (in comparison, for the Tm : YAG it is 0.2 mm, Ho : YAG -0.4-0.7 mm) (10). This feature may decrease the risk of complications and minimize collateral damage (18). Secondly, the silica fiber instead of YAG-crystal decreases the energy consumption and heat production. It allows instead to create an air-cooling system (instead of water-cooling in Ho : YAG), so the device is smaller and lighter compared with other lasers (19). Also, the decreased energy consumption comes about from using the standard 220V wall plugs without any proprietary connectors or any custom voltage. Thirdly, in TFL a Q-switcher system was applied to convert the super pulsed (SP) mode to quasi-continuous (QCW) for better soft tissue cutting.
Due to those properties, the modifications of TFL combining in itself both (QCW) and (SP) modes exist today (20).
The thulium fiber laser (TFL) was created to combine the advantages of thulium-based effective cutting with holmium-like lithotripsy. The development of this device was followed by a series of preclinical tests, carefully studying each feature of the laser. This meant that the efficiency of the laser could be tested on a preclinical basis, and that the findings could be translated into surgical practice. In this paper, we will show how the preclinical results of TFL were tested in the clinic, and how our understanding of the device's physics and build will affect the outcomes.

Materials and methods
We performed a systematic literature search using two databases (Medline (PubMed), Scopus and Cochrane library) where the majority of the TFLs preclinical and clinical trials results are comprehensively described. We used the following search query: "(TFL OR "Thulium fiber laser" NOT tensor) AND ((Soft tissu*) OR Cutting OR ThuFLEP OR EEP OR enucleation OR BPH OR "en bloc" OR resection)". Such an approach was chosen because a precise search would definitely ensure that we do not miss any data related to the use of the Thulium fiber laser in BPH treatment.
The inclusion criteria were as follows: all types of studies (both prospective and retrospective) containing their own data on TFLs preclinical and clinical trial results. We included only articles in English. Any other literature without original data or sufficient information were excluded. These might include different types of reviews, comments, single cases, editorial material, books as well as conference abstracts.
Firstly, AA and CA performed a title review. No additional filters or limitations to the search were used. Only articles in English were included. Secondly, MT and AO independently performed abstract reviews according to the same criteria. Once the title and abstract were reviewed, AA and CA manually removed any duplicates. Different types of reviews, editorial material, books, comments and clinical case reports were excluded. In addition, all articles that deal with the use of TFL for lithotripsy were excluded. Also, MT, CA and AA excluded all studies which went beyond the scope of urologic surgery. As a last step, MT, AO and AA independently performed a full-text review. In the event of any disagreement, each party made their case and tried to resolve it. If they could not come to an agreement, DE made the final decision. All in all, 21 articles were included in our review -9 preclinical and 12 clinical (Figure 1).
Thulium fiber laser for soft tissues Thulium fiber laser for soft tissues: preclinical trials The first in-vitro trial on TFL was conducted by Fried et al. (21,22) showing the TFL potential in tissue cutting with a prostate (canine model) vaporization rate of 0.83+/-0.11 g/ minute and with the hope that it would lead to an effective hemostasis. To assess the impact of the different TFL modes on soft tissue and to compare it with the other lasers, Taratkin et al. conducted a preclinical study using a non-frozen porcine kidney (23). The Ho : YAG incision had a conical ablation zone with a deep tissue rupture at the apex of the cone. The margins also were ruptured and shallow with a thin coagulation area without any carbonization. The QCW TFL mode made a coniform ablation zone approximately 1.5 times larger than Ho : YAG, with a rounded apex with a moderate carbonization. The Superpulsed (SP) mode of TFL produced an incision shape that was similar to Ho : YAG with minimal carbonization (23).
This finding was supported in another trial, assessing the impact of the fiber diameter (200 vs 600 mm) in different laser modes. No significant differences were observed irrespective of the fiber diameter except for the width of the coagulation zone for QCW TFL (smaller for 600 mm). QCW TFL made a coagulation zone 3 -5 times larger than the SP TFL. The QCW laser mode cuts the tissues faster, its incision was 1.5-2 times deeper, and the vaporization volume was 2-5 times higher, and yet it leads to increased tissue carbonization. The SP TFL incision showed no carbonization, but its hemostasis may be considered insufficient due to lower coagulation depth. These results suggest that QCW TFL may be a good option for soft tissue cutting with adequate hemostasis (24).
Another preclinical study aimed to compare the distancedependent impact of different lasers on soft tissue. Only Ho : YAG made an incision of a distance ≥ 2 mm (25). The deepest incision performed in the contact mode (fiber-tissue distance = 0 mm) was made by QCW TFL (70-90% higher than other lasers); at the fiber-tissue distance at 1 mm all of those lasers showed the similar results. The coagulation depth demonstrated similar patterns -QCW TFL coagulation was 70-90% deeper than that for other lasers at the distance <2 mm; no coagulation was noticed at the distance >3 mm. So, the authors recognized QCW TFL as the most effective for tissue cutting and cauterizing in contact mode. SP TFL has a similar pattern to Ho : YAG. However, the authors consider SP TFL to be the safer device as it showed no tissue damage at 2 mm (Ho : YAG show tissue rupture at >3 mm) (25). Comparing the impact on the soft tissues of TFL and Hybrid laser (combination of a Thulium fiber and Blue diode laser), Becker et al. obtained the following results (28): the Hybrid laser demonstrated the best vaporization and coagulation properties (50% more than TFL and 2-3 times more than Ho : YAG) with a coagulation zone smaller (by 10%) compared to the QCW TFL. The Hybrid laser's carbonisation was significantly lower than those for TFL (28). Those properties for both TFL and Hybrid laser were observed by Arkhipova et al. in their study (29).
All data on the preclinical studies is collected in Table 1.
Thulium fiber laser for soft tissues: clinical trials The above-mentioned preclinical studies demonstrated that TFL lends itself to soft tissue surgery for it is efficient at both cutting and coagulation. As a next step, these findings should be backed up with evidence from clinical trials.
A pioneered clinical study for thulium fiber laser enucleation of the prostate (ThuFLEP) was presented by Enikeev et al. on 2018 (30). ThuFLEP's efficacy (in voiding parameters improvement) and safety (in complication rate) turned out to be in no way inferior to TURP which remains the standard benchmark when it comes to these kind of comparisons. Also,  ThuFLEP led to a pronounced prostate-specific antigen (PSA) decrease which implies that there was a more complete removal of the prostate tissue (30). Compared to a simple prostatectomy in large volume BPH (> 80 cc), ThuFLEP proved to be as equally effective: the mean operative time, resection speed and resected tissue weight were comparable in both procedures (31). After simple prostatectomy, the patients stayed in hospital longer (9.0 days vs 3.3 days, p<0.001). At the 6-month follow-up, the stress urinary incontinence rate was 1,1% after ThuFLEP and 2.5% after simple prostatectomy (31). QCW TFL was successfully applied to different enucleation techniques like en bloc and two-lobe (32). Another study using this laser showed that routine stenting after ureteral orifice damage should not be considered mandatory, largely thanks to its short laser penetration depth (33).
A large retrospective study comparing ThuFLEP, HoLEP and MEP (monopolar enucleation of the prostate) reported no significant differences between those procedures regarding the complications rate at intraoperative, early postoperative period, as well as 6 months after surgery (34). As for the learning curve for these 3 endoscopic enucleation techniques, ThuFLEP was slightly superior (without significant difference [p>0.05]) to HoLEP and MEP in terms of the overall enucleation rate -1.0 g/min vs. 0.8 g/min and 0.7 g/min, respectively. Also, similar enucleation rates at the initial stages of training (first 20 surgeries) were observed, but after that period laser endoscopic enucleation techniques favored MEP (p<0.001) (35).
Also, Enikeev et al. compared the severity of irritative symptoms after HoLEP and ThuFLEP (38). No differences in functional outcomes (IPSS, Qmax), rate of SUI or irritative symptoms were found. Both surgeries were comparable in terms of duration and postoperative complication rates (38).
Elmansy et al. (39) compared TFL with Ho : YAG modified with Moses technology in patients with BPH undergoing transurethral enucleation of the prostate. The key differences were in median enucleation, hemostasis, and morcellation times which were longer in TFL group (p < 0.001). Otherwise, there were no significant differencesso, safety and efficacy profile with comparable postoperative outcomes were similar for those lasers (39).
The study of Maltagliati et al. (40) is of great interest because it compared ThuFLEP with Thulium solid-state laser enucleation of the prostate (ThuLEP). The authors reported only one difference between these proceduresthe duration of BPH surgery aside, TFL proved itself to be a suitable device for en bloc resection of bladder tumor (ERBT), predominantly NMIBC, within a prospective clinical trial (41). It was shown that patients after TFL ERBT had a better relapse-free rate than TURBT at both 3 (97.2% and 84.5%, p = 0.011) and 6 months (91.5% and 67.2%, p < 0.001). Also, TFL ERBT demonstrated a lower complication rate (like obturator nerve reflex, perforation) and better specimen quality compared to conventional TURBT (showing better detrusor rate on pathology). The only reported disadvantage for TFL ERBT was the prolonged surgery duration time (39.0 ( ± 16.5) vs 34.0 ( ± 8.8) min for TURBT) (41).
All data on the clinical studies is collected in Table 2.

Discussion
The thulium fiber laser is a novel device which can be applied for both soft tissue cutting and lithotripsy. This laser has 2 modes to complete these tasksquasi-continuous (QCW) and super pulsed (SP), respectively. QCW is close in properties to Tm : YAG laser, so it can be applied only in soft tissue surgeryfor surgical treatment of BPH or NMIBC. It also may be used for UTUC resection/vaporization but there are currently no studies regarding TFL application. SP TFL mode is close in its properties to Ho : YAG laser, so it may be used in both soft tissue and stone surgery.
There are 3 major differences between SP TFL and Ho : YAG. Firstly, SP TFL has a potentially higher frequency (up to 25 -40 times -2000 Hz for SP TFL and 50-80 Hz for Ho : YAG) (42). Secondly, its peak power is lower (SP TFL -500 W, Ho : YAG -2-10 kW). Thirdly, its pulse duration is longer (TFL: 500 ms; Ho : YAG: 350 at same Energy-Frequency settings) (43). The last difference is determined by different pulse profile -SP TFL has a Gaussian profile while Ho : YAG has a rapidly approaching power peak. In stone surgery those features are associated with lower stone retropulsion and faster soft stone dusting in favor of SP TFL. At the same laser setting, SP TFL and Ho : YAG do not differ in their soft tissue cutting propertiesin in vitro studies they were almost the same in terms of ablation depth, coagulation depth and carbonization mode (23, 25). As for clinical practice in BPH surgery, SP TFL may be associated with longer operation time, decreased hemoglobin drop and reduced urinary incontinence rate due to sphincter damage compared to Ho : YAG. Those features may be associated with reduced peak power and increased laser frequency. Unfortunately, we have no data of SP TFL and Ho : YAG clinical comparison in different laser settings. As for QCW TFL, it has established itself as a effective and safe device for EEP which is not inferior in these terms to Tm : YAG and Ho : YAG. QCW TFL may be safer than Tm : YAG in terms of carbonizationthe quasi-continuous mode decreases the thermal damage to tissue reducing carbonization and simplifying the intraoperative navigation (16,17). Unfortunately, there is no one preclinical comparison of those lasers yet. In a clinical comparison, TFL and Tm : YAG showed themselves to be similar in terms of safety and functional outcomes (40). TFL was associated with longer operation time, which may be caused with decreased vaporization speed. Thus, TFL may have a reduced tissue heating profile compared to Tm : YAG, so insignificant differences in hemoglobin drop and in catheterization or hospitalization time may be signs of its better safety profile. If our assumption is correct, carbonization may also be lower when using TFL. In comparing TFL and pulsed Tm : YAG (27), no significant differences were found. That can be explained by the change of laser pulse generation. Classic Tm : YAG is a continuous wave laser, so it influences the tissue continuously and the tissue heating occurs constantly over time. TFL is a quasi-continuous wave laserprolonged periods of tissue heating alternate with transient periods of tissue relaxation. So, when Tm : YAG functions as a pulsed laser, the effect on the tissue is directly comparable to those for TFL. This explains the lack of significant differences between these lasers.
In comparison with Ho : YAG, TFL proved to be comparable in terms of efficacy and safety. At the same time, using TFL for EEP was associated with longer operation time, insignificant decrease of complication rate and hemoglobin drop and better functional outcomes. The prolonged operation time may be associated with lower laser tissue penetration depth, absence of explosive vaporization effect and complicated intraoperative navigation due to carbonization. A hemoglobin drop may be associated with better QCW TFL hemostatic properties due to deeper coagulation and the lack of an explosive vaporization effect. The reduced complication rate and the better functional outcomes may be associated with minimized sphincter traumatization due to lower tissue penetration depth and the lack of an explosive vaporization effect. So, TFL may be considered as an effective and safe tool for EEP on a par with Ho : YAG.
As for the difference in learning curves, residents may reach the plateau faster using TFL because of its physical properties. At first, the fact that there was no explosive vaporization makes it easier to dissect along the capsulethat effect would accelerate the operation time but slow down the learning curve. The resident is led to believe that he can do EEP easily, and so he slows down to perfect oneself. This assumption is also supported by the fact that surgeons leave more adenomatous tissue when using Ho : YAG then TFL (35). We assume that gradual and more slow cutting during ThuFLEP may lead to a more predictable dissection. So the resident studying ThuFLEP, begins to identify the prostate capsule and to get into subcapsular layer earlier then resident using other EEP procedures. However, there is no evidence to support these assumptions. So far we have only discussed the properties of TFL and did not comment on its usability and serviceability. The thulium fiber laser setups are smaller than those for Ho : YAG, so they require less space in the operating theatre. Also TFL laser setups are lighter than those for Ho : YAG which makes it easier to use in theatre. Besides, the TFL setup requires a standard 220V or 110V electrical socket without any conversion. All these features are very useful and convenient for hospital administration because they make less demands on placement in small operation rooms. As for the surgeon's comfort, Moore et al. determined that TFL produces less noise than Ho : YAG (44). This makes it more pleasant to use TFL and means that surgeons and nurses can easily talk to one another during the procedure (44).
As it stands, TFL is something that urological residents who are just setting out to learn EEP should familiarize themselves withthey are likely to quickly reach an EEP learning curve plateau using TFL compared to other cutting agents. TFL may also be interesting for experienced surgeons who are accustomed to performing EEP or ERBT using thulium solid-state laser (Tm : YAG). TFL could also be used within hospital administration because this laser makes fewer demands on placement in small operation theatres and incorporates two toolsan effective laser for soft tissue cutting and a useful device for stone ablation.

Limitations
Our study has a few limitations. At first, we have not added any data regarding clinical studies laser settings because no relevant data in the original studies were to be found. So, the only data that we had was information about which laser mode was used -SP or QCW. Secondly, we have not found any preclinical studies that compare the effects of TFL with continuous-wave Tm : YAG. Therefore, we cannot compare the vaporization speed and the carbonization mode for those lasers. Yet, we have described in detail the physics of the lasers so that the reader may form easily his or her impression based on the theoretical background. We hope that this makes up for the lack of experimental data.

Conclusions
TFL is a safe and effective tool for BPH surgery. In terms of parameters, it is in no way inferior to Tm : YAG or Ho : YAG during EEP. However, TFL surpasses these lasers in terms of usability and serviceability. These advantages are likely to render it more popular over time.