Endoscopic Conservative Treatment of Upper Urinary Tract Urothelial Carcinoma with a Thulium Laser: A Systematic Review

Introduction: Thulium lasers (TLs), namely the Thulium fiber laser (TFL) and the Thulium:YAG (Tm:YAG), are being increasingly adopted for the conservative treatment of upper urinary tract urothelial carcinoma (UTUC). However, to date, the real clinical impact of TLs on UTUC management remains not well-characterized. We performed a review of the literature to summarize the current evidence on TLs for UTUC treatment. Materials and Methods: We performed a systematic review in January 2023 using the Embase and Medline online databases, according to the PRISMA recommendations and using the PICO criteria. Outcomes of interest were: (i) to assess the safety and feasibility of TLs in the treatment of UTUC, and (ii) to evaluate the oncological outcomes in terms of tumor recurrence and conservative treatment failure. Moreover, we described TL characteristics and its interaction with soft tissue. Results: a total of 458 articles were screened, and six full texts including 273 patients were identified. All the included studies were retrospective series. Mean patient age ranged from 66 to 73 years. The indication of a conservative treatment was elective and imperative in 21.7–85% and 15–76% of cases, respectively. Laser power settings varied from 5 to 50 W. No intraoperative complications were reported, and all the procedures were successfully performed. The tumor recurrence rate was 17.7–44%, and the indication to radical nephroureterectomy was 3.7–44% during a follow-up of 6–50 months. Most of the postoperative complications were mild and transient, and ureteral strictures were reported in two studies. Major limitations were the retrospective nature of the studies, the small sample sizes, and the short follow-up. Conclusions: TL is an effective and safe technology for endoscopic UTUC treatment. However, current available literature lacks prospective and multicentric studies with large population sizes and long-term follow-up.


Introduction
An upper urinary tract urothelial carcinoma (UTUC) is a relatively rare disease with an annual incidence of 1-2 cases per 100,000 inhabitants in Western countries [1]. Until 2013, radical nephroureterectomy has traditionally been the gold standard of care for localized UTUC regardless of tumor characteristics, and endoscopic conservative treatment has been reserved only in cases of imperative indications for kidney-sparing surgery (namely a bilateral UTUC, a solitary kidney, and an impaired renal function) [2]. Based on European Association of Urology (EAU) guidelines, UTUCs are categorized into low-risk and highrisk tumors [3]. Low-risk UTUCs include unifocal disease with size < 2 cm, negative

Study Population and Aims
The population, intervention, comparator, and outcome (PICO) criteria were used to frame the aims of this SR. The population of interest consisted of patients with UTUCs managed conservatively with RIRS; patients with either elective or imperative indications for UTUC endoscopic conservative treatment were considered (P). Thulium laser-either TFL or Tm:YAG laser-represented the evaluated intervention; no dual lasers including TL were considered (I). No other laser or surgical alternative comparators were considered mandatory for the specific purpose of the current review (C). The primary aim was to evaluate the safety and feasibility of TLs in the conservative treatment of UTUCs in terms of surgical complications and complete execution of the surgery. The secondary outcome was to evaluate the oncological outcomes in terms of tumor recurrence and conservative treatment failure (O). Moreover, we decided to describe TL characteristics and its interaction with soft tissue in a narrative modality to summarize the operating principles of this new laser technology and its potential benefits in UTUC treatment.

Literature Search and Data Analysis
A systematic web search was performed on 21 January 2023, according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, with no time restrictions, using the Embase and Medline online databases. The terms "Thulium", "Thulium:YAG", and "TFL" were pooled together with the Boolean operator "OR". The terms "UTUC" and "carcinoma" were pooled together with the Boolean operator "OR". The results were then pooled together with the Boolean operator "AND". The web Search was implemented by manual search (references of web search included articles). Two authors (L.C. and E.V.) independently screened all items. Disagreements about whether or not to include a study were resolved through consensus or by consultation with a third and senior author (O.T.). Only full-text publications in the English language were considered for the evidence synthesis of the SR. Case reports, editorials, letters, in vitro and experimental animal studies, reviews, and meeting abstracts were excluded from the analysis. Exclusion criteria included studies not reporting data on TLs and studies on dual lasers. Figure 1 shows a flow diagram of the selection process.
operator "OR". The results were then pooled together with the Boolean operator "AND". The web Search was implemented by manual search (references of web search included articles). Two authors (L.C. and E.V.) independently screened all items. Disagreements about whether or not to include a study were resolved through consensus or by consultation with a third and senior author (O.T.). Only full-text publications in the English language were considered for the evidence synthesis of the SR. Case reports, editorials, letters, in vitro and experimental animal studies, reviews, and meeting abstracts were excluded from the analysis. Exclusion criteria included studies not reporting data on TLs and studies on dual lasers. Figure 1 shows a flow diagram of the selection process. A narrative synthesis of included studies was performed. Descriptive statistics were used to summarize the studies' data and results. Due to the heterogeneity of the study outcomes presentation and the lack of standardization of the follow-up schedule, a metaanalysis of the results was not performed. [13,14,[16][17][18] Thulium ion is a rare-earth element with an infrared wavelength emission. For medical laser applications, TL is optimized to emit photons with wavelength of 1940 and A narrative synthesis of included studies was performed. Descriptive statistics were used to summarize the studies' data and results. Due to the heterogeneity of the study outcomes presentation and the lack of standardization of the follow-up schedule, a metaanalysis of the results was not performed. [13,14,[16][17][18] Thulium ion is a rare-earth element with an infrared wavelength emission. For medical laser applications, TL is optimized to emit photons with wavelength of 1940 and 2010 nm for TFL and Tm:YAG, respectively. These wavelengths closely match the infrared absorption peak of water, thus leading to high laser energy absorption of water molecules and hence vapor formation in the target tissue. Cell heating mediated by the laser at different laser settings determines the tissue incision, vaporization, or coagulation through a photothermal effect. TFL consists of a long and thin coiled silica fiber doped with thulium ions excited by diode lasers during laser activation. The Tm:YAG laser consists of a Yttrium-Aluminum-Garnet (YAG) crystal chemically doped with thulium ions excited via flash lamps in the laser cavity. Therefore, the thulium ions excitation modality for TFL and Tm:YAG is different. On the one hand, TFL is activated by matched diode lasers with minimal heating dissipation; on the other hand, Tm:YAG is activated by pulsed flash lamps that increase temperature during laser activation. Consequently, the latter laser technology needs a water cooling system to avoid overheating, resulting in bigger and heavier laser machines, while TFL systems are air cooled, thus leading to smaller and more practical machines. TL beams can be set with a large spectrum of different energies (0.025-6 J), frequencies (up to 2000 Hz), and pulse shapes, allowing for a huge number of possible of laser settings with a maximum laser power of 60 W. TL beams are transmitted from the laser source to the target tissue through flexible fibers, with small diameters of potentially up to 150 µm, providing endoscopes with maximal deflection and optimal navigation in the urinary tract without affecting laser transmission.

Thulium Laser Characteristics and Soft Tissue Interaction
Compared to Holmium:YAG, TL presents a longer pulse length with a lower pick power, resulting in greater cutting precision and hemostatic capacity with a variable tissue carbonization effect, depending on the pulse emission mode. One important advantage of TL in UTUC treatment is its shallow penetration depth in tissue (0.15-0.2 mm), making a precise incision with lower risk of tissue scarring and stricture formation possible.
TFL laser beams are emitted in pulsated emission mode, while Tm:YAG historically operated in a continuous way. Novel pulsated Tm:YAG generators are available, yet without clinical data reported in the literature. This characteristic determines different properties in soft tissue interaction for TFL and Tm:YAG. Particularly, the former causes a smooth incision with excellent coagulation and hemostasis but with more tissue carbonization that may impair tumor visualization during ablation. Conversely, pulsated TFL produces an accurate incision and a fine hemostasis with little carbonization effect.
Given this evidence, TLs showed several advantages compared the Holmium:YAG in terms of soft tissue incision precision and coagulation that allow for excellent cutting and hemostasis during UTUC ablation.

Clinical Data
Titles and abstracts from 458 articles were reviewed, and six full texts were finally selected for this SR ( Figure 1). All the included studies were retrospective series (five single centers and one multicenter series), and were published between 2011 and 2022 [19][20][21][22][23][24]. A Thulium:YAG laser and a TFL were used in four [19,[21][22][23] and two [20,24] series, respectively. Most of these studies aimed to assess TL safety and effectiveness in conservative UTUC treatment, and reported the short-term complications rate and oncological outcomes. TL was not directly compared with other laser or surgical alternatives in five studies. However, Wen et al. [20] compared oncological outcomes of the 32 patients treated with TL with a control group of 107 patients who underwent radical nephroureterectomy for UTUC in the same center. Moreover, Defidio et al. [19] reported differences between TLs and Holmium:YAG in laser properties through a Likert score for laser performance indicators (e.g., fiber tip stability, fiber tip precision, etc.).
Overall, 273 patients with UTUC were treated conservatively with a TL. Each study presented a relatively small sample size, ranging from 28 to 78 patients (Table 1).

Surgical Technique
Surgical techniques differed slightly among studies. In general, procedures were performed in the lithotomy position under general anesthesia. After urethrocystoscopy and guidewire insertion in the ureteral orifice up to the renal cavities, semi-rigid ureteroscopes were used to manage distal ureteral UTUCs and flexible scopes for proximal tumor treatments. However, Proietti et al. [24] avoided the placement of a guidewire when feasible before the URS ("no touch technique"), and Wen et al. [20] and Bozzini et al. [23] used only flexible scopes for treating UTUCs, regardless the location in the upper urinary tract. Bladder and selective ureteral/renal urine samples were systematically collected for cytological analysis. Ureteral sheath access was often placed in cases of proximal UTUCs. Tumor tissue biopsies for pathological analyses were carried out with stone retrieval baskets or endoscopic forceps. A TL was then used to ablate the residual tumor and for mucosal hemostasis. The diameter of the laser fibers ranged from 200 to 600 µm. Regarding the TL settings, the total power ranged from 5 to 50 W in different studies, with a trend to use less energy and a lower frequency in the ureter compared to the renal cavities to avoid the risk of ureteral damage and potential post-operative stricture formation ( Table 1). Most of the surgeons placed a single J or double J ureteral stent after the procedure. Of note, to the best of our knowledge, no series regarding patients treated with a conservative TL for UTUC treatment with a percutaneous surgical approach are available in the literature.

URS II Look and Endoscopic Follow-Up Schedule
EAU guidelines recommend performing a second-look endoscopic procedure within 6-8 weeks after the first URS. Moreover, stringent endoscopic follow-up is mandatory for patients managed conservatively with repeated URS timing, depending on the UTUC risk class [3].
A systematic URS second-look was performed by only Proietti et al. [24], while Defidio et al. [19], Wen et al. [20], and Musi et al. [21] performed early second procedures in cases of non-complete ablation at the first surgery. Nevertheless, in the other series, a second URS was performed at 3 months postoperatively (Table 1).

Patients and UTUC Characteristics
Patients' mean age ranged from 66 to 73 years old. Patients were predominantly males in all series, expect in the study by Hsieh et al. in which female patients represented 70% of the entire population [22]. Regarding the indication for kidney sparing surgery, conservative treatment was elective in 21.7-85% of cases, while it was imperative in 15-76% of patients. The number of lesions was reported only in three studies; UTUCs were a single lesion in 44-83.8% and multiple lesions in 16.7-56% of patients. Likewise, the tumor location in the upper urinary tract widely varied among studies ( Table 2). The mean tumor size was homogeneous among the different series (13-15.3 mm of maximal diameter). At final pathology, most of the UTUCs were low grade, expect in the study by Hsieh et al. in which 74% of tumors were high grade [22] (Table 2).  LG 67.8% HG 28.6% Inconclusive 3.6%

Surgical and Oncological Outcomes
No intraoperative complications during TL UTUC ablation were reported, and every procedure was completed without technical failures. Only Defidio et al. [19] reported that the median total operative time was 45 (20-90) minutes. In the same study, the authors found that TL was superior to Holmium:YAG in terms of laser fiber tip stability and precision, intraoperative bleeding, mucosal perforation, and operative time for tumors < 1.5 cm [19]. Regretfully, no other data regarding total operative time, laser-on time, and total delivered energy were reported in the other studies.
In the study by Defidio et al. [19], 97% of patients were discharged the day after the procedure. However, Wen et al. [20] reported a postoperative length of hospital stay of 3.6 ± 1.9 days.
One study did not report data on postoperative complications [19]. Three studies reported postoperative complications according to the Clavien-Dindo criteria [21,23,24]. Postoperative complications occurred in 10.5 to 38% of patients. Overall, most of the complications were mild and transient (namely postoperative pain requiring analgesia, hematuria without the need of blood transfusion, urinary tract infection). Regarding major complications, Wen et al. [20] and Hsieh et al. reported four and five [22] developments of ureteral strictures during the follow-up period, Musi et al. [21] performed an hemostatic URS, and Proietti et al. [24] experienced an acute obstructive renal failure that required a double J placement.
Patients' follow-up ranged from 6 to 50 months among studies. Only Proietti et al. [24] systematically performed a second look procedure within 8 weeks from the first URS, reporting absence of UTUC persistence in 70.4% cases. Overall, UTUCs' recurrence rate ranged from a minimum of 17.7% of cases with a follow up of 1 year to a maximum of 44% of cases with mean follow-up of 25 months. The longest median follow-up (26.4 months) was reported by Defidio et al. [19], which found a tumor recurrence rate of 37.3%. Conservative endoscopic UTUC treatment failure during the follow-up-namely the indication for a radical nephroureterectomy-was clearly reported in five studies, and it ranged from 3.7 to 39.7% of cases (Table 3). Hsieh et al. [22] reported the development of metastasis in two patients, and cancer-specific death during the follow-up in four (12%) patients. In the study by Wen et al. [20], the authors compared the outcomes of patients treated with TL with a control group of patients treated with nephroureterectomy. The authors found that, despite the lower postoperative creatinine level and the shorter length of hospitalization, patients in the TL group experienced a higher tumor recurrence rate of 21.9% vs. 7.8% in the radical surgery group (p < 0.01).

Limitations and Future Directions
This SR has some limitations. First, all the included studies were retrospective series, thus potentially having an impact toward the generalizability of the findings. Second, the sample sizes of the studies were small, and the follow-up times were generally short. Moreover, the follow-up schedule differs among studies. Third, most of the included studies were single-center series and did not use a control group against which to compare TL outcomes. Additionally, the intrinsic differences between TFL and Tm:YAG limit the generalizability of the results. Lastly, the results are presented mainly in a narrative fashion, since a meta-analysis of the data was not performed for the reasons reported in the methods section.
We should highlight that kidney-sparing management itself was identified as a costsaving alternative to radical nephroureterectomy, with USD 252,272 per patient saved in 5 years [25]. Actually, we did not find studies that analyzed the impact of TL from an economic point of view in the setting of UTUC conservative treatment. Ryan et al. recently reported that TFL has a significantly shorter operative time and decreased cost when compared to the standard Ho:YAG in endoscopic laser lithotripsy [26]. Future studies are needed to investigate the cost effectiveness ratio of TL compared to either to Holmium:YAG or radical nephroureterectomy in patients with UTUCs.

Conclusions
In the last 10 years, a number of studies on UTUCs managed endoscopically with TLs have been conducted, thus reflecting the growing interest on this laser technology in urooncology. Both the TFL and Tm:YAG are safe and feasible laser options to conservatively treat UTUCs. As a whole, TLs showed few complications and an effective tumor ablation rate. Despite these promising results, this laser technology is still characterized by a relatively high short-term rate of UTUC recurrence and conservative treatment failure. The currently available literature lacks prospective and multicentric studies with large population sizes and long-term follow-up. Moreover, there are no studies that directly compare TLs with Holmium:YAG lasers in this setting.
Further multicenter prospective studies with longer follow-ups, larger numbers of patients, and standardized follow-up schedules comparing TLs with other surgical alternatives for endoscopic UTUC management are needed to confirm these findings.