A Systematic Review of Green-Light Laser Vaporization for Supercial Bladder Cancer

Background: The related research of green-light laser vaporization in the treatment of non-muscle invasive bladder cancer (NMIBC) is limited. This study focused on analyzing the effectiveness and safety of it from the perspective of an extensive literature review. Methods: A comprehensive search of CNKI, WanFang, VIP, PubMed, Embase, and CENTRAL databases for photoselective vaporization of bladder tumor and transurethral resection of bladder tumor treatment of non-muscle invasive bladder cancer (NMIBC). The search included studies from January 1996 to December 2019. Two reviewers independently screened literature, extracted data, assessed the risk of bias of included studies. RevMan 5.3 software was used for Meta-analysis. Results: A total of 18 RCTs involving 1648 patients met the predened criteria. Meta-analysis data demonstrated that the PVBT group exhibited a signicant advantage over the TURBT group in intraoperative obturator nerve reex and bladder perforation and postoperative 1-year recurrence. The PVBT procedure has advantages over TURBT in the amount of surgical bleeding and the length of hospital stay, bladder irrigation time, and catheter indwelling time. There was no difference between the two types of surgery in the incidence of postoperative urethral stricture and the length of surgery. Conclusion: Our systematic review and meta-analysis suggests that PVBT is better than TURBT as an alternative treatment for patients with NMIBC in safe aspect. However, whether it is equally effective in terms of oncological control remains to be elucidated, and additional high quality RCTs are needed to conrm our ndings. 2 meta-analysis using xed effect heterogeneous meta-analysis. sensitivity α

end of the last century, laser technology has been used throughout urology. This technology has been widely used in clinical practice due to its safety, minimal invasiveness, and a positive therapeutic effect [7]. In 2002, Laserscope pioneered the 80W green laser surgery system and applied it to benign prostatic hyperplasia. Since then, green laser has emerged as a new technology for the treatment of urinary diseases [8]. The green laser (KTP laser) is easily absorbed by oxidized hemoglobin, but it is not easily absorbed by water, so it is called "selective light." As a result, it can better utilize its energy in human tissues to generate thermal energy, thus causing a vaporization effect. The green laser surgery system is mainly limited to the shallow surface of the tissue surface with a depth of approximately 0.8 mm. At the same time the tissue is vaporized, a solidi cation zone of 1-2 mm is formed on the surface of the tissue, which facilitates a strong hemostasis. Another advantage of the green laser is that it does not produce an electric eld effect. In theory, it can avoid the stimulation of the obturator nerve by the current as well as induce nerve re ex, which reduces the incidence of bladder perforation [9,10]. We performed a systematic review of RCTs using meta-analysis to determine whether there are any differences between the intraoperative and postoperative outcomes, in addition to oncologic outcomes, between these two approaches, in order to determine whether transurethral laser treatment techniques can be appropriate alternatives to TURBT.

Methods
The search terms and search strategies were developed according to the Cochrane Handbook for Systematic Reviews of Interventions [11]. The search languages were Chinese and English, and the CNKI, VIP, WangFang, CBM, PubMed, EMBase, and the Cochrane Library databases were utilized for this study. The databases were searched from January 1996 until December 2019. The corresponding search terms were "laser," "KTP laser," "electric resection," "bladder tumor," "green laser" and "urinary bladder neoplasms." Some of the search terms had no subject word correspondence, such as "NMIBC," so the search was supplemented by free words and synonyms, such as "green laser", "greenlight laser", "PVBT", "KTP", "urinary bladder neoplasms", "bladder neoplasm", "bladder tumor", "urinary bladder cancer" and "bladder cancer". Additionally, search terms were linked together via using the appropriate logical operators, synonyms were connected with "or", "and" was applied to search terms with different meanings (Supplementary le-search strategy).
For a study to be considered eligible, it had to meet the following criteria: (1) It was a randomized controlled clinical trial; (2) The study subjects were patients diagnosed with NMIBC; (3) The experimental group was treated with transurethral bladder tumor green laser selective vaporization (PVBT group) and the control group was treated with transurethral resection of bladder tumor (TURBT group). (4) Research indicators must include at least four or more of the following indicators, such as the amount of surgical bleeding and the length of hospital stay, bladder irrigation time, and catheter indwelling time, urethral stricture, obturator nerve re ex and bladder perforation and postoperative recurrence rate. Studies were excluded if they met the following criteria: (1) Non-randomized controlled trials; (2) Too small of a total sample size (< 40 cases rendered the complication index di cult to observe); (3) The original research data could not be obtained. Even if you contact the original author by email or other means. The study was a repeat publication, or the original data record was incomplete; (4) Presence of upper urinary tract tumors and other operations at the same time; (5) Non-green lasers such as helium neon, holmium laser, red laser, 2 µm laser, and semiconductor laser, among others; (6) There were too few outcome indicators. After contacting the author, if these problems could not be recti ed, no further research was conducted.
The search process was completed by two independent researchers (researcher Xu, researcher Wu). If there was any disagreement in the search process, Professor Chen would provide professional advice and a research may have been completed. In the end, Professor Chen will check whether the retrieval process and the retrieval results are correct. The quality of the included research literature was evaluated based on the improved Jadad scale. The evaluation of literature quality is mainly based on the following aspects: random sequence generation, random hiding, blind method implementation, exit and loss of follow-up.
Study parameters included duration of surgery, intraoperative blood loss, length of hospital stay, duration of catheterization, bladder irrigation, obturator nerve re ex, bladder perforation, tumor recurrence, and urethral stricture. Meta-analysis was performed using RevMan 5.3 statistical software (London, United Kingdom). The count data used Relative Risk (RR) as the effect index, and the measurement data used Mean Difference (MD) as the effect index. Each effect amount provided a point estimate and a 95% Con dence Interval (CI). First, heterogeneity analysis was carried out for each study. The χ 2 test was also carried out (the test level was set to α = 0.1), and the heterogeneity was judged by I 2 . If the studies were homogenous (I 2 < 50%), a meta-analysis was performed using a xed effect model. If the studies were heterogeneous (I 2 > 50%), a random effects model was used for meta-analysis. For obvious heterogeneity, sensitivity analysis and other methods were used for processing. The test level for the meta-analysis was α = 0.05.
Sensitivity analysis was not performed on the research indicators with good homogeneity in the included studies. For the indicators with greater heterogeneity, two methods, single-removal method and selection model analysis method, were used for sensitivity analysis. If there is no difference in the results of two methods, the meta-analysis is reliable. If there are differences in the results of the sensitivity analysis, it is suggested that there are factors that affect the effectiveness of the intervention, and caution must be exercised when interpreting the results and drawing conclusions.
For research indicators with more than 10 included articles, funnel charts were used to determine whether there is publication bias. If the points are evenly distributed on both sides of the midline in the funnel chart, it indicates that there is no publication bias. On the contrary, there is publication bias. If there is too little relevant literature for an index, no funnel chart was made.
According to the original data obtained from the literature, baseline data, such as surgical grouping, age, gender, tumor staging/grading, tumor number, and position, were plotted and compared, and all the studies were consistent with baseline data (Table 1). Tumor staging in different articles at different time period was based on different AJCC staging versions which are 5th, 6th, and 7th, respectively. Nevertheless, the staging of super cial bladder cancer was consistent in these tumor staging criteria. Therefore, the AJCC staging doesn't affect our results.  There were 14 publications [11, 13-17, 19, 20, 22-24, 26-28] met the criteria of obturator nerve re ex inclusion. The heterogeneity analysis results (I 2 = 0, P = 0.72) indicated good homogeneity among various studies. Meta-analysis of them revealed that the obturator nerve re ex in the operation was lower in the PVBT group than in the TURBT group and the result was statistical signi cant (RR = 0.09, 95% CI [0.04, 0.18], Z = 6.91, P < 0.00001, Fig. 2A). Funnel plot showed no publication bias (Fig. 4A).
Of the 18 articles included in the study, only three speci cally described the urethral stricture after surgery [18,20,28]. Quantitative analysis of the data regarding urethral stricture post-surgery in these three papers was performed [18,20,28] (RR = 0.53, 95% CI [0.15, 1.83], Z = 1.00, P = 0.32, Fig. 3A). Hence, there was no difference in the incidence of postoperative urethral stricture between the PVBT group and the TURBT group.
Funnel plot showed that the distribution of each point was diffuse and uneven, so publication bias was considered (Fig. 4E).
Quantitative analysis of the underlying data of 12 studies [12-19, 21, 23, 25, 30] (MD = − 2.60, 95% CI [− 3.30, − 1.90], Z = 7.29, P < 0.00001) indicated that the duration of catheter indwelling of PVBT group was signi cantly less than TURBT group (Fig. 3D). There was a strong heterogeneity depending on the heterogeneity analysis results (I 2 = 98%, P < 0.00001). The sensitivity analysis suggested there was no difference between results of removal single study and change effect model. A considered publication bias was shown in funnel plot (Fig. 4F).
Heterogeneity was considered according to the heterogeneity analysis results (I 2 = 99%, P < 0.00001). After sensitivity analysis, no difference between results of removal single study and change effect model was shown, so the analysis was still reliable.
Through analysis, it was found that obturator nerve re ex, bladder perforation, urethral stricture, and tumor recurrence all showed good homogeneity. However, the amount of surgical bleeding, the duration of operation, length of hospital stay, the duration of catheter indwelling, postoperative bladder irrigation time showed greater heterogeneity. The inconsistency of measurement tools, measurement units and measurement accuracy should be regarded as the source of heterogeneity.
Sensitivity analysis of the operation time were inconsistent, so the reliability of its related results and conclusions should be doubted. The amount of surgical bleeding, length of hospital stay, catheter indwelling time and bladder irrigation time all showed high heterogeneity. But after sensitivity analysis, the results were still statistically signi cant, indicating that the results were reliable.

Discussion
Although societal and living standards have improved, the incidence of bladder cancer has increased, trending toward a younger age of diagnosis [1]. Bladder cancer ranks third among global male cancers, with NMIBC accounting for 70% of cases [1]. TURBT is the preferred surgical method for the treatment of NMIBC. However, with the continuous improvement of medical technology, TURBT has come to be criticized for its various drawbacks [30]. TURBT uses a high-frequency current to cut tumor tissue, and it is easy for thermal penetrating injuries to take place during the cutting process. It can also damage surrounding tissues and form eschar and scar tissue [30]. Due to its electric eld effect, it is apt to obturator nerve re ex, especially bladder wall tumors, thereby increasing clinical complications that include bladder perforation and adhesion formation [30]. The rate of recurrence following TURBT is also high [1]. In TURBT, the tumor tissue is repeatedly cut into pieces, which violates the principle of surgical tumor-free, i.e., in order to prevent the spread of the tumor, the tumor should be removed as a whole, rather than from many individual tissues.
Green laser vaporization is already widely used in the treatment of bladder tumors, mainly in NMIBC. It is also used in muscle invasive bladder cancer [31]. PVBT has obvious advantages over TURBT with regards to surgical complications including obturator nerve re ex, bladder perforation, and surgical bleeding. This is because the green laser does not produce an electric eld effect, so it does not induce nerve re ection. At the same time, the tissue penetration is shallow, the incidence of bladder perforation is small, and its selective absorption causes almost no bleeding during intraoperative bleeding. Long-term follow-up studies have also demonstrated it to be superior to traditional resection in terms of postoperative recurrence rate [30]. The green laser directly vaporizes the tumor tissue, reducing the probability that the tumor cells will be scattered in the bladder and cause distal implantation. The green laser vaporizes tissue at the same time to form a vaporization zone on the surface of the tissue, which effectively blocks the microvessels and lymphatic vessels and reduces the possibility of cancer cells entering the lumen [32].
Regarding the amount of surgical bleeding, hospitalization time, the duration of bladder irrigation and catheter indwelling, this meta-analysis showed that PVBT is superior to TURBT. Because of the heterogeneity, sensitivity analysis was carried out and showed that the conclusions of the four indicators are reliable. Therefore, the e ciency and safety of PVBT were veri ed. Heterogeneous sources are often considered inconsistent with the familiarity of the green laser surgery system and the inconsistent measurement methods.
In the incidence of postoperative urethral stricture and duration of the operation, the meta-analysis showed that there was no difference between the two surgical methods (P > 0.05), and the sensitivity analysis suggested that the results are stable and the conclusion is reliable. Overall, the e ciency and safety of PVBT has once again been veri ed [29]. Based upon these ndings, we surmise that PVBT is worth promoting as a standard procedure for the treatment of NMIBC.
Limitations of this study are as follows. 1) Although the incorporated literature is described as a randomized indicators, which in turn affect the reliability of the conclusions [33], especially regarding to the recurrence rate of tumor. Hence, although the recurrence rate of tumor showed that PVBT was better than TURBT in the analysis of forest map, the analysis of recurrence rate was biased and the conclusion was not reliable.

Conclusions
Based on the data included in our meta-analysis, PVBT is safer than TURBT for patients with NMIBC, but whether it is equally effective in terms of oncological control remains to be elucidated. However, additional randomized controlled trials with longer follow-up periods and larger sample sizes should be performed to verify our ndings.

Declarations
Ethics approval and consent to participate Not applicable.

Consent for publication
Not applicable.

Availability of data and material
The data and materials can be obtained by contacting the rst author.

Competing interests
All the authors declare that there are no competing interests

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