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ORIGINAL ARTICLE
Year : 2022 | Volume
: 18
| Issue : 7 | Page : 1894-1902
Efficacy and safety of 2-micron laser versus conventional trans-urethral resection of bladder tumor for non-muscle-invasive bladder tumor: A systematic review and meta-analysis
Jun Gu, Zexi He, Zhenjie Chen, Haichao Wu, Mingxia Ding
Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, Yunnan, China
Correspondence Address:
Mingxia Ding
Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming 650101, Yunnan
China
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/jcrt.jcrt_608_22
Aim: To compare the clinical efficacy and safety of 2-micron laser and conventional trans-urethral resection of bladder tumor (TURBT) in the treatment of non-muscle-invasive bladder tumor (NMIBT), providing evidence-based evidence for clinical treatment.
Materials and Methods: PubMed, Embase, Cochrane Library, CMB, CNKI, and WanFang databases were searched since their inception until December 2021 for all eligible randomized controlled trials (RCTs) related to 2-micron laser and TURBT for treating NMIBT. Two researchers independently screened the literature, extracted outcome indicators, and assessed the risk of bias according to the inclusion and exclusion criteria. Binary and continuous variables were calculated by relative risk (RR) and mean difference (MD) with 95% confidence interval (95%CI), respectively. RevMan 5.4 and Stata 15.0 software were used for all statistical analysis.
Results: A total of ten RCTs involving 1,163 patients were included: 596 cases in the 2-micron laser group and 567 cases in the TURBT group. The results of the meta-analysis revealed that 2-micron laser has advantages over the TURBT in operative duration (MD = −2.94, 95% confidence interval (CI) [−8.55, 2.68], P = 0.31), operative blood loss (MD = −19.93, 95%CI [−33.26, −6.60], P = 0.003), length of hospital stay (MD = −0.94, 95%CI [−1.38, −0.50], P < 0.001), post-operative bladder irrigation time (MD = −28.60, 95%CI [−50.60, −6.59], P = 0.01), period of catheterization days (MD = −1.07, 95%CI [−1.73, −0.40], P = 0.002), obturator nerve reflex (RR = −0.06, 95%CI [0.02, 0.15], P < 0.001), bladder perforation (RR = 0.14, 95%CI [0.06, 0.35], P < 0.001), and bladder irritation (RR = 0.30, 95%CI [0.20, 0.46], P < 0.001). There was no significant difference between the two surgical methods in post-operative urethral stricture and short-term recurrence of NMIBT.
Conclusion: Compared with TURBT, 2-micron laser may be safer and more effective for NMIBT management. However, these conclusions need to be validated through more high-quality RCTs because of the quality limitations and publication bias of the included studies.
Keywords: 2-micron laser, bladder cancer, meta-analysis, randomized controlled trials, trans-urethral resection of bladder tumor
Bladder cancer is one of the most common cancers in the urinary system. In 2020, there were 573,278 new bladder cancer cases and 212,536 new bladder cancer-related deaths worldwide.[1] Several independent risk factors for bladder cancer have been identified, such as smoking, exposure of dyes, GSTM1-null genotype, gender, and so on.[2],[3] Importantly, non-muscle-invasive bladder tumor (NMIBT) accounts for approximately three-quarters of newly diagnosed bladder cancers, so treatment targeting NMIBT is critical.
The recommended treatment for NMIBT by domestic and foreign guidelines is trans-urethral resection of bladder tumor (TURBT) plus post-operative intravesical chemotherapy. TURBT resects the visible bladder tumor in the urethra with a high-frequency current to obtain high-quality specimens, which allows histological diagnosis and treatment of the disease. Two-micron laser technology is a new minimally invasive technique widely used in the management of bladder cancer. Using a 2-micron continuous wave laser, this surgical method can synchronize vaporization and cutting, simultaneously leading to less intra-operative bleeding and better vaporization cutting effects.[4] The penetration of a 2-micron laser in the bladder tumor tissue is only 0.3 mm, which avoids causing tissue edema and necrosis, while accurately removing the tumor tissue.[5] At present, whether 2-micron laser or TURBT is safer and more effective in the treatment of NMIBT remains unclear. Thus, this study aimed to conduct a meta-analysis of published randomized controlled trials (RCTs) to provide evidence-based results for clinical treatment selection.
> Materials and MethodsSearch strategy
The search strategy was developed based on the Cochrane Collaboration workbook.[6] The PubMed, Embase, Cochrane Library, CMB, CNKI, and WanFang databases were searched until December 2021 for this meta-analysis. There were no language restrictions. The combination of subject words and free words to search in electronic databases and the corresponding search terms were “2 μm laser,” “2-μm laser,” “2 mum laser,” “2-mum laser,” “2 micrometer laser,” “2-micrometer laser,” “2 micron laser,” “2-micron laser,” “Revolix 2 μm,” “two micrometer laser” and “continuouswave laser,” “urinary bladder neoplasms [Mesh],” “bladder neoplasm,” “bladder tumor,” “bladder cancer,” “non-muscle invasive bladder tumor,” and “non-muscle invasive bladder cancer.” Boolean logic operators (AND/OR/NOT), positional operators, and truncation operators were used to determine the search expression. Furthermore, the references in the retrieved literature, especially the RCTs and reviews, were manually searched to further identify relevant articles meeting the inclusion and exclusion criteria.
Study inclusion and exclusion criteria
Our study was limited to RCTs. All eligible RCTs included patients harboring NMIBT with an indication for 2-micron laser and TURBT. There was no restriction on the age, sex, and race of patients. The inclusion criteria were as follows: ① All patients were diagnosed with NMIBT by pre-operative cystoscopic biopsy or post-operative pathological results, excluding patients with muscle layer infiltration or regional and distant lymph node metastasis. Simultaneously, patients with other bladder diseases were excluded. All patients without obvious contraindications for surgery, who voluntarily accepted the relevant surgical treatment plan; ② Experimental group: Trans-urethral 2-micron laser resection (2-micron laser group); control group: trans-urethral resection; ③ Outcome indicators include ≥ 1 of the following: operative duration, operative blood loss, length of hospital stay, post-operative bladder irrigation time, period of catheterization, obturator nerve reflex, bladder perforation, post-operative urethral stricture, bladder irritation, and short-term recurrence. Related outcome indicators could be calculated or combined. The exclusion criteria were as follows: ① The full text of this article or related outcome indicators could not be obtained; ② Patients with diseases with a greater impact on post-operative outcomes, such as severe cardiopulmonary dysfunction, severe blood system diseases, severe urinary tract infections, and so on; ③ Studies with unreasonable experimental design, inconsistent outcome indexes, or inability to combine effect sizes; ④ Reviews, conference papers, retrospective studies, case-control studies, single studies, current studies, animal studies, and case reports; ⑤ Studies with a small sample size or old publication date.
Literature screening and data extraction
According to the title, abstract, and full text of the study reports, the two researchers independently conducted literature screening and data extraction; consequently, they reviewed each other's results. In case of disagreement, the two researchers negotiated and tried to contact the author to obtain the missing literature. The main data extracted included: ① Basic information: title, first author, publication year, research type, and so on; ② Basic subject characteristics: sample size of experimental and control groups, age, sex, tumor size, and so on; ③ Measurement data of relevant outcome indicators; ④ Risk assessment indicators of bias.
Quality evaluation of the evidence
Two researchers evaluated and reviewed the included literature. The improved Jadad scale was used to evaluate the quality of selected RCTs, including random sequence generation, randomization concealment, blind method, withdrawals, and dropouts. A Jadad score between 1 and 3 is considered of general quality, and 4–7 points indicate high quality.[7]
Statistical analysis
The basic data extracted from the studies were analyzed using RevMan 5.4 and Stata 15.0 software. The mean difference (MD) was used for continuous variables and the relative risk (RR) was used for dichotomous variables to calculate the effect size and 95% confidence interval (CI). The heterogeneity of the included studies was tested with the χ2 test (α = 0.1 test level). For I2 ≤50%, the difference was not statistically significant, and a fixed-effect model was adopted. If I2 > 50%, a significant statistical heterogeneity requires that the source of heterogeneity be further investigated.[8] After excluding the factors that significantly affected clinical heterogeneity, a random effect model was used for meta-analysis. We excluded clinical heterogeneity by sensitivity and sub-group analyses, or we only performed descriptive statistics and analyses. The meta-analysis level was α = 0.05. Publication bias was measured by the funnel plot, Begg test, and Egger test. Sensitivity analysis was performed to assess the stability of the results by sequentially excluding individual studies.
> ResultsSearch results
According to the retrieval strategy formulated in this paper, a total of 1138 related reports were obtained. Then, by reading the title, abstract, and full text of the article, the literature was screened layer by layer according to the inclusion and exclusion criteria. Ultimately, a total of ten RCTs were included.[9],[10],[11],[12],[13],[14],[15],[16],[17],[18] A total of 1163 patients were enrolled, including 596 in the 2-micron group and 567 in the TURBT group. The literature screening process and results are shown in [Figure 1].
Figure 1: Flow diagram of studies [PubMed (n = 331), Embase (n = 76), Cochrane (n = 9), CNKI (n = 524), Wanfang (n = 131), CBM (n = 67)]Basic characteristics and quality evaluation of included studies
Baseline data such as sex, average age, tumor size, and tumor number were extracted from the original literature and compared among patients in the two surgical groups. The baseline data for all studies were comparable [Table 1]. An improved Jadad scale was used to evaluate the quality of ten articles. Among them, there were three high-quality studies and seven general-quality ones [Table 1].
Meta-analysis results
Peri-operative indicators
Operative duration
Ten studies were included comparing the duration of the two surgical methods.[9],[10],[11],[12],[13],[14],[15],[16],[17],[18] Before meta-analysis, the same research indicators were tested for heterogeneity. The results (P < 0.001, I2 = 97%) indicated significant differences and poor homogeneity; thus, the random effect model was used for meta-analysis. Meta-analysis showed that the operative duration of the 2-micron laser group was significantly shorter than that of the TURBT group (MD = −2.94, 95%CI [−8.55, 2.68], Z = 1.02, P = 0.31, [Figure 2]a).
Figure 2: Forest plot showing the peri-operative indicators of 2-micron laser and TURBT for NMIBT. (a) Operative Duration; (b) Operative Blood Loss; (c) Length of hospital stay; (d) Post-operative bladder irrigation time; (e) Period of catheterization (days)Operative blood loss
Five studies assessed the operative blood loss for both types of surgery.[11],[13],[14],[15],[16] The results of heterogeneity analysis (I2 = 98%, P < 0.001) showed poor homogeneity among studies, so the random effect model was used for meta-analysis. The MD was − 19.93, (95%CI [−33.26, −6.60]; Z = 2.93; P = 0.003), showing that patients in the 2-micron laser group had statistically less operative blood loss than those in the TURBT group [Figure 2]b.
Length of hospital stay
Combined quantitative analysis (MD = −0.94, 95%CI [−1.38, −0.50], Z = 4.19, P < 0.001) was performed on the basic data from seven articles.[9],[11],[12],[13],[15],[16],[17] There was a significant difference in the length of hospital stay between the 2-micron laser group and the TURBT group [Figure 2]c. The included literature was highly heterogeneous (I2 = 93%, P < 0.001). However, the sensitivity analysis showed that the results did not change significantly after excluding individual studies one by one, indicating that the conclusion of this index is reliable.
Post-operative bladder irrigation time
Only three of all included studies specifically described post-operative bladder irrigation time.[9],[14],[17] There was a significant difference in post-operative bladder irrigation time between the 2-micron laser group and TURBT group (MD = −28.60, 95%CI [−50.60, −6.59], Z = 2.55, P = 0.01, [Figure 2]d). Because of the strong heterogeneity (I2 = 100%, P < 0.001), a sensitivity analysis revealed no difference between the single removal study and the change effect model, suggesting reliable analysis of post-operative bladder irrigation time.
Period of catheterization days
There were eight studies comparing the period of catheterization days between surgey groups.[9],[11],[12],[13],[14],[16],[17],[18] Quantitative meta-analysis revealed that the period of catheterization of the 2-micron laser group was significantly shorter than that of the TURBT group (MD = −1.07, 95%Cl [−1.73, −0.40], Z = 3.16, P = 0.002, [Figure 2]e). The results of heterogeneity analysis showed strong heterogeneity among studies (P < 0.001, I2 = 99%) and no differences when removing a single study and changing effect model.
Complications
Obturator nerve reflex
Nine articles[9],[10],[11],[12],[13],[14],[15],[16],[17] evaluated the obturator nerve reflex with these two surgical procedures. There was good homogeneity among studies (I2 = 0%, P = 0.99); thus, a fixed-effect model was selected for analysis. The combined meta-analysis showed RR = 0.06, 95%CI [0.02, 0.15], Z = 6.08, P < 0.001, indicating that the intra-operative obturator nerve reflex of the 2-micron laser group was lower than that of the TURBT group [Figure 3]a].
Figure 3: Forest plot showing the complications of 2-micron laser and TURBT for NMIBT. (a) Obturator nerve reflex; (b) Bladder perforation; (c) Post-operative urethral stricture; (d) Post-operative bladder irritationBladder perforation
Seven studies[9],[10],[12],[13],[14],[15],[16] were included to assess the incidence of intra-operative bladder perforation. The results revealed that the bladder perforation of the 2-micron laser group was significantly lower than that of the TURBT group (RR = 0.14, 95%CI [0.06, 0.35], Z = 4.18, P < 0.001, [Figure 3]b). There was good homogeneity among the included studies (I2 = 0%, P = 0.79).
Post-operative urethral stricture
The included studies[9],[10],[12],[15],[17] were homogeneous (I2 = 0%, P = 0.66). However, quantitative analysis found no significant difference between the two surgical methods in terms of post-operative urethral stricture (RR = 0.75, 95%CI [0.29, 1.92], Z = 0.60, P = 0.55, [Figure 3]c).
Post-operative bladder irritation
Quantitative analysis of the basic data of four RCTs[9],[13],[16],[17] showed statistically lower incidence of post-operative bladder irritation in the 2-micron laser group than in the TURBT group ((RR = 0.30, 95%CI [0.20, 0.46], Z = 5.58, P < 0.001); [Figure 3]d). The included studies had good homogeneity (I2 = 0%, P = 0.83).
Short-term recurrence
Among the included studies, eight RCTs[9],[10],[11],[12],[13],[14],[15],[17] described post-operative recurrence of bladder tumor, but the two surgical methods in Wang TM's literature[13] did not show post-operative recurrence, which did not allow performing a quantitative analysis and were removed. Accordingly, the data of only seven RCTs were analyzed. Although they showed good homogeneity (I2 = 0%, P = 0.95), the results showed no significant differences between groups (RR = 0.97, 95% CI [0.78, 1.22], Z = 0.23, P = 0.81; [Figure 4]).
Figure 4: Forest plot showing the short-term recurrence of 2-micron laser and TURBT for NMIBTPublication bias
Funnel plot, Begg test, and Egger test were used to evaluate publication bias [Figure 5]a, [Figure 5]b, [Figure 5]c, [Figure 5]d, [Figure 5]e, [Figure 5]f, [Figure 5]g, [Figure 5]h, [Table 2]. However, publication bias analyses of post-operative bladder irrigation time and bladder irritation were not performed because fewer studies were included. Publication bias was only found for short-term recurrence (Begg test: P = 0.230; Egger test: P = 0.030).
Figure 5: Funnel plot of published bias analysis. (a) Operative duration; (b) Operative blood loss; (c) Length of hospital stay; (d) Period of catheterization (days); (e) Obturator nerve reflex; (f) Bladder perforation; (g) Post-operative urethral stricture; (h) Short-term recurrence > Discussion Bladder cancer is the tenth most common cancer in the world. Approximately 70% of newly diagnosed bladder cancer is NMIBT, but the post-operative recurrence rate is as high as 50–70% in newly diagnosed patients, which may be closely related to tumor size, lesion number, stage, grade, and prior recurrence.[19],[20] In addition, about 10–20% of patients will develop muscle-infiltrating bladder cancer,[21] and women tend to have a worse prognosis than men.[22] Therefore, the treatment of bladder cancer mainly focuses on the management of NMIBT.
At present, trans-urethral bladder tumor resection is the main method for diagnosis and treatment of non-muscular-invasive bladder cancer.[23] However, some studies have indicated 15.2–70.0% of tumor residual rate of NMIBT patients after secondary resection and a tumor stage increase rate of 0–24.4%,[24],[25],[26] mainly related to the technical characteristics of TURBT itself. TURBT uses a high-frequency current to generate heat and cut the tumor tissue, which may cause thermal damage to the tissue edge, affecting the tumor's pathological evaluation. It can also cause damage to surrounding and deep tissues, leading to scarring of the bladder wall, which can affect normal bladder functions. In the case of bladder tumor in the lateral wall, the high-frequency current from the incision ring stimulates the obturator nerve adjacent to the bladder wall,[27] leading to contraction of the thigh adductor muscle group in the pelvis, known as the obturator nerve reflex, and eventually bladder perforation.[28],[29] Moreover, incomplete resection of the tumor base and the fragmented cutting method are possible increasing the risk of bladder tumor recurrence.[30],[31] At present, scholars have proposed the total bladder tumor resection (ERBT) technique; numerous studies have confirmed that ERBT is superior to traditional TURBT in terms of peri-operative indicators and complications.[32],[33],[34]
In recent years, 2-micron laser has been used as a minimally invasive technique for treating bladder tumors, especially NMIBT.[35] The wavelength of the 2-micron laser is close to the water's peak absorption energy. This way, the dual function of efficient evaporation and accurate cutting can cut all fine layers of the bladder wall muscle layer so that the performer can more clearly identify the cutting level. The penetration depth of 2-micron laser on tissues is 0.3 mm, and tissues 2 mm from the front end of the fiber will not be damaged, increasing its safety. There are no currents, electric field effects, and obturator nerve reflexes, and there is little thermal damage to the target tissue. Two-micron laser vaporization can be used for the tumor resection on the lateral wall of the bladder and to reduce the incidence of surgical complications.[9] In addition, the continuous wave can evaporate on the tissue surface during tumor cutting, forming a 1 mm solidification layer, effectively sealing capillaries and lymphatic vessels, reducing intra-operative and post-operative wound bleeding, and reducing post-operative tumor recurrence.[36],[37]
In this study, a total of ten published studies involving 1163 patients were included: 596 in the 2-micron laser group and 567 in the TURBT group. The present meta-analysis showed that 2-micron laser was significantly superior to TURBT in reducing obturator nerve reflex, bladder perforation, and bladder stimulation (I2 <50% in heterogeneity test, P < 0.05); the results are consistent with current views, indicating that 2-micron laser has good safety.[13],[16],[29] This meta-analysis showed that 2-micron laser was superior to TURBT in terms of surgical blood loss, length of hospital stay, bladder flushing time, indwelling catheter time, and other aspects. However, there was high heterogeneity among studies. Sensitivity analysis showed the conclusions of the analysis of these four indicators to be reliable, which verifies the safety of 2-micron laser. The heterogeneity may be related to the level of local medical care, the surgeon's experience and proficiency in laser surgery with 2-micron, and measurement methods. In terms of the incidence and recurrence of post-operative urethral stricture, our meta-analysis showed no differences between the two surgical methods (P > 0.05); the results of sensitivity analysis were stable and reliable, as in a previous report.[37] In general, 2-micron laser therapy for NMIBT is a safe and effective surgical method. However, more high-quality RCTs are needed to confirm this conclusion.
Nevertheless, this study has some limitations. First, although the included studies were RCTs, the quality was poor and there was basically no specific description of random sequence generation or hidden randomization methods. Second, there was high heterogeneity in the meta-analyses of peri-operative indicators, which may have limited the value of the results. Third, these studies do not specify whether TURBT was unipolar or bipolar, a factor which may affect the results. In addition, the funnel plot in this study shows some bias in the analysis of recurrence rates in the included reports, mainly because of different post-operative follow-up times and different post-operative bladder infusion chemotherapy schemes, which may affect the evaluation of post-operative recurrence indicators.[38] Therefore, these results should be treated with caution. More large, multi-center, high-quality prospective RCTs are required to confirm these findings.
> ConclusionIn summary, based on our meta-analysis, 2-micron laser has many advantages for the management of NMIBT. Compared with TURBT, 2-micron laser is safer and more effective but does not seem to be better in controlling tumor recurrence. Additional high-quality multi-center RCTs are needed to confirm long-term efficacy in the future.
Ethical approval
This study was a meta-analysis based on the previous published articles. Therefore, no consents of patients and approval of Institutional Review Boards are required.
Financial support and sponsorship
This study was supported by the Applied Basic Research of Yunnan Province - Kunming Medical Joint Special Project [2019FE001(-226)], the Construction Project of Innovation Team of Colleges and Universities in Yunnan Province (Yunnan education〔2019〕 NO.58), Famous Doctor Project of “Ten Thousand People Plan” in Yunnan Province, Leading Talents Program of Yunnan Province (L-2018009).
Conflicts of interest
There are no conflicts of interest.
> References
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