Transurethral holmium laser resection and transurethral electrocision combined with intravesical epirubicin within 24 hours postoperatively for treatment of bladder cancer.

OBJECTIVE: To investigate the efficacy and safety of transurethral holmium laser resection (THOLR) and transurethral electrocision (TUR) combined with intravesical epirubicin within 24 hours postoperatively for treatment of non-muscular invasive bladder cancer.
METHODS: A total of 218 consecutive patients who were newly diagnosed with bladder cancer were enrolled in this prospective study from July 2014 to December 2017. The patients were randomly divided into THOLR and TUR groups. All patients received intravesical epirubicin (30 mg dissolved in 5% glucose solution) within 24 hours postoperatively. The operation time, blood loss, rate of obturator reflex, hospitalization time, catheterization time, complications, and recurrence were analyzed.
RESULTS: Operation, hospitalization, and catheterization times were significantly greater in the TUR group than in the THOLR group. The rates of blood loss and intraoperative obturator reflex were also significantly greater in the TUR group. There were no significant differences in complications, recurrence rate survival, or recurrence-free survival between the two groups, with the exception of bladder perforation rate.
CONCLUSIONS: THOLR and TUR combined with intravesical epirubicin within 24 hours postoperatively were both safe and effective for treatment of bladder tumor; however, patients who undergo THOLR might experience more rapid recovery.

Introduction

Bladder cancer is the ninth most common cancer worldwide, as well as the fourth most common cancer in men and ninth most common in women; a total of 430,000 new cases worldwide were reported in 2012.[1-3] The estimated incidence of bladder cancer is approximately 9.5 per 100,000 in developed countries.[4-6] Despite numerous studies regarding bladder cancer, effective clinical treatment remains challenging. Generally, resection surgery is the first choice for treatment of non-muscular invasive bladder tumors.[7-9] Traditional surgical techniques include open surgery and transurethral resection (TUR).[10,11] A recent meta-analysis showed that narrow band imaging-assisted TUR could reduce the rate of bladder cancer recurrence, compared with the rate following white light imaging TUR.[12] In recent years, advances in the use of holmium lasers have facilitated new approaches for such surgeries.[13] Surgery with holmium lasers exhibits minimal invasiveness, greater effectiveness, and improved safety, compared with traditional surgeries, during treatment of a variety of benign conditions such as strictures, benign prostatic hyperplasia, and bladder cancer.[14-16]

In addition to surgical techniques, postoperative intravesical chemotherapy is an important component of bladder cancer treatment.[17] Many drugs can be used for administration of intravesical chemotherapy, including gemcitabine, epirubicin, and mitomycin.[18-20] Notably, epirubicin is an anti-tumor drug with proven cytotoxicity and effectiveness in intravesical chemotherapy.[21] Intravesical administration of epirubicin has been shown to enhance the treatment efficacy of TUR and reduce the rate of bladder cancer recurrence. Gezginci et al.[22] demonstrated that the application of epirubicin improved symptoms of bladder cancer patients. However, there is a need for further clinical research regarding the efficacy and safety of intravesical epirubicin following transurethral holmium laser resection (THOLR). In the present study, we compared efficacy and safety between THOLR combined with intravesical epirubicin and TUR combined with intravesical epirubicin within 24 hours postoperatively for treatment of non-muscular invasive bladder cancer. The findings of this study may provide additional clinical evidence to guide the application of THOLR and epirubicin for treatment of bladder cancer.

Methods

Patients

This prospective study enrolled patients who were newly diagnosed with bladder cancer in The First People’s Hospital of Zhangjiagang City from July 2011 to December 2017. All patients were consecutively enrolled during the study period in accordance with the following inclusion criteria: a diagnosis of non-muscular invasive bladder tumor, confirmed by cystoscopy and histological analysis in accordance with the European Association of Urology and American Urological Association guidelines for treatment of non-muscular invasive bladder tumors,[23] and a tumor stage (tumor, node, metastasis [TNM] classification) of I–II. The following patients were excluded: those with other urinary diseases, such as urethral calculi, prostatic hyperplasia, and urethral stricture; those with other severe systemic diseases, such as severe infection, renal diseases, or liver diseases; and those with tumor history or patients who had received anti-tumor treatment before the study. Patients lost to follow-up were also excluded from the study. Written informed consent was obtained from all patients prior to enrollment in the study. The study protocol was approved by the Ethics Committee of the First People’s Hospital of Zhangjiagang City.

Surgical treatment

The patients were randomly divided into two groups of equal size: THOLR combined with intravesical epirubicin and TUR combined with intravesical epirubicin. All patients received routine preoperative examinations consisting of whole blood tests, routine examination of fecal content, and immunological examination regarding the presence of infections with hepatitis B and C viruses, human immunodeficiency virus, and Treponema pallidum (syphilis-causing bacterium). For the THOLR and intravesical epirubicin group, a Versapulse Power Suite Holmium system (100 W, optical fiber 550 µm; Lumenis, San Jose, CA, USA) was used for resection. Briefly, after induction of anesthesia, the cystoscope was introduced to the bladder through the urethra, using electronic video monitoring. The laser power was set to 10–30 W. For small tumors, the tumor pedicle or basal portion was burned by the laser; for large tumors or tumors with small pedicles, the sections of tumor that interfered with access to the basal portion of the tumor were cleared and the laser was then used to burn the tumor pedicle and the basal section. Laser vaporization of normal mucosal tissues was performed at a distance of 1–2 cm from the tumor after resection. Tissue biopsy was performed at random locations on the tumor base and wound margin.

For the TUR group, a Bi-Polar Conmed SABRE 2400 high frequency electrosurgical knife (Spectronics, Westbury, NY, USA) was used for resection. Briefly, after induction of anesthesia, the cystoscope was introduced to the bladder through the urethra, using electronic video monitoring. The electrocoagulation power was set to 40–60 W. For small tumors, the tumor pedicle or basal portion was resected until exposure of the muscularis; for large tumors, resection was performed from the exposed region of the tumor until its basal portion. After resection, electrocautery of normal mucosal tissues was performed at a distance of 1–2 cm from the tumor. Tissue biopsy was performed at random locations on the tumor base and wound margin.

Within 24 hours postoperatively, all patients underwent intravesical administration of epirubicin as follows. Briefly, patients were asked to empty the bladder before treatment. Epirubicin (50 mg dissolved in 50 mL normal saline) was used to apply intravesical chemotherapy through a catheter. The treatment duration was 40–60 minutes each time, once per week. After eight treatments, the frequency of intravesical chemotherapy was reduced to once per month. Overall, intravesical chemotherapy was performed for 1 year.

Data collection

Patient characteristics were collected, including age, sex, TNM stage, tumor diameter, and tumor position. Intraoperative outcomes were recorded, including operation time, blood loss, and rate of obturator reflex; hospitalization and catheterization times were also recorded. After the completion of treatment, all patients were followed up for 1 year. Postoperative B-mode ultrasound and cystoscopy examinations were performed at 3-month intervals. Finally, side effects and complications were recorded.

Statistical analysis

The measurement data were expressed as means ± standard deviations. Rates were compared by the chi-squared test. Comparisons between two groups were performed using Student’s t-test. The Kaplan–Meier curve was used to analyze recurrence-free survival. P < 0.05 was considered statistically significant. All calculations were performed using IBM SPSS Statistics for Windows, version 20.0 (IBM Corp., Armonk, NY, USA).

Results

Patient characteristics

A total of 218 patients were included in this study; the THOLR group included 109 patients (mean age, 59.5 ± 8.1 years) and the TUR group included 109 patients (mean age, 58.0 ± 8.0 years). Among all patients, 202 had tumor at the trigone of the bladder and 16 patients had tumor at the lateral wall. No transfusions were required in either group. There were no significant differences in patient or tumor characteristics between the two groups (Table 1).

Table 1.

Characteristics of patients with bladder cancer who underwent surgical resection and intravesical chemotherapy.

Characteristics	THOLR, n = 109	TUR, n = 109	P value
Age, years	59.5 ± 8.1	58.0 ± 8.0	0.182
Sex, male: female	76: 33	80: 29	0.548
TNM, n (%)			0.787
Ta	61 (56.0)	59 (54.1)
T1	48 (44.0)	50 (45.9)
Tumor grading, n (%)			0.777
G1	73 (67.0)	71 (65.1)
G2	36 (33.0)	38 (34.9)
Diameter, n (%)			0.719
≤3 cm	94 (86.2)	92 (84.4)
>3 cm	15 (13.8)	17 (15.6)
Position, n (%)			0.607
Trigone of bladder	102 (93.6)	100 (91.7)
Lateral wall	7 (6.4)	9 (8.3)

Rates were compared by the chi-squared test. Comparisons between two groups were performed using Student’s t-test.

Abbreviations: THOLR, transurethral holmium laser resection; TNM, tumor, node, metastasis; TUR, transurethral resection.

Intraoperative indices, catheterization time, and hospitalization time

The operation time and blood loss were significantly greater in the TUR group than in the THOLR group (P < 0.001, Table 2). In addition, 58 and 0 patients showed obturator reflex in the TUR and THOLR groups, respectively (P < 0.001). Finally, the hospitalization and catheterization times were significantly longer in the TUR group than in the THOLR group (P < 0.001), indicating that THOLR might facilitate a smaller surgical wound and better postoperative recovery.

Table 2.

Comparison of intraoperative indices and hospitalization time.

Parameters	THOLR, n = 109	TUR, n = 109	P value
Operation time, minutes	23.4 ± 3.3	27.9 ± 3.8	<0.001
Blood loss, mL	32.7 ± 4.6	41.1 ± 6.1	<0.001
Obturator reflex, n (%)	0 (0)	58 (53.2)	<0.001
Catheterization time, days	3.6 ± 1.2	4.7 ± 1.7	<0.001
Hospitalization time, days	7.9 ± 1.7	9.7 ± 2.6	<0.001

Rates were compared by the chi-squared test. Comparisons between two groups were performed using Student’s t-test.

Abbreviations: THOLR, transurethral holmium laser resection; TUR, transurethral resection.

Side effects and complications during intravesical chemotherapy

Comparison of complications during intravesical chemotherapy showed that patients in both groups exhibited bladder irritation, hematuria, and infections; notably, eight patients in the TUR group exhibited bladder perforation, whereas this was not observed in the THOLR group. In all patients who experienced bladder perforation, the perforations were small; therefore, surgery could be completed in these patients. All other complications resolved after the appropriate treatment was provided and did not affect the administration of intravesical chemotherapy. There were no significant differences in side effects and complications between the two groups, with the exception of the bladder perforation rate (P < 0.001) (Table 3).

Table 3.

Comparison of side effects and complications.

Parameters	THOLR, n = 109	TUR, n = 109	P value
Bladder irritation, n (%)	24 (22.0)	25 (20.2)	0.755
Bladder perforation, n (%)	0 (0.0)	8 (7.3)	<0.001
Hematuria, n (%)	19 (17.4)	17 (15.6)	0.732
Infection, n (%)	3 (2.8)	2 (1.8)	0.637
Total, n (%)	46 (42.2)	27 (40.4)	0.796

Rates were compared by the chi-squared test. Comparisons between two groups were performed using Student’s t-test.

Abbreviations: THOLR, transurethral holmium laser resection; TUR, transurethral resection.

Comparison of recurrence within 2 years postoperatively

Within 2 years postoperatively, 13 (11.9%) patients showed in situ relapse in the THOLR group, while 15 (13.8%) patients showed in situ relapse in the TUR group. The recurrence-free survival time (from the end of the surgery to the diagnosis of recurrence) was compared between groups using Kaplan–Meier analysis (Figure 1). During the follow-up period, 10 (9.2%) patients in the THOLR group and 11 (10.1%) patients in the TUR group developed muscular invasive bladder cancer; the rates of recurrence did not significantly differ between the two groups.

Figure 1.

Kaplan–Meier analysis of recurrence-free survival time in all patients (P > 0.05 by log-rank test)

Discussion

Bladder cancer is one of the most common urinary system cancers, which affects millions of patients.[1-3] THOLR and TUR are both widely used for surgical treatment of solid bladder tumors; however, there remains a lack of consensus regarding which method provides better outcomes and further research is needed. Although intravesical chemotherapy has been used for treatment of bladder tumor for many years, the use of different drugs results in different outcomes;[18-20] thus, additional clinical data are needed to confirm the suitability of epirubicin for broad application in intravesical chemotherapy. In the present study, we demonstrated that intravesical administration of epirubicin within 24 hours after either THOLR or TUR was safe and effective for treatment of bladder tumor; however, patients with THOLR might experience more rapid recovery.

Holmium laser resection is widely used in the treatment of many tumors and shows good efficacy.[14-16] In the present study, we found that holmium laser resection resulted in low rates of recurrence and complications. In addition, holmium laser resection could facilitate more rapid recovery, compared with standard TUR. Canogarcía et al.[24] reported that holmium laser could be used for treatment of recurrent low-grade superficial bladder cancer under local anesthesia. Calaway et al.[25] demonstrated that concomitant holmium laser enucleation of the prostate and robotic-assisted laparoscopic bladder diverticulectomy was safe and effective treatment for a patient with benign prostate hyperplasia and a large bladder tumor.

In this study, we found that both THOLR and TUR had similar efficacies; however, holmium laser resection could facilitate more rapid postoperative recovery. Comparisons between holmium laser resection and TUR have also been reported in several prior studies. Teng et al.[26] performed a meta-analysis of holmium laser versus conventional TUR in the treatment of bladder cancer; they found that holmium laser was effective as an alternative method for TUR. Li et al.[27] conducted a meta-analysis of holmium laser versus conventional TUR in the treatment of benign prostate hyperplasia; they concluded that there were no clinically relevant differences in early and late postoperative complications between the two techniques, but noted that holmium laser enucleation resulted in reductions in catheterization and hospitalization times.

Finally, we demonstrated that epirubicin could be used for intravesical chemotherapy in patients with bladder cancer, within 24 hours after either THOLR or TUR. Combined use of intravesical chemotherapy with holmium laser resection or TUR provided good efficacy. The use of intravesical chemotherapy for treatment of bladder tumor has been reported in many prior studies. In a controlled prospective study, Melekos et al.[28] demonstrated that the use of intravesical epirubicin and bacillus Calmette-Guérin treatment was safe and effective in the treatment of superficial bladder cancer. Recently, Liu et al.[19] investigated the use of a novel hydrogel-based epirubicin delivery system for intravesical chemotherapy; they found that epirubicin-loaded gelatin hydrogel could enhance the efficacy of epirubicin during intravesical instillation treatments for bladder cancer.

In conclusion, this prospective study investigated the safety and efficacy of THOLR and TUR combined with intravesical chemotherapy for treatment of bladder cancer. THOLR and TUR combined with intravesical epirubicin within 24 hours postoperatively were both safe and effective for treatment of bladder tumor; however, patients with THOLR might experience more rapid recovery.