Comparison of the safety and efficacy of conventional monopolar and 2-micron laser transurethral resection in the management of multiple nonmuscle-invasive bladder cancer

Abstract

Objectives

To compare the safety and efficacy of conventional monopolar transurethral resection of bladder tumour (TURBT) and 2-micron continuous-wave laser resection (2-µm laser) techniques in the management of multiple nonmuscle-invasive bladder cancer (NMIBC), and to investigate long-term effects on tumour recurrence.

Methods

Patients with multiple NMIBC were randomized to receive TURBT or 2-µm laser in a nonblinded manner. All patients received intravesical chemotherapy with epirubicin (40 mg/40 ml) for 8 weeks, beginning 1 week after surgery, followed with monthly maintenance therapy for 12 months. Three-year follow-up data of preoperative, operative and postoperative management were recorded.

Results

In total, 120 patients were included: 56 in the TURBT group and 64 in the 2-µm laser group. Intra- and postoperative complications (including bladder perforation, bleeding and irritation) were less frequently observed in the 2-µm laser group compared with the TURBT group. There were no significant differences in first time to recurrence, overall recurrence or occurrence of urethral strictures.

Conclusions

The 2-µm laser resection method was more effective than TURBT in reducing rates of intra- and postoperative complications, but offered no additional benefit regarding tumour recurrence.

Keywords

Bladder carcinoma 2-µm continuous-wave laser transurethral resection of bladder tumour TURBT recurrence rate

Introduction

Bladder cancer is the second most common urological malignancy.¹ Approximately 70–80% of newly diagnosed bladder cancers are of the nonmuscle-invasive type. Nonmuscle-invasive tumours include papillary tumours confined to the mucosa (pTa), those that have invaded subepithelial connective tissue (pT1), or flat high-grade in situ tumours in the mucosa (Tis),^2–4 for which initial treatment has traditionally been transurethral resection of bladder tumour (TURBT), followed by adjuvant intravesical chemotherapy or immunotherapy.⁵ The goals of TURBT are to remove all visible tumours and obtain enough tissue for histological diagnosis, with minimal morbidity to the patient.⁶ Optimal penetration is, however, difficult to control during surgery; consequently, TURBT is associated with substantial morbidities and complications, such as obturator nerve reflex (ONR), bladder perforation and intraoperative bleeding.^7,8 Khorrami et al.⁹ used transvesical obturator nerve block to prevent ONR and leg jerking during TURBT, but this approach is not completely effective and it can be difficult to locate the obdurate nerve. The advent of modern laser technology offers an alternative to TURBT in treating nonmuscle-invasive bladder cancer (NMIBC). Various laser types have been used to treat bladder or upper urinary tract urothelial tumours. Holmium yttrium aluminum garnet laser (Ho : YAG) is effective, but a major drawback of this technique is the lack of tissue collection for histological examination.^10–12 In 2005, the thulium laser (Tm : YAG) was investigated surgically, to see if it improved some of the shortcomings of the Ho : YAG.¹³Tm : YAG generates a wavelength of 2 µm, which is suitable for resection in an aqueous medium, and provides excellent haemostasis.¹⁴ Unlike Ho : YAG, Tm : YAG operates in a continuous-wave mode (which evaporates tissue continuously, without generating pressure waves). Thus, clean cuts are achieved by moving the fibre tip across the tissue.

The 2-µm continuous-wave laser has been shown to be efficacious, and to have a favourable safety profile, for the resection of benign prostatic hyperplasia, and in the management of NMIBC.^15–17 The present study investigated the possible advantages and long-term effects of 2-µm (thulium) continuous-wave laser treatment over TURBT, in the management of multiple NMIBC.

Patients and methods

Study population

Consecutive patients with newly diagnosed NMIBC, attending the University Department of Urology, The First People’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China, were enrolled in this study between October 2006 and May 2008. Patients were eligible for inclusion if they had a papillary tumour at cystoscopy with no extravesical extension, lymphatic metastasis or invasion of adjacent organs apparent by imaging studies. Patients were excluded if they had urothelial papillomas, muscle-invasive bladder tumours, in situ carcinomas or upper urinary tract tumours.

A detailed history of all patients was collected and standard physical examinations were performed before surgery. Ultrasonography, computed tomography (CT) and cystoscopy with biopsy were performed for diagnosing and staging bladder cancer preoperatively. Tumour location was classified as lateral or other, and the tumour base was defined as pedicles (stalk-like) or sessile (flat). CT urography was performed to exclude upper urinary tract tumours. Histopathological evaluation was conducted in accordance with the 2004 World Health Organization grading system.¹⁸ Tumour stage was classified according to the 2002 tumour–node–metastasis classification system.¹⁹

Patients were randomly assigned, using computer-generated random numbers, to the 2-µm (thulium) continuous-wave laser or TURBT group. Randomization was not stratified according to tumour grade, stage, location, sex or age.

The study protocol was approved by the Institutional Review Board of The First People’s Hospital Affiliated to Shanghai Jiao Tong University, and informed written consent was obtained from all patients.

Anaesthetic and surgical procedures

Following randomization to the treatment groups, the same urologist (H.L.) performed either 2-µm (thulium) continuous-wave laser or TURBT on all patients. Patients were placed in a lithotomy position and continuous epidural anaesthesia was administered. Each patient received an anaesthetic maintenance dose of 6–12 mg/kg/h propofol by continuous intravenous (i.v.) infusion, a maintenance dose of 0.001–0.002 mg/kg fentanyl i.v. and 0.05 mg/kg vecuronium i.v. as a muscle relaxant. All patients received premedication (either 0.1 g phenobarbital intramuscularly [i.m.] or 0.5 mg atropine i.m.), and postoperative pain relief (50 mg tramadol sustained-release tablets twice a day or 100 mg pethidine i.m.) with a re-use interval of 4–6 h.

Tumour resections were performed routinely with a semifilled bladder (containing 200–300 ml irrigation fluid [transurethral irrigation flushing fluid 3000 ml/150 g of 5% mannitol solution; 2-µm laser rinse solution of 3000 ml/27 g of 0.9% sodium chloride]) A 2-µm thulium laser system (LISA laser products OHG, Katlenburg-Lindau, Germany), operated in continuous-wave mode, was used to treat patients in the laser group.²⁰ En bloc resection was performed to allow adequate tissue for postoperative pathological examination. The power of the laser was set at 30 W–50 W in advance, which was adjusted during the operation according to the volume of the tumour and the position of the surgical resection (in order to protect healthy tissue). Energy was delivered via a 550-mm end-firing PercuFib fibre (LISA laser products OHG), introduced via a 26-F continuous flow resectoscope (Karl Storz, Tuttlingen, Germany). Saline irrigation was used throughout the procedure in all cases.

Conventional monopolar TURBT was performed using a Wolf 26-F continuous flow resectoscope with loop electrode (Richard Wolf, Knittlingen, Germany); cutting and coagulation power were set at 140 W and 100 W, respectively.

Regardless of the technique applied, the bladder mucosa was coagulated 20 mm away from the tumour base. Biopsies were performed intraoperatively and randomly, at a minimum of two positions from the tumour base and the mucosa, 2 cm around the tumour margin. Postoperative pathological examinations were performed to determine tumour stage and grade. All patients were catheterized after surgery, to drain urine from the bladder. The duration of bladder irrigation was based on the duration of postoperative haemorrhage. Bladder irrigation was terminated as early as 30 min postoperatively, if gross haematuria was absent.

Adjuvant intravesical chemotherapy

Adjuvant intravesical chemotherapy with 40 mg/40 ml epirubicin was administered weekly for 8 weeks, beginning 1 week after the operation, and followed with monthly maintenance therapy for 12 months.

Follow-up

Patients attended postoperative follow-up appointments for 3 years: they were examined using ultrasound, urinary cytology and cystoscopy every 3 months for the first 2 years and every 6 months during the final year. Adverse events were well documented throughout the study. The primary endpoint was tumour recurrence rate. Patients with recurrence were excluded from the study on the date of their last known follow-up.

Statistical analyses

Statistical analyses were performed using the SPSS® statistical software package, version 13.0 (SPSS Inc., Chicago, IL, USA) for Windows®. Data were presented as mean ± SD or mean and range. Between-group comparisons were performed using one-way analysis of variance for continuous variables and the χ²-test for categorical variables. A P-value of < 0.05 was considered to be statistically significant.

Results

A total of 120 patients were randomized to receive 2-µm (thulium) continuous-wave laser (n = 64) or conventional monopolar TURBT (n = 56). Patient and tumour characteristics before surgery were similar in each group and are presented in Table 1. All cases had specimens that were sufficient for accurate diagnosis, including tumour staging and grading. Of the 120 patients, 21 had a papillary urothelial neoplasm of low malignant potential, 87 had low-grade papillary urothelial carcinoma and 12 had high grade papillary urothelial carcinoma (Table 1). No residual tumour tissue was found >2 cm from the tumour base or the mucosa around the tumour margin. There were 71 cases with Ta stage and 49 cases with T1 stage tumours.

Table 1.

Demographic and baseline tumour characteristics in patients with multiple nonmuscle-invasive bladder cancer, undergoing 2-µm (thulium) continuous-wave laser treatment or transurethral resection of bladder tumour (TURBT).

Variable	2-µm laser n = 64	TURBT n = 56
Sex
Male	46 (71.9)	40 (71.4)
Female	18 (28.1)	16 (28.6)
Age, years	67.1 ± 8.3 (39.0–77.0)	66.3 ± 9.8 (38.0–76.0)
Tumour number	2.8 ± 1.2 (2.0–5.0)	2.7 ± 1.5 (2.0–5.0)
Tumour size, mm	13.1 ± 2.3 (5.0–31.0)	12.8 ± 3.1 (4.0–30.0)
Tumour location
Lateral	24 (37.5)	21 (37.5)
Other	40 (62.5)	35 (62.5)
Tumour base
Pedicles	42 (65.6)	37 (66.1)
Sessile	22 (34.4)	19 (33.9)
Stage
Ta	37 (57.8)	34 (60.7)
T1	27 (42.2)	22 (39.3)
Tumour grade¹⁸
PUNLMP	11 (17.2)	10 (17.9)
Low	46 (71.9)	41 (73.2)
High	7 (10.9)	5 (8.9)

Data presented as n (%) or mean ± SD (range).

PUNLMP, papillary urothelial neoplasms of low malignant potential.

The mean operation time per patient (and per individual tumour resection) was not significantly different between the two groups (Table 2). None of the patients in the 2-µm (thulium) continuous-wave laser group experienced intraoperative ONR, but in the TURBT group 10 patients experienced ONR for a total of 24 times (P < 0.01). There were no cases of bladder perforation in the 2-µm (thulium) continuous-wave laser group, but five patients experienced bladder perforation in the TURBT group (P < 0.01; Table 2). No deaths were reported during the operation.

Table 2.

Intra- and postoperative characteristics of patients with multiple nonmuscle-invasive bladder cancer, treated with transurethral resection of bladder tumour (TURBT) or 2-µm (thulium) continuous-wave laser techniques.

Variable	2-µm laser n = 64	TURBT n = 56	Statistical significance^a
Operative duration, min
Per patient	48.2 ± 15.8 (20.5–90.0)	45.6 ± 13.5 (18.4–85.2)	NS
Per tumour	13.6 ± 4.6	12.4 ± 5.2	NS
ONR	0 (0)	10 (17.9)^b	<0.01
Bladder perforation	0 (0)	5 (8.9)	<0.01
Bladder irritation	15 (23.4)	42 (75.0)	<0.01
Postoperative bladder irrigation time, h	8.2 ± 1.3 (2.3–24.0)	14.5 ± 2.1 (3.2–48.2)	<0.01
Period of catheterization, days	2.34 ± 0.43 (24.3–112.0)	4.21 ± 0.92 (34.5–144.3)	<0.01
Period of hospitalization, days	3.51 ± 0.34 (2.5–6.1)	5.42 ± 0.65 (4.2–7.2)	<0.01
Postoperative urethral stricture	2 (3.0)	2 (4.0)	NS

Data presented as mean ± SD (range) or n (%).

One-way analysis of variance for continuous variables; χ²-test for categorical variables.

ONR occurred 24 times in these 10 patients.

ONR, obturator nerve reflex.

A significantly higher proportion of patients in the TURBT group experienced symptoms of bladder irritation postoperatively, compared with patients in the 2-µm (thulium) continuous-wave laser group (P < 0.01) (Table 2). The durations of postoperative bladder irrigation, catheterization and hospitalization were all significantly lower in the 2-µm (thulium) continuous-wave laser group compared with the TURBT group (P < 0.01). There were no significant between-group differences in the occurrence of urethral strictures.

During the 3-year follow-up period, two patients died: one patient, aged 76 years who underwent TURBT, died of cerebral haemorrhage ∼1 year after surgery; oneother patient, aged 75 years and treated with 2-µm (thulium) continuous-wave laser, died of cardiovascular disease within 1 year of surgery. In both cases there was no evidence of tumour recurrence.

There was no significant difference in the cumulative tumour recurrence rate between the 2-µm (thulium) continuous-wave laser and TURBT groups (Figure 1). Twelve months after the initial complete resection of visible tumours, seven patients (10.9%) in the 2-µm (thulium) continuous-wave laser group and six patients (10.7%) in TURBT group showed tumour recurrence by surveillance cystoscopy. Postoperative follow-up after 12, 24 and 36 months showed recurrence rates of 10.9%, 19.5% and 31.3% in the 2-µm (thulium) continuous-wave laser group and 10.7%, 22.9% and 33.9% in the TURBT group, respectively.

Figure 1.

Cumulative tumour recurrence rate during 12-, 24- and 36-month follow-up examinations in patients with multiple nonmuscle-invasive bladder cancer undergoing 2 µm (thulium) continuous-wave laser (n = 64) or conventional transurethral resection of bladder tumour (n = 56). There were no significant between-group differences, χ²-test.

Discussion

The present study demonstrated that 2-µm (thulium) continuous-wave laser is associated with significantly fewer intraoperative complications during resection of bladder tumours than TURBT. The main focus for intraoperative complications was on ONR or bladder perforation. As a consequence, classification systems (such as the Clavien classification or National Cancer Institute system^21,22) were not applied to grade surgical complications in this study. None of the patients in the 2-µm (thulium) continuous-wave laser group experienced ONR or bladder perforation, which could be attributed to the precise nature of such resections and the absence of a strong local electric field. In contrast, 10 (17.9%) patients experienced ONR and 5 (8.9%) had bladder perforation in the TURBT group. Higher rates of bladder perforation with TURBT were reported in a study where routine cystograms, performed after TURBT, showed contrast extravasation (asymptomatic perforation) in 21/36 patients (58.3%).²³

To improve comparability between the groups and reduce the deviation of the results, all of the operations were carried out by the same surgeon. Furthermore, the proportion of patients with lateral bladder-wall tumours in both groups was the same (37.5%). Using the same surgeon could, however, have introduced personal bias. As such, these findings require further verification from additional randomized, blinded, studies. Lack of blinding could also have introduced bias into the study.

The significant rates of morbidities and complications, such as ONR and bladder perforation, observed with TURBT in the present study are consistent with other reports.^7,8 In the 2-µm (thulium) continuous-wave laser group, however, ONR or bladder perforation were not observed. Although this may have been weakly influenced by bias, the obvious contrast of the two treatment approaches suggested that these observed benefits were related to the laser treatment. Moreover, TURBT requires hands-on training to reduce the likelihood of complications.²⁴ Thus, the 2-µm (thulium) continuous-wave laser technique could be a promising alternative in the resection of NMIBC, especially for recurrent, heavily treated and posterior lateral wall tumours.

The precise resection of tumours in multiple NMIBC that was demonstrated with the laser technique can be attributed to its dual function of vaporization and resection. This enables en bloc resection from the tumour base with no bleeding, while the power of the laser can be adjusted according to the size of tumours. In addition, the laser technique is effective at inducing coagulation in blood vessels and lymphatic ducts around the tumour, thereby reducing the efflux of tumour cells and distant tumour recurrence. In contrast, the control of intraoperative bleeding in TURBT was less effective compared with the 2-µm (thulium) continuous-wave laser technique, because cutting and coagulation were separate procedures in TURBT. The less-invasive nature of 2-µm continuous-wave laser and the reduced bleeding associated with this technique contributed to a faster recovery time, with significantly shorter durations of postoperative bladder irrigation and catheterization being observed for 2-µm continuous-wave laser compared with TURBT.

The standard treatment of NMIBC is transurethral resection followed by adjuvant intravesical chemotherapy or immunotherapy, as it is recognized that (other than modification to the surgical technique) intravesical chemotherapy and immunotherapy will change the course of bladder cancer behaviour.²⁵ In the present study, epirubicin was used as the chemotherapy agent in both groups. The 2-µm (thulium) continuous-wave laser treatment was not inferior to TURBT in terms of the tumour recurrence rate, which was comparable with (and slightly better than) that reported in other studies that used epirubicin adjuvant therapy.^26,27

The majority of patients were able to ambulate after discontinuation of bladder irrigation, but still remained hospitalized while they carried a Foley catheter. It was evident in this study that 2-µm (thulium) continuous-wave laser resection significantly reduced the duration of hospitalization compared with TURBT.

The use of 2-µm (thulium) continuous-wave laser in the resection of NMIBC has been investigated previously, but earlier studies involved small patient numbers and only employed a single treatment arm.^16,28,29 To the authors’ knowledge, this is the first study to provide a detailed head-to-head comparison between 2-µm (thulium) continuous-wave laser and TURBT.

In summary, 2-µm (thulium) continuous-wave laser was superior to TURBT in terms of reducing the incidence of intraoperative ONR and bladder perforation, and minimizing postoperative bladder irritation, catheterization time and duration of hospital stay. Consequently, the 2-µm continuous-wave laser technique may therefore be an effective alternative to TURBT, with an improved safety profile, in the management of multiple NMIBC. Larger, prospective, multicentre studies need to be performed, to validate findings of the present study.

Footnotes

Declaration of Conflicting Interest

The authors had no conflicts of interest to declare in relation to this article.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References

Zhu

Shen

. Inflammatory pathways as promising targets to increase chemotherapy response in bladder cancer. Mediators Inflamm 2012; 2012: 528690–528690.

Agrawal

Bansal

. The safety and efficacy of different doses of bacillus Calmette-Guérin in superficial bladder transitional cell carcinoma. Urology 2007; 70: 1075–1078.

Kirkali

Chan

Manoharan

. Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology 2005; 66(suppl 1): 4–34.

Lopez-Beltran

Montironi

. Non-invasive urothelial neoplasms: according to the most recent WHO classification. Eur Urol 2004; 46: 170–176.

Aldousari

Kassouf

. Update on the management of non-muscle invasive bladder cancer. Can Urol Assoc J 2010; 4: 56–64.

Herr

. Surgical factors in the treatment of superficial and invasive bladder cancer. Urol Clin North Am 2005; 32: 157–164.

Golan

Baniel

Lask

. Transurethral resection of bladder tumour complicated by perforation requiring open surgical repair – clinical characteristics and oncological outcomes. BJU Int 2011; 107: 1065–1068.

Xishuang

Deyong

Xiangyu

. Comparing the safety and efficiency of conventional monopolar, plasmakinetic, and holmium laser transurethral resection of primary non-muscle invasive bladder cancer. J Endourol 2010; 24: 69–73.

Khorrami

Javid

Saryazdi

. Transvesical blockade of the obturator nerve to prevent adductor contraction in transurethral bladder surgery. J Endourol 2010; 24: 1651–1654.

10.

Kramer

Bach

Wolters

. Current evidence for transurethral laser therapy of non-muscle invasive bladder cancer. World J Urol 2011; 29: 433–442.

11.

Muraro

Grifoni

Spazzafumo

. Endoscopic therapy of superficial bladder cancer in high-risk patients: Holmium laser versus transurethral resection. Surg Technol Int 2005; 14: 222–226.

12.

Soler-Martínez

Vozmediano-Chicharro

Morales-Jiménez

. Holmium laser treatment for low grade, low stage, noninvasive bladder cancer with local anesthesia and early instillation of mitomycin C. J Urol 2007; 178: 2337–2339.

13.

Fried

Murray

. High-power thulium fiber laser ablation of urinary tissues at 1.94 µm. J Endourol 2005; 19: 25–31.

14.

Bach

Xia

Yang

. Thulium:YAG 2 µm cw laser prostatectomy: where do we stand? World J Urol 2010; 28: 163–168.

15.

Xia

Zhuo

Sun

. Thulium laser versus standard transurethral resection of the prostate: a randomized prospective trial. Eur Urol 2008; 53: 382–389.

16.

Zhong

Guo

Tang

. Clinical observation on 2 micron laser for non-muscle-invasive bladder tumor treatment: single-center experience. World J Urol 2010; 28: 157–161.

17.

Gravas

Bachmann

Reich

. Critical review of lasers in benign prostatic hyperplasia (BPH). BJU Int 2011; 107: 1030–1043.

18.

Sauter

Algaba

Amin

Tumours of the urinary system: non-invasive urothelial neoplasias. In: Eble

Sauter

Epstein

(eds). WHO Classification of Tumours of the Urinary System and Male Genital Organs, Lyon: IARCC Press, 2004.

19.

Sobin

Wittekind

. TNM classification of malignant tumours, 6th ed. New York: Wiley-Liss, 2002, pp. 199–202.

20.

Liu

Xue

Ruan

. 2-micrometer continuous wave laser treatment for multiple non-muscle-invasive bladder cancer with intravesical instillation of epirubicin. Lasers Surg Med 2011; 43: 15–20.

21.

Clavien

Barkun

de Oliveira

. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg 2009; 250: 187–196.

22.

Kohler

Ward

McCarthy

. Annual report to the nation on the status of cancer, 1975–2007, featuring tumors of the brain and other nervous system. J Natl Cancer Inst 2011; 103: 714–736.

23.

Balbay

Cimentepe

Unsal

. The actual incidence of bladder perforation following transurethral bladder surgery. J Urol 2005; 174: 2260–2263.

24.

Nieder

Meinbach

Kim

. Transurethral bladder tumor resection: intraoperative and postoperative complications in a residency setting. J Urol 2005; 174: 2307–2309.

25.

Sander

Beisland

Superficial bladder cancer. In: Smith

Jr (ed.) Lasers in Urologic Surgery, St. Louis: Mosby Year Book, 1994, pp. 126–134.

26.

Sylvester

Brausi

Kirkels

. Long-term efficacy results of EORTC Genito-Urinary Group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guérin, and bacillus Calmette-Guérin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol 2010; 57: 766–773.

27.

van der Meijden

Brausi

Zambon

. Intravesical instillation of epirubicin, bacillus Calmette-Guérin and bacillus Calmette-Guérin plus isoniazid for intermediate and high risk Ta, T1 papillary carcinoma of the bladder: a European Organization for Research and Treatment of Cancer Genito-Urinary Group randomized phase III trial. J Urol 2001; 166: 476–481.

28.

Gao

Ren

. Thulium laser resection via a flexible cystoscope for recurrent non-muscle-invasive bladder cancer: initial clinical experience. BJU Int 2008; 102: 1115–1118.

29.

Wolters

Kramer

Becker

. Tm:YAG laser en bloc mucosectomy for accurate staging of primary bladder cancer: early experience. World J Urol 2011; 29: 429–432.