Development of Bladder Outlet Obstruction After a Single Treatment of Prostate Cancer with High-Intensity Focused Ultrasound: Experience with 226 Patients

Abstract

Purpose:

To investigate the occurrence of bladder outlet obstruction (BOO) after high-intensity focused ultrasound (HIFU) therapy of prostate cancer, the need for secondary transurethral interventions for BOO, and the benefit of transurethral resection of the prostate (TURP) before HIFU.

Patients and Methods:

After a single HIFU treatment between 2002 and 2007, 226 consecutive patients were examined and followed at least 2 years. The Ablatherm Maxis and the Integrated Imaging devices were used. The sites of BOO were recorded.

Results:

Median follow-up after HIFU was 52 months (range 24–80 mos). BOO developed in 58 (25.66%) patients. Repeated BOO episodes were observed in 27 (11.94%), three to seven episodes in 13 (5.75%) patients. Patients with repeated BOO were older than patients with singular BOO (71.75 ± 4.97 vs 68.18 ± 5.03; P = 0.024). In primary BOO, multiple sites of obstruction were more often involved than in repeated BOO (25/58 vs 8/27). Conversely, isolated bladder neck stenosis was predominantly found in patients with ≥two episodes of BOO. The rate of primary BOO was significantly different between patients who had undergone TURP the same day as HIFU or within 2 days of HIFU (33/96; 34.38%) and patients with TURP more than 1 month (16/89; 17.98%) before HIFU (P = 0.032). BOO occurred in 21.95% (9/41) of the patients who were treated with HIFU only.

Conclusions:

BOO after HIFU is common, particularly affecting the bladder neck. The risk of repeated BOO is associated with age. A longer interval between TURP and HIFU (>1 month) might reduce the risk for the development of BOO.

Introduction

H igh-intensity focused ultrasound (HIFU) has been considered recently as a minimally invasive alternative therapy to radical prostatectomy (RP) or radiotherapy (RT) in selected patients with organ-confined prostate cancer.^1,2 Prostate tissue is destroyed by coagulative necrosis with HIFU.³ Ideally, micturition should normalize spontaneously after the elimination of necrotic debris. The formation of bladder outlet obstruction (BOO), however, is actually the most common side effect during follow-up.⁴ BOO from edema in the initial perioperative period is basically managed by suprapubic or transurethral catheterization. Subsequent infravesical obstruction is caused by sloughing of necrotic tissue or by scarring.⁵ Additional transurethral interventions (TI) were necessary in up to one third of the patients after HIFU.^6,7

Some specialized centers proposed to perform transurethral resection of the prostate (TURP) before HIFU,⁸ because the combined approach has led to a remarkable reduction of postoperative catheter time as well as development of BOO.^8
–10 Moreover, TURP allows treatment of even grossly enlarged prostate glands by reducing the volume and adapting the gland to the limited penetration depth of the ultrasound. In addition, intravesical middle lobes and prostate stones that reflect the ultrasound and leave the underlying tissue untreated can be removed.

In the present study, we retrospectively investigated the occurrence of BOO, the need for secondary TI for BOO, and the benefit of TURP before HIFU within a follow-up period of at least 2 years.

Patients and Methods

In our department, 277 patients were treated with HIFU between December 2002 and September 2007 by using the Ablatherm Maxis^® and the Integrated^® imaging HIFU devices (EDAP, Technomed, Lyon, France). HIFU was performed with the Ablatherm Maxis^® device until February 2006; afterwards, the Integrated^® imaging device was used. Patients with localized prostate cancer as diagnosed by prostate biopsies or TURP (pT_1a/1b) were recruited to the study. The following patients were excluded from analysis: Lost to follow-up, 2; death in the first year of follow-up, 5; primary RT, 19; primary RP, 1; secondary RT, 3; secondary RP, 3; development of rectourethral fistula, 6; repeated HIFU sessions, 12. Finally, 226 patients were enrolled in the study.

All men underwent a single HIFU treatment; 93 men received antihormonal pretreatment. The decision for HIFU of the prostate based on the patient`s age, comorbidity, and the decline of any kind of surgery. Preoperative assessment included transrectal ultrasonography with biopsies of the prostate, digital rectal examination, pelvic CT scan and/or MRI, serum prostate-specific antigen (PSA) determination, and bone scan. Medical history was evaluated in all patients. Informed consent was obtained from all participants before treatment.

All patients had a minimum follow-up of 24 months, including determination of serum PSA level at postoperative day 1 after HIFU, after 2 and 3 months, and thereafter quarterly. A control biopsy was performed after 6 months or in the case of rising PSA values.¹¹

The patients were stratified into subgroups according to the risk of treatment failure, as proposed previously¹²: low risk—clinical stage ≤T_2a, Gleason score ≤6, and a PSA level of ≤10 ng/mL; intermediate risk—clinical stage T_2b, Gleason score 7, and/or PSA level of 10.1 to 20 ng/mL; high risk—clinical stage ≥T_2c, Gleason score higher than 7, and/or PSA level higher than 20.1 ng/mL. As a modification, patients with stages cT_3a and cT_3b were also assigned to the high-risk group. Accordingly, 85 (37.6%) patients were at low, 73 (32.3%) at intermediate, and 68 (30.1%) at high risk. The following parameters were analyzed in each patient: Age, prostate volume at first visit, treated volume by HIFU, lesions at HIFU, interval TURP/HIFU, Gleason score, PSA level, risk status and interval HIFU/BOO.

TURP was performed before HIFU to downsize enlarged glands, endovesical middle lobes, and to reduce the anterior-posterior diameter that allows a complete treatment of the peripheral zone with HIFU in a single session.⁸ TURP was also performed to remove microcalcifications and abscesses of the prostate. The median preoperative prostate volume (assessed by transrectal ultrasound, TRUS) was 29 cc (range 9–95 cc). The median tissue weight after TURP was 23 cc (14–68 cc). The indications for previous androgen-deprivation therapy were: Patients with primary androgen-deprivation therapy, who were then assigned to our department; patients with intermediate/high risk prostate cancer and an interval between first consultation and treatment of more than 3 months; and to downsize glands of more than 40 cc.

BOO events were classified as bladder neck stenosis, prostate necrosis, stenosis/stricture within the prostatic urethra, distal stenosis close to the sphincter, urethral stones, or as a combined lesion. TIs were also recorded and included internal urethrotomy, bladder neck incision/resection, and TURP. BOO events that were managed by a noninvasive approach (eg, insertion of a transurethral/suprapubic catheter, dilatation of the urethra, or urethrocystoscopy) were recorded but excluded from analysis. BOO events were managed with visualized internal urethrotomy and conventional TUR(P) until December 2005. The 2 μm continous wave thulium:yttrium-aluminum-garnet (YAG) laser (RevoLix,^® LISA Laser Products, Katlenburg, Germany) was then applied to manage BOO the same way as with conventional TI.

Statistical analysis was performed by using the calculating program SPSS (SPSS, Inc., Chicago, IL, version 11.5.1) for Windows. The data were expressed as the mean ± standard deviation and as a median with the interquartile range, with differences between the groups assessed using the Mann-Whitney U test. Categorical variables were compared by using the chi-square-test. P < 0.05 was considered statistically significant.

Results

A total of 226 patients with single HIFU therapy were analyzed. The mean age at HIFU was 70.06 ± 5.79 years. Mean follow-up after HIFU was 50.01 ± 18.01 months (range 24–80 mos).

Actuarial cumulative incidences of BOO after HIFU at 1, 2, and 3 years were 20.8%, 23.89%, and 24.34%. BOO developed in 58 (25.66%) patients. Repeated BOO episodes were observed in 27 (11.94%), with three to seven episodes in 13 (5.75%) patients. In primary BOO, multiple sites of obstruction were more often involved than in repeated BOO (25/58 vs 8/27). In patients with two or more episodes of BOO, isolated bladder neck stenosis was found predominantly. Necrotic tissue was removed in 28 patients with primary BOO and 2 patients (48.27% vs 7.4%) with secondary BOO, respectively (Table 1). Accordingly, multimodal TIs were performed in most primary BOO because of multiple sites of obstruction. In contrast, TIs were limited to the bladder neck in repetitive BOO episodes. The median time between HIFU and BOO was 6 (episodes 2, 3:9, 14) months, respectively (Table 1).

Table 1.

Occurrence of Bladder Outlet Obstruction and Site of Obstruction

BOO episodes	Bladder neck stenosis	Prostate necrosis	Stenosis/stricture in prostatic urethra	Distal stenosis close to the sphincter	Stones	Urethral stenosis	Overall (%)	Median time between HIFU and BOO ^a event
1	32	28	26	4	3	6	58/226 (25.66)	6 (3; 10)
2	21	2	6	1	1	6	27/226 (11.94)	9 (7.25; 14.75)
3	10		2	2	1		13/226 (5.75)	14 (10.5; 17)
4	8			1		1	9/226 (3.98)
5	5					1	5/226 (2.21)
6	5						5/226 (2.21)
7	5	1					5/226 (2.21)

Data presented as number of patients; multiple nominations possible.

Median (interquartile range) [months].

BOO = bladder outlet obstruction; HIFU = high-intensity focused ultrasound.

There were no differences between patients with and without BOO episode regarding age, prostate volume, volume preoperatively planned, lesions at HIFU session, treated volume by HIFU, Gleason score, and preoperative PSA level (Table 2). Age was not significantly associated with higher rate of primary BOO (P = 0.504). Patients with multiple BOO episodes were significantly older than patients with a single BOO episode (P = 0.024) (Table 3). BOO developed in 19 of 93 (20.4%) patients with preoperative hormonal therapy. There were no significant differences in the development of single/multiple BOO episodes if preoperative hormonal therapy was administered (P = 0.165/P = 0.569).

Table 2.

Comparison of Patients With and Without Bladder Outlet Obstruction After High-Intensity Focused Ultrasound

Factor	No obstruction (n = 168)	BOO (n = 58)	P value
Age	70.19 ± 5.9	69.68 ± 5.27	0.504
Prostate volume (TRUS in cm³)	28.16 ± 17.89	29.78 ± 13.66	0.065
Volume preoperatively planned (cm³)	18.91 ± 7.49	18.91 ± 5.9	0.829
Lesions at HIFU session	605.41 ± 169.3	591.48 ± 147.67	0.833
Treated volume by HIFU (cm³)	39.37 ± 12.2	38.92 ± 8.51	0.753
Gleason score	6.23 ± 1.39	6.12 ± 1.1	0.416
Preoperative PSA level (μg/L)	12.57 ± 19.09	9.69 ± 7.65	0.933

Data indicated as mean values ± standard deviation.

BOO = bladder outlet obstruction; TRUS = transrectal ultrasonography; HIFU = high-intensity focused ultrasound; PSA = prostate-specific antigen.

Table 3.

Comparison of Patients with Single and Multiple Bladder Outlet Obstruction Events

Factor	Single obstruction (n = 31)	Multiple obstruction (n = 27)	P value
Age	68.18 ± 5.03	71.75 ± 4.97	0.024
Prostate volume (TRUS in cm³)	29.16 ± 11.36	30.76 ± 16.93	0.979
Volume preoperatively planned (cm³)	19.45 ± 6.17	18.14 ± 5.74	0.351
Lesions at HIFU session	590.39 ± 155.74	593.04 ± 138.7	0.881
Treated volume by HIFU (cm³)	39.5 ± 7.5	38.17 ± 9.81	0.993
Gleason score	6.18 ± 0.92	6.04 ± 1.33	0.405
Preoperative PSA level (μg/L)	10.23 ± 7.73	8.94 ± 7.65	0.219

Data indicated as mean values ± standard deviation. TRUS = transrectal ultrasonography; HIFU = high-intensity focused ultrasound.

Stratifying by risk group, BOO after HIFU developed in 20 (23.53%) of 85, 24 (32.88%) of 73, and 14 (20.59%) of 68 at low, intermediate, and high risk, respectively. There were no significant differences in the development of BOO between the groups (P = 0.211). Referring to the total patient population, the rate of primary BOO was significantly different between patients who had undergone TURP the same day as HIFU or within 2 days of HIFU (34.38%) and patients with TURP more than 1 month (17.98%) before HIFU (P = 0.032). BOO occurred in 21.95% of the patients who were treated with HIFU only. There was no recurrence of BOO in those patients (Table 4). The difference was even more pronounced in those 130 patients in whom the combination of TURP and HIFU was planned and performed as the most promising approach for cure.

Table 4.

Interval Between Transurethral Resection of the Prostate-High-Intensity Focused Ultrasound and Development of Bladder Outlet Obstruction

Approach	Overall	BOO	Multiple BOO
Total	226	58 (25.66%)	27 (11.94%)
HIFU ≥1 month after TURP	89	16 (17.98%)	9 (10.11%)
HIFU 0–2 days after TURP	96	33 (34.38%)	18 (18.75%)
HIFU without TURP	41	9 (21.95%)	0

Data presented as number of patients, with percentages in parentheses.

BOO = bladder outlet obstruction; HIFU = high-intensity focused ultrasound; TURP = transurethral resection of the prostate.

BOO developed in 38 (29.2%) patients during follow-up. Remarkably, the rate of BOO was significantly different between patients who had undergone TURP the same day as HIFU or within 2 days of HIFU (35.16%) and patients with TURP more than 1 month (15.38%) before HIFU (P = 0.023). There were no significant differences in the occurrence of multiple BOO episodes between both groups (P = 0.453).

Median follow-up was 64 months (range 33–80 mos) in patients who were treated with the Maxis device and 30 months (range 24–42 mos) with the Integrated Imaging device. Regarding the HIFU devices, no differences in the manifestation of primary BOO (24.4% vs 27.47%; P = 0.609) and repeated BOO (12.6% vs 10.91%; P = 0.384) were observed. There were no significant differences between both devices regarding the mean time to BOO occurrence after HIFU (7.77 vs 8.95 mos) (P = 0.077).

The following conventional (thulium:YAG laser) TIs were performed in patients with primary BOO: Bladder neck incision/resection in 5 (8), internal urethrotomy in 3 (3), TURP in 9 (5), and combined treatment in 11 (14) patients, respectively. There were no differences in BOO recurrence after initial thulium:YAG laser treatment (14/31) compared with patients with conventional TI (13/27) (P = 0.820).

Discussion

The first clinical application of transrectal HIFU was in the management of benign prostate hyperplasia.¹³ Despite initial reduction of obstructive symptoms,¹³ long-term results indicated a rate of TURP in 43.8% of the patients within 4 years after HIFU.¹⁴ Later, transrectal HIFU was applied to prostate cancer using the Ablatherm and the Sonablate device (Focus Surgery, Indianapolis, IN). Up to 30% of the patients who were treated with the Ablatherm^5,6 and 27% with the Sonablate^® device⁷ needed secondary TI.

The concept of performing TURP before HIFU was originally introduced to reduce prolonged perioperative urinary retention.^8,10 Poissonnier and associates⁹ (31% vs 6%), Chaussy and Thüroff⁸ (27% to 8%), and Gelet and coworkers¹⁵ (25.9 to 8.7%), however, also demonstrated a significant decrease in the rate of secondary TI. This is in contrast to our findings. The rate of TI after HIFU remains high, even if TURP is performed before HIFU to reduce the volume of the prostate. A significant decrease of BOO (from 34.38% to 17.98%) was only notable if the time interval between TURP and HIFU was extended to more than 1 month. Thus, these results do not argue against the value of a combined approach but lead us to the recommendation to split the procedures. This is supported by Blana and associates.⁵ In their series, BOO developed in 25.1% of the patients, but no significant differences were noted between patients with (24.8%) and without (25.7%) TURP before HIFU. Similarly, they observed a trend toward lower rates of BOO (12.5%) with a longer interval between TURP and HIFU (>3 months).⁵

As suggested by these authors, the immediate combination of the two procedures might impair the reconstruction of the prostatic urethra because of thermal effects.⁵ Excessive inflammatory tissue reactions could induce a pronounced constriction of the prostate. This would explain why, in our study, at the first episode of BOO multiple sites were involved inside the prostate cavity and at the bladder neck and the elimination of necrotic debris was impaired. It remains unknown why only part of the patients were affected. Advanced age was marked as an influencing factor by other investigators,⁵ but this is not confirmed by our study.

Mean follow up of BOO occurrence after HIFU was 50.01 months in our study, compared with 27 months,⁹ 18.7 months,⁸ and 40 months,⁵ respectively. BOO occurred at a median of 6 months after HIFU, while other studies gave divergent results—mean 6 months⁸ and 15.2 months,⁵ respectively. Blana and colleagues⁵ concluded that the higher BOO occurrence in their study is because of the longer follow-up period. The actuarial cumulative incidences of BOO after HIFU at 1 and 2 years, however, were 20.8% and 23.89% in our series. Nearly all cases of BOO were detected within 2 years after HIFU. Longer follow-up only led to a slight increase of total BOO occurrence in our series (25.66%).

The risk of repetitive BOO was first described by Blana and coworkers.⁵ A second TI was performed at least in 6.03% and a third TI in 3.5% of their patients,⁵ respectively. This is in accordance with our findings. A second TI became necessary in 11.94% of the patients, while three or more TIs were barely needed (5.75%). The median time between each BOO episode ranged from 3 to 7 months.

Necrotic prostate tissue was found in 48.27% of our patients with primary BOO but only in 7.4% with secondary TI, in comparison with 30.4% and 8.3% in the series from Blana and associates.⁵ In contrast, bladder neck stenosis by scarring of the prostate was noted in 55.2% of our patients with primary and 77.8% with secondary BOO episode, compared with 81% and 100%.⁵ These findings suggest that the long-term effect of HIFU is scarring of the prostate, predominantly affecting the bladder neck.

Regarding the influencing factors, age was significantly associated with the manifestation of repetitive BOO. Therefore, older patients should be informed about the risk for development of multiple BOO episodes. TURP before HIFU seems to play an important role in the formation of repetitive BOO as well. Again, a prolonged time interval (4 months and more) between both procedures gave better results. Remarkably, a second TI was never needed in patients without TURP, although the number is small (n = 40).

Cold knife incision is commonly used as the treatment of BOO and also has been proposed for the treatment of manifest singular and repetitive BOO after HIFU.⁵ We used TURP and later the thulium:YAG laser at the time of the first episode of BOO. When analyzing the frequency of repetitive BOO, however, no difference could be noted. Thus, the problem of an appropriate treatment has not yet been resolved.

BOO remains a crucial problem after HIFU, although its prevalence appears to be comparable with other treatment modalities. Recently, Berge and coworkers¹⁶ examined in a large study of 12,711 patients the need for secondary surgical intervention after initial treatment in patients with organ-confined prostate cancer. More than one-third of the patients needed additional surgical intervention within 66 months of initial treatment with RP, RT, androgen-deprivation therapy (ADT), and watchful waiting (WW), respectively. In particular, BOO managed with TURP or bladder neck incision was found in 6.8%, 10.1%, 8.2%, and 3.7% in patients after RT, WW, ADT, and RP, respectively. In addition, urethral dilatation procedures were performed in 16.2%, 13.1%, 12.5%, and 13.1% of the patients with RP, RT, ADT, and WW, respectively.¹⁶

In other studies, anastomotic strictures after RP occurred in 0.48% up to 32% of the patients, predominantly affecting the bladder neck.^17
–19 BOO was found in 2% and 12% of patients after brachytherapy and external beam therapy, respectively.²⁰

Conclusions

Transrectal HIFU is a minimally invasive procedure for selected patients with prostate cancer. The concept of combining HIFU with TURP decreases the perioperative urinary retention time but may lead to delayed development of BOO (25.66%) after HIFU, particularly affecting the bladder neck. A considerable proportion of patients may need one or two secondary TIs, which is important, especially in the elderly population with prostate cancer. A longer interval between TURP and HIFU (>1 month) might reduce this risk. Nevertheless, the ideal of an uncomplicated elimination of necrotic tissue and restoration of the prostatic urethra should be dismissed.

Footnotes

Disclosure Statement

No competing financial interests exist.

Abbreviations Used

References

NICE. High-intensity focused ultrasound for prostate cancer. http://www.nice.org.uk/guidance/IPG118. 2007 July .

Rebillard

, Soulié

, Chartier-Kastler

et al. Association Francaise d'Urologie. High-intensity focused ultrasound in prostate cancer; a systematic literature review of the French Association of Urology. BJU Int, 2008; 101:1205–1213.

Chapelon

, Margonari

, Vernier

et al.

In vivo effects of high-intensity ultrasound on prostatic adenocarcinoma Dunning R3327 (1992)

Cancer Res, 1992; 52:6353–6357.

Rebillard

, Gelet

, Davin

et al. Transrectal high-intensity focused ultrasound in the treatment of localized prostate cancer. J Endourol, 2005; 19:693–701.

Blana

, Hierl

, Rogenhofer

et al. Factors predicting for formation of bladder outlet obstruction after high-intensity focused ultrasound in treatment of localized prostate cancer. Urology, 2008; 71:863–867.

Chaussy

, Thüroff

. Results and side effects of high-intensity focused ultrasound in localized prostate cancer. J Endourol, 2001; 15:437–440.

Uchida

, Ohkusa

, Yamashita

et al. Five years experience of transrectal high-intensity focused ultrasound using the Sonablate device in the treatment of localized prostate cancer. Int J Urol, 2006; 13:228–233.

Chaussy

, Thüroff

. The status of high-intensity focused ultrasound in the treatment of localized prostate cancer and the impact of a combined resection. Curr Urol Rep, 2003; 4:248–252.

Poissonnier

, Chapelon

, Rouvière

et al. Control of prostate cancer by transrectal HIFU in 227 patients. Eur Urol, 2007; 51:381–387.

10.

Vallancien

, Prapotnich

, Cathelineau

et al. Transrectal focused ultrasound combined with transurethral resection of the prostate for the treatment of localized prostate cancer: Feasibility study. J Urol, 2004; 171:2265–2267.

11.

Pfeiffer

, Cellarius

, Netsch

, Gross

. Early decision-making after a single treatment session with high-intensity focused ultrasound (HIFU) for prostate cancer. Eur Urol, 2009; 8,suppl:334Abstract.

12.

Thüroff

, Chaussy

, Vallancien

et al. High-intensity focused ultrasound and localized prostate cancer: Efficacy results from the European multicentric study. J Endourol, 2003; 17:673–677.

13.

Madersbacher

, Kratzik

, Susani

, Marberger

. Tissue ablation in benign prostatic hyperplasia with high intensity focused ultrasound. J Urol, 1994; 152:1956–1961.

14.

Madersbacher

, Schatzl

, Djavan

et al. Long-term outcome of transrectal high-intensity focused ultrasound therapy for benign prostatic hyperplasia. Eur Urol, 2000; 37:687–694.

15.

Gelet

, Chapelon

, Bouvier

et al. Transrectal high intensity focused ultrasound for the treatment of localized prostate cancer: Factors influencing the outcome. Eur Urol, 2001; 40:124–129.

16.

Berge

, Thompson

, Blackman

. Additional surgical intervention after radical prostatectomy, radiation therapy, androgen-deprivation therapy, or watchful waiting. Eur Urol, 2007; 52:1036–1043.

17.

Besarani

, Amoroso

, Kirby

. Bladder neck contracture after radical retropubic prostatectomy. BJU Int, 2004; 94:1245–1247.

18.

Augustin

, Pummer

, Daghofer

et al. Patient self-reporting questionnaire on urological morbidity and bother after radical retropubic prostatectomy. Eur Urol, 2002; 42:112–117.

19.

Elliott

, Meng

, Elkin

et al. CaPSURE Investigators. Incidence of urethral stricture after primary treatment for prostate cancer: Data from CaPSURE. J Urol, 2007; 178:529–534.

20.

Zelefsky

, Wallner

, Ling

et al. Comparison of the 5-year outcome and morbidity of three-dimensional conformal radiotherapy versus transperineal permanent iodine-125 implantation for early-stage prostatic cancer. J Clin Oncol, 1999; 17:517–522.