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Rhenium-188 Mercaptoacetyltriglycine–filled Balloon Dilation in the Treatment of Recurrent Urethral Strictures: Initial Experience with Five Patients
Rhenium-188 Mercaptoacetyltriglycine–filled Balloon Dilation in the Treatment of Recurrent Urethral Strictures: Initial Experience with Five Patients Ji Hoon Shin, MD, Ho-Young Song, MD, Dae Hyuk Moon, MD, Seung-Jun Oh, PhD, Tae-Hyung Kim, MS, and Jin-Oh Lim, RT PURPOSE: To evaluate the efficacy of -irradiation therapy with use of a rhenium-188 mercaptoacetyltriglycine (188Re-MAG3)–filled balloon for the prevention of restenosis in urethral strictures refractory to repetitive surgical or interventional procedures. MATERIALS AND METHODS: Five male patients with traumatic (n ⴝ 4) or postoperative anastomotic (n ⴝ 1) recurrent urethral strictures were included. One to four sessions of 20 –30 Gy -irradiation at a 1-mm tissue depth with 188 Re-MAG3–filled balloon dilation were undertaken in each patient. RESULTS: No procedural complications or toxicities were noted. During the mean follow-up period of 16.2 months, the stricture did not recur in two patients, whereas three patients required additional interventional procedures. In two of these patients, the treatment intervals between the required sessions were significantly prolonged. For the entire group, the mean treatment interval was prolonged from 2.2 months before 188Re-MAG3–filled balloon dilation to 10.7 months after therapy. CONCLUSION: 188Re-MAG3–filled balloon dilation shows promise in preventing or delaying stricture recurrence in patients with recurrent urethral strictures. J Vasc Interv Radiol 2006; 17:1471–1477 Abbreviation:
MAG3 ⫽ mercaptoacetyltriglycine
MANAGEMENT of urethral strictures, particularly strictures that are
From the Department of Radiology and Research Institute of Radiology (J.H.S., H.Y.S., T.H.K., J.O.L) and Department of Nuclear Medicine (D.H.M., S.J.O), University of Ulsan College of Medicine, Asan Medical Center, 388-1, Pungnap-2dong, Songpa-gu, Seoul 138-736, Korea. Received March 7, 2006; revision requested June 12; final revision received June 13; and accepted June 19. Address correspondence to J.H.S.; E-mail: [email protected] This study was supported by a grant (2004-312) from the Asan Institute for Life Sciences, Seoul, Korea; a grant (#R01-2003-000-11716-0) from the Korea Science and Engineering Foundation, Republic of Korea; and the Korea Institute of Science & Technology Evaluation and Planning (KISTEP) and the Ministry of Science & Technology (MOST), Government of Korea, through its National Nuclear Technology Program. None of the authors have identified a conflict of interest. © SIR, 2006 DOI: 10.1097/01.RVI.0000235738.28095.04
refractory to conventional procedures such as visual internal urethrotomy or stent placement, remains a challenge (1– 6). Visual internal urethrotomy is considered the primary treatment, but it has been plagued by high rates of recurrent stricture ranging from 38% to 82% within 2 years as a result of hypertrophic intraurethral scar formation (2– 6). The initial results of stent placement seemed to be excellent. However, long-term results are discouraging; for example, only two of the 15 urethral stents in the study of de Vocht et al (1) were patent during a follow-up time of more than 10 years. To solve the problems of high recurrent stricture rates associated with visual internal urethrotomy and stent placement, intraurethral brachytherapy with an iridium-192 source has been applied after visual internal urethrotomy, with good initial results
(5,7,8). The rationale for the use of 192Ir was based on the concept that intraurethral tissue hyperplasia and resultant scar formation is the result of an excessive wound-healing phenomenon (5,8). The investigators postulated that ionizing irradiation could be applied to prevent urethral restenosis because it successfully prevented recurrent arterial narrowing (5,8). On the basis of recent publications of animal studies in the canine urethra (9,10), we found that intraurethral tissue hyperplasia secondary to stent placement can be suppressed by a rhenium-188 mercaptoacetyltriglycine (MAG3)–filled balloon, which adds a functional effect (ie, ionizing irradiation) to the mechanical effect (ie, balloon dilation) of lumen restoration. The liquid-filled balloon catheter also provides uniform irradiation to the urethral wall. The purpose of this
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Patient Data Stricture Duration* (months)
Pt. No./ Age (y)
Cause
Site
Length (mm)
1/34 2/49
TA TA
Bulbous urethra Bulbous urethra
5 15
One urethroplasty, three VIU, four SP One urethroplasty, five VIU, two SP, two BD
12 14
3/60 4/49
RP TA
Prostatic urethra Bulbous urethra
5 10
Five VIU, one SP, two BD One UroLume stent, nine VIU
12 38
5/26
TA
Bulbous urethra
5
One UroLume stent, 10 VIU, two TUR, one SP
43
Treatment Record before
188
Re BD
* Duration between the onset of urethral strictures and initial 188Re-MAG3–filled balloon dilation. † Mean interval for one treatment procedure before and after initial 188Re-MAG3–filled balloon dilation. Note.—BD ⫽ balloon dilation; PTFE ⫽ polytetrafluoroethylene; RP ⫽ radical prostatectomy; SP ⫽ stent placement; TA ⫽ traffic accident; TUR ⫽ transurethral resection; VIU ⫽ visual internal urethrotomy.
study was to evaluate the efficacy of -irradiation with a 188Re-MAG3– filled balloon dilation catheter for the treatment of recurrent urethral strictures refractory to repetitive surgical or interventional procedures such as visual internal urethrotomy or stent placement.
MATERIALS AND METHODS Patients and Inclusion Criteria Our prospective study was approved by the institutional review board, and informed consent was obtained from all patients. A total of five consecutive male patients (median age, 49 years; range, 26 – 60 y) with recurrent urethral strictures were treated between July 2004 and June 2005 with 188Re-MAG3–filled balloon dilation (Table). In four patients, the strictures were located at the posterior bulbous urethra near the external sphincter and resulted from traumatic strictures caused by traffic accidents. In the fifth patient, the stricture was located at the prostatic urethra and resulted from an anastomotic stricture as a result of radical prostatectomy for prostatic cancer. This patient did not undergo external radiation therapy or chemotherapy. The median duration between the onset of urethral strictures and initial 188ReMAG3–filled balloon dilation was 14 months (mean, 24 months; range, 12– 43 months).
Inclusion criteria included recurrent urethral strictures refractory to repetitive surgical or interventional procedures such as visual internal urethrotomy or stent placement. Refractoriness was defined by a stricture requiring repetitive treatments with a mean treatment interval of less than 4 months during a follow-up period of more than 12 months. The previous treatment records for urethral strictures are described in the Table. Two patients (patients 4 and 5) had received UroLume stents (American Medical Systems, Minnetonka, MN) 38 and 12 months earlier, respectively, but these patients experienced stricture recurrence as a result of ingrowing tissue hyperplasia through the stent at 22 and 6 months, respectively, after stent insertion. The UroLume stent was completely removed from patient 4 at 1 day before 188 Re-MAG3–filled balloon dilation, whereas the stent was incompletely removed from patient 5 at 10 months before 188Re-MAG3–filled balloon dilation. Overall, for all five patients, the mean treatment interval was 2.2 months for one session of surgical or interventional procedures (median, 1.5 months; range, 1.3–3.8 months). Preparation for 188Re-MAG3–filled Balloon Dilation Re is a high-energy -emitter with a maximum energy of 2.12 MeV. This isotope has a half-life of 17 hours and is available as a 188Re-perrhenate 188
solution from a tungsten W 188/188Re generator (Oak Ridge National Laboratory, Oak Ridge, TN). After the 188 Re-MAG3 solution was prepared from 188Re-perrhenate and MAG3 (Technescan; Mallinckrodt Medical, St. Louis, MO) with a synthesizer (11), the solution was concentrated to the desired radioactivity and volume. It was mixed with nonionic contrast medium (Ultravist 300; Schering, Berlin, Germany) to make a 30% contrast medium in a 188Re solution (9,10). On the basis of dosimetric data, the irradiation time was calculated to deliver 20 Gy or 30 Gy at a depth of 1 mm into the urethral wall from the balloon/ wall interface, depending on the actual radioactivity of the 188Re-MAG3 solution. Balloon Dilation Technique 188 Re-MAG3–filled balloon dilation was performed on an outpatient basis while patients were under moderate sedation with intravenously administered meperidine hydrochloride (Demerol; Keukdong Pharmaceuticals, Seoul, Korea). The patient was placed in a left anterior oblique position with his knees bent. After disinfection of the external urethral orifice with 0.05% chlorhexidine, the urethra was anesthetized topically with 10 mL of lubricating jelly containing 2% lidocaine. Immediately before balloon dilation, the site, severity, and length of the stricture were evaluated with retrograde urethrography. A 0.035-inch
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Treatment Interval† (months)
No.
Dose (Gy)
Before
After
1 4
20 20, 20, 20, 30
1.5 1.3
20 5
1 2
20 20, 30
1.3 3.8
19.0 6.5
1
30
3.0
3.0
guide wire (Radifocus M; Terumo, Tokyo, Japan) was inserted through the urethra across the stricture into the urinary bladder under fluoroscopic guidance. Then, an angioplasty balloon catheter (Cordis, Roden, The Netherlands) was passed over the guide wire to a position covering the stricture. The balloon catheters used were 10 mm in diameter and 4 cm long. The balloon was slowly inflated by manual pressure with diluted nonionic contrast medium (Ultravist 300) for 1 minute until the hourglassshaped deformity created by the stricture disappeared from the balloon contour. If the balloon could not be fully dilated with use of manual pressure, a conventional pressure-controlled inflation device was used to dilate the stricture. In cases in which full dilation of the stricture was not achieved even with the inflation device, a cutting balloon catheter (8 mm in diameter, 2 cm in length; Boston Scientific, Watertown, MA) was used to disrupt the tight strictures on the basis of our assumption that failure to adequately dilate the stricture would be predictive of recurrent stricture after 188Re-MAG3–filled balloon dilation. Immediately after conventional or cutting balloon dilation, the catheter was replaced with a new balloon catheter. For 188Re-MAG3–filled balloon dilation, a 188Re-MAG3–filled syringe and an inflation device were connected to the balloon with a three-way stopcock. After complete removal of
Effect and Complications
Follow-up (months)
No recurrent stricture, dysuria (2 d) Increased treatment interval, dysuria (1 week) at second 188Re BD No recurrent stricture Increases treatment interval, dysuria (3 weeks) at second 188Re BD Recurrent stricture
20 20
air from the balloon, the 188Re-MAG3 solution was manually injected into the balloon. Balloon inflation was maintained with a nominal pressure of 3 atm and was performed with the balloon center at the center of the stricture (Figs 1, 2). After the appropriate balloon inflation time, the 188Re-MAG3 solution was aspirated from the balloon catheter. The whole system was then removed and taken to the department of nuclear medicine for appropriate disposal. Follow-up We evaluated the patients’ conditions by means of a questionnaire that was adapted to the clinical signs and symptoms of recurrent urethral stricture at 1 week, every month for 3 months, and then every 6 months after 188 Re-MAG3–filled balloon dilation. The questionnaire contained questions about dysuria, hematuria, fever, and need for pain medicine. The patients were questioned by one author and advised to visit an outpatient clinic when they suspected a recurrence of dysuria similar to their condition before 188Re-MAG3–filled balloon dilation. Follow-up retrograde urethrography was scheduled at 1 month and 3 months and then every year after 188 Re-MAG3–filled balloon dilation to provide morphologic information about stricture recurrence. To assess the treatment efficacy of
19 13 9
Comments – Predilation with cutting balloon at fourth 188Re BD – Predilation with cutting balloon at second 188Re BD PTFE-covered stent for 1 week after failed 188Re BD
188
Re-MAG3–filled balloon dilation, we calculated the mean treatment interval between each 188Re-MAG3– filled balloon dilation and the next balloon dilation or any other interventional procedure carried out to treat the urethral stricture.
RESULTS 188
Re-MAG3–filled Balloon Dilation
The mean stricture length was 8 mm (range, 5–15 mm). We performed nine successful 188Re-MAG3–filled balloon dilations in the five patients, with an average of 1.8 procedures per patient (range, 1– 4). There were no procedure-related complications such as intolerable pain or balloon catheter rupture. Fluoroscopy demonstrated full dilation of the balloon catheters in all patients and no gaps between the 188 Re-MAG3–filled balloons and the urethral walls. Cutting balloon catheters had to be used before 188Re-MAG3–filled balloon dilation in two sessions (in patients 2 and 4) as a result of incomplete expansion of the conventional balloon catheters even with use of the pressure-controlled inflation device (Fig 2). With cutting balloon catheters, the stenotic portion could be successfully dilated fully without formation of a waist of the balloon. The applied irradiation dose was 20 Gy in six sessions and 30 Gy in three sessions at a depth of 1 mm into the
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Figure 1. Images from patient 1. (a) Retrograde urethrogram in left anterior oblique projection immediately before 188Re-MAG3–filled balloon dilation demonstrates a urethral stricture (arrow) near the external sphincter. There is a pouch-like contrast agent pooling (arrowheads) caused by urethral injury at the level of the external sphincter. (b) During 188Re-MAG3–filled balloon dilation, the balloon can be fully expanded (arrows). (c) Retrograde urethrogram in left anterior oblique projection immediately after 188Re-MAG3–filled balloon dilation reveals a significantly dilated lumen (arrow). (d) A retrograde urethrogram obtained 1 year after 188Re-MAG3–filled balloon dilation shows slightly reduced lumen (arrow) as a result of minimal stricture recurrence. However, the patient was free of symptoms.
urethral wall from the balloon/wall interface. Since June 2005, we have increased the irradiation dose from 20
Gy to 30 Gy because 20 Gy seemed to be less effective in some patients. For all nine sessions, the mean in-
flation time for 188Re-MAG3 application was 10.6 minutes (range, 6.5–17.0 min).
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Figure 2. Images from patient 4. (a) Retrograde urethrogram immediately before 188Re-MAG3–filled balloon dilation demonstrates restenosis (arrow) at the site of a UroLume urethral stent (arrowheads), which had been placed 38 months earlier. The first session of 188 Re-MAG3–filled balloon dilation had been performed 1 day after complete removal of the UroLume stent (not shown). (b– e) The second session of 188Re-MAG3–filled balloon dilation had to be performed because of recurrent dysuria 4 months later. A radiograph and retrograde urethrogram in left anterior oblique projection show a dilated lumen (arrow in c ) after cutting balloon dilation (arrows in b). Subsequently, 188Re-MAG3–filled balloon dilation (arrows in d) was performed and the lumen was fully dilated (arrow in e). (f) Left anterior oblique retrograde urethrogram obtained 3 months after second 188Re-MAG3–filled balloon dilation shows a slight restenosis (arrow). However, this patient was been free of dysuria until the end of the follow-up period of 9 months after the second 188 Re-MAG3–filled balloon dilation.
Follow-up There was no hematuria, fever, or need for pain medication after 188ReMAG3–filled balloon dilation in any patient. Three patients (patients 1, 2, and 4) experienced dysuria immediately after 188Re-MAG3–filled balloon dilation in three sessions. Although dysuria symptoms persisted for 2 days, 1 week, and 3 weeks, respectively, all patients managed to urinate by themselves. As a result of these symptoms reported by the first patients, we inserted Foley catheters immediately after 188Re-MAG3–filled balloon dilation to ease urination in two
patients (patients 2 and 5). The Foley catheter was kept in place for 2 weeks, and there was no immediate dysuria after catheter removal in these patients. During the mean follow-up period of 16.2 months (range, 9 –20 months) after initial 188Re-MAG3–filled balloon dilation, no further treatment was necessary in two patients (patients 1 and 3) (Fig 1), and further 188Re-MAG3– filled balloon dilation or stent placement was performed in the remaining three patients. Of these three patients, three additional sessions of 188ReMAG3–filled balloon dilation were
performed for stricture recurrence during the follow-up period of 20 months in one patient (patient 2). However, in this patient, the treatment interval increased from 1.3 months to 5 months after 188Re-MAG3–filled balloon dilation, so the patient has been satisfied with this treatment. In another patient (patient 4), one additional session of 188Re-MAG3–filled balloon dilation was necessary because of stricture recurrence 4 months after the initial balloon dilation (Fig 2). In the other patient (patient 5), a polytetrafluoroethylene-covered retrievable nitinol stent (Taewoong Medical,
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Ilsan, Korea) was inserted 3 months after 188Re-MAG3–filled balloon dilation because of stricture recurrence, although this stent was removed 1 week later because of stent migration. The patient refused further 188Re-MAG3– filled balloon dilation at that time and currently has dysuria similar to that he experienced before 188Re-MAG3–filled balloon dilation. The treatment interval ranged from 3 to 20 months for one session of 188ReMAG3–filled balloon dilation for all five patients. The mean and median treatment intervals increased from 2.2 months and 1.5 months, respectively, before 188Re-MAG3–filled balloon dilation to 10.7 months and 6.5 months, respectively, after 188Re-MAG3–filled balloon dilation.
DISCUSSION In the present study, we observed an increase of treatment interval or no stricture recurrence in four of five patients. After this procedure, the mean and median treatment intervals increased by a factor of more than four compared with the intervals before 188 Re-MAG3–filled balloon dilation. Moreover, 188Re-MAG3–filled balloon dilation in all five patients was performed while patients were under moderate sedation on an outpatient basis. Our results are preliminary because the patient population was very small. The improvements noted with 188 Re-MAG3–filled balloon dilation compared with conventional balloon dilation may have been caused by the ionizing irradiation in the former procedure. When it is considered that the success of endovascular irradiation to control recurrent arterial narrowing is based on the concept that restenosis is primarily an excessive healing phenomenon secondary to mechanical injury (12,13), the same treatment rationale can be applied to a urethral stricture secondary to trauma or anastomosis. Increased epithelial and submucosal thickness in canine urethras was observed after covered stent placement, which was reduced by 188 Re-MAG3–filled balloon dilation (9,10). Histologically, tissue hyperplasia consists of richly vascularized connective tissue with new capillary formation and numerous fibroblasts in the submucosa (9,14). Irradiation of
the human urethra may inhibit the cellular proliferative response by mechanisms similar to those observed during irradiation-induced suppression of the proliferative response in arterial cells (15,16). In the treatment of urethral strictures, 188Re-MAG3–filled balloon dilation has several advantages compared with intraurethral brachytherapy with a 192Ir source. First, -irradiation caused by 188Re has a low penetration depth, with a maximum of 11 mm, minimizing the exposure to patient and operator and decreasing the potential damage to adjacent normal tissue. By contrast, 192Ir, a ␥-emitter, is deeply penetrating and is not effectively shielded by standard lead aprons. Second, self-centering irradiation is possible with 188Re-MAG3– filled balloon dilation as a result of the properties of equidistant radiation from the balloon surface. By contrast, deviation of a catheter-based 192Ir source by as little as several millimeters from the center can lead to significant differences in dose distribution to the urethral wall (17,18). Third, compared with solid 192Ir sources, which use expensive afterloading devices, the 188Re-MAG3–filled balloon dilation system can be used with standard balloon dilation technology. Fourth, the target lesion in our study can be dilated with conventional or cutting balloon catheters before -irradiation. The mechanical dilation of the stenosed urethra can lacerate the strictured mucosa and possibly substitute for urethrotomy. We think laceration of the strictured mucosa before -irradiation is prerequisite for better results because elastic recoil predominate over irradiation effect in nonlacerated lumen. In our study, the chosen radiation dose was 20 Gy or 30 Gy at a depth of 1 mm into the tissue from the balloon surface. This dose was within the range of doses of intraurethral -irradiation used in previous studies, which ranged from 15 Gy to 40 Gy at a 1-mm tissue depth from the balloon surface, although the data were obtained in a canine urethral model (9,10) and transferred to the human setting. We avoided higher doses of 40 Gy because severe fibrosis and degeneration of the muscularis propria were reported when 48 –90 Gy at a 1-mm tissue depth were delivered with hol-
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mium Ho 166 –impregnated stents in a canine esophageal model (19). When it is taken into account that doses of 6 –16 Gy at a 1-cm tissue depth were used with a 192Ir source in the treatment of benign strictures of the urethra or bronchi (5,8,18,20), the radiation dose used in the present study, 20 –30 Gy at 1-mm tissue depth, can be considered low even though direct comparison of - and ␥-irradiation is not accurate. Patients treated with high-dose brachytherapy can experience irradiation-associated toxicities such as fever or epididymitis. In a previous report, such adverse events were reported in four of 17 patients (8). The three patients who experienced stricture recurrence after 188Re-MAG3– filled balloon dilation had a longer duration between the onset of urethral stricture and initial balloon dilation than did the two patients who did not experience stricture recurrence. In addition, the UroLume stent was incompletely removed from one patient, who experienced stricture recurrence 3 months after 188Re-MAG3–filled balloon dilation, which suggests that the remaining stent fragments may have continued to irritate the urethral mucosa or submucosa. Therefore, the milieu of the urethral tissue and its surroundings seem to be strongly associated with the clinical outcome. The adverse events of temporary dysuria in three patients in the present study suggest that congestion and edema of the urethral mucosa can occur and cause dysuria. In previous reports of 192Ir ␥-irradiation for urethral strictures (5,8), Foley catheters were kept in place for 1– 6 weeks to prevent edema-induced dysuria. After observing dysuria in three patients, we inserted Foley catheters for 2 weeks in the two patients treated subsequently. Our findings suggest that temporary Foley catheter placement should be performed after 188Re-MAG3–filled balloon dilation for urethral strictures. We assume that this kind of 188ReMAG3–filled balloon dilation might be applied to benign strictures of other nonvascular luminal organs such as the ureter, airway, or esophagus because the stricture mechanism and underlying histologic background would be similar. The major limitation of this study was its lack of urologic flowmetry in-
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formation. Urologic flowmetry gives an excellent indication of the urodynamic success of the endoluminal treatment. However, the patients were monitored in the department of urology in their local hospital. Therefore, timely urologic flowmetry was not performed. Our decision for repeat intervention was based on patients’ symptoms, primarily dysuria. We assessed the clinical success of the treatment by calculating the intervals between the successive treatment sessions. Another limitation of this study was the small number of patients. However, this study was performed to achieve an initial experience with 188 Re-MAG3–filled balloon dilation. For future trials, a randomized comparison with intraurethral ␥-irradiation for recurrent urethral strictures will be necessary. Last, there is a risk of balloon rupture with the risk of leakage and spillage of a -emitter into the urinary system as well into adjacent tissue in case of coincident urethral wall rupture. Utmost care, such as avoidance of excessive pressure, has to be taken to prevent balloon rupture. In case of balloon rupture, full hydration of the patient and stimulation of diuresis and urination for fast excretion of the radioisotope can minimize radiation hazard (9,21). In summary, the present data suggest that 188Re-MAG3–filled balloon dilation shows promise in preventing or delaying stricture recurrence in patients with recurrent urethral strictures. References 1. De Vocht TF, van Venrooij GE, Boon TA. Self-expanding stent insertion for urethral strictures: a 10-year follow-up. BJU Int 2003; 91:627–630. 2. Albers P, Fichtner J, Bruhl P, et al.
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12.
Long-term results of internal urethrotomy. J Urol 1996; 156:1611–1614. Bodker A, Ostri P, Rye-Andersen J, et al. Treatment of recurrent urethral stricture by internal urethrotomy and intermittent self-catheterization: a controlled study of a new therapy. J Urol 1992; 148:308–310. Mandhani A, Chaudhury H, Kapoor R, et al. Can outcome of internal urethrotomy for short segment bulbar urethral stricture be predicted? J Urol 2005; 173:1595–1597. Olschewski T, Kropfl D, Seegenschmiedt MH. Endourethral brachytherapy for prevention of recurrent urethral stricture following internal urethrotomy: first clinical experiences and results. Int J Radiat Oncol Biol Phys 2003; 57:1400–1404. Song HY, Park H, Suh TS, et al. Recurrent traumatic urethral strictures near the external sphincter: treatment with a covered, retrievable, expandable nitinol stent: initial results. Radiology 2003; 226:433–440. Kropfl D, Olschewski T, Seegenschmiedt MH. Endourethral brachytherapy for the prevention of recurrent strictures following internal urethrotomy. Urologe A 2004; 43:1254–1261. Sun YH, Xu CL, Gao X, et al. Intraurethral brachytherapy for prevention of recurrent urethral stricture after internal urethrotomy or transurethral resection of scar. J Endourol 2001; 15: 859–861. Shin JH, Song HY, Moon DH, et al. Reduction of tissue hyperplasia with a rhenium-188 mercaptoacetyltriglycine3–filled balloon: preliminary study in a canine urethral model. J Vasc Interv Radiol 2004; 15:737–743. Shin JH, Oh SJ, Kim JS, et al. Effects of irradiation using a radioisotope-filled balloon on tissue hyperplasia caused by stent placement in a canine urethral model. Acta Radiol 2006; 47:436–443. Oh SJ, Moon DH, Ha HJ, et al. Automation of the synthesis of highly concentrated 188Re-MAG3 for intracoronary radiation therapy. Appl Radiat Isot 2001; 54:419–427. Weinberger J, Giedd KN, Simon AD, et
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al. Radioactive beta-emitting solution–filled balloon treatment prevents porcine coronary restenosis. Cardiovasc Radiat Med 1999; 1:252–256. Wohlfrom M, Kotzerke J, Kamenz J, et al. Endovascular irradiation with the liquid beta-emitter rhenium-188 to reduce restenosis after experimental wall injury. Cardiovasc Res 2001; 49: 169–176. Mayoral W, Fleischer D, Salcedo J, et al. Nonmalignant obstruction is a common problem with metal stents in the treatment of esophageal cancer. Gastrointest Endosc 2000; 51:556–559. Diamond DA, Vesely TM. The role of radiation therapy in the management of vascular restenosis. Part I: biologic basis. J Vasc Interv Radiol 1998; 9:199– 208. Wilcox JN, Waksman R, King SB, et al. The role of the adventitia in the arterial response to angioplasty: the effect of intravascular radiation. Int J Radiat Oncol Biol Phys 1996; 36:789–796. Hoher M, Wohrle J, Wohlfrom M, et al. Intracoronary beta-irradiation with a liquid (188)Re-filled balloon: six-month results from a clinical safety and feasibility study. Circulation 2000; 101: 2355–2360. Kennedy AS, Sonett JR, Orens JB, et al. High dose rate brachytherapy to prevent recurrent benign hyperplasia in lung transplant bronchi: theoretical and clinical considerations. J Heart Lung Transplant 2000; 19:155–159. Won JH, Lee JD, Wang HJ, et al. Selfexpandable covered metallic esophageal stent impregnated with beta-emitting radionuclide: an experimental study in canine esophagus. Int J Radiat Oncol Biol Phys 2002; 53:1005–1013. Kramer MR, Katz A, Yarmolovsky A, et al. Successful use of high dose rate brachytherapy for non-malignant bronchial obstruction. Thorax 2001; 56: 415–416. Hang CL, Fu M, Hsieh BT, et al. Intracoronary beta-irradiation with liquid rhenium-188: results of the Taiwan radiation in prevention of post-pure balloon angioplasty restenosis study. Chest 2003;124:1284–1293.
MAG3 ⫽ mercaptoacetyltriglycine
MANAGEMENT of urethral strictures, particularly strictures that are
From the Department of Radiology and Research Institute of Radiology (J.H.S., H.Y.S., T.H.K., J.O.L) and Department of Nuclear Medicine (D.H.M., S.J.O), University of Ulsan College of Medicine, Asan Medical Center, 388-1, Pungnap-2dong, Songpa-gu, Seoul 138-736, Korea. Received March 7, 2006; revision requested June 12; final revision received June 13; and accepted June 19. Address correspondence to J.H.S.; E-mail: [email protected] This study was supported by a grant (2004-312) from the Asan Institute for Life Sciences, Seoul, Korea; a grant (#R01-2003-000-11716-0) from the Korea Science and Engineering Foundation, Republic of Korea; and the Korea Institute of Science & Technology Evaluation and Planning (KISTEP) and the Ministry of Science & Technology (MOST), Government of Korea, through its National Nuclear Technology Program. None of the authors have identified a conflict of interest. © SIR, 2006 DOI: 10.1097/01.RVI.0000235738.28095.04
refractory to conventional procedures such as visual internal urethrotomy or stent placement, remains a challenge (1– 6). Visual internal urethrotomy is considered the primary treatment, but it has been plagued by high rates of recurrent stricture ranging from 38% to 82% within 2 years as a result of hypertrophic intraurethral scar formation (2– 6). The initial results of stent placement seemed to be excellent. However, long-term results are discouraging; for example, only two of the 15 urethral stents in the study of de Vocht et al (1) were patent during a follow-up time of more than 10 years. To solve the problems of high recurrent stricture rates associated with visual internal urethrotomy and stent placement, intraurethral brachytherapy with an iridium-192 source has been applied after visual internal urethrotomy, with good initial results
(5,7,8). The rationale for the use of 192Ir was based on the concept that intraurethral tissue hyperplasia and resultant scar formation is the result of an excessive wound-healing phenomenon (5,8). The investigators postulated that ionizing irradiation could be applied to prevent urethral restenosis because it successfully prevented recurrent arterial narrowing (5,8). On the basis of recent publications of animal studies in the canine urethra (9,10), we found that intraurethral tissue hyperplasia secondary to stent placement can be suppressed by a rhenium-188 mercaptoacetyltriglycine (MAG3)–filled balloon, which adds a functional effect (ie, ionizing irradiation) to the mechanical effect (ie, balloon dilation) of lumen restoration. The liquid-filled balloon catheter also provides uniform irradiation to the urethral wall. The purpose of this
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Patient Data Stricture Duration* (months)
Pt. No./ Age (y)
Cause
Site
Length (mm)
1/34 2/49
TA TA
Bulbous urethra Bulbous urethra
5 15
One urethroplasty, three VIU, four SP One urethroplasty, five VIU, two SP, two BD
12 14
3/60 4/49
RP TA
Prostatic urethra Bulbous urethra
5 10
Five VIU, one SP, two BD One UroLume stent, nine VIU
12 38
5/26
TA
Bulbous urethra
5
One UroLume stent, 10 VIU, two TUR, one SP
43
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Re BD
* Duration between the onset of urethral strictures and initial 188Re-MAG3–filled balloon dilation. † Mean interval for one treatment procedure before and after initial 188Re-MAG3–filled balloon dilation. Note.—BD ⫽ balloon dilation; PTFE ⫽ polytetrafluoroethylene; RP ⫽ radical prostatectomy; SP ⫽ stent placement; TA ⫽ traffic accident; TUR ⫽ transurethral resection; VIU ⫽ visual internal urethrotomy.
study was to evaluate the efficacy of -irradiation with a 188Re-MAG3– filled balloon dilation catheter for the treatment of recurrent urethral strictures refractory to repetitive surgical or interventional procedures such as visual internal urethrotomy or stent placement.
MATERIALS AND METHODS Patients and Inclusion Criteria Our prospective study was approved by the institutional review board, and informed consent was obtained from all patients. A total of five consecutive male patients (median age, 49 years; range, 26 – 60 y) with recurrent urethral strictures were treated between July 2004 and June 2005 with 188Re-MAG3–filled balloon dilation (Table). In four patients, the strictures were located at the posterior bulbous urethra near the external sphincter and resulted from traumatic strictures caused by traffic accidents. In the fifth patient, the stricture was located at the prostatic urethra and resulted from an anastomotic stricture as a result of radical prostatectomy for prostatic cancer. This patient did not undergo external radiation therapy or chemotherapy. The median duration between the onset of urethral strictures and initial 188ReMAG3–filled balloon dilation was 14 months (mean, 24 months; range, 12– 43 months).
Inclusion criteria included recurrent urethral strictures refractory to repetitive surgical or interventional procedures such as visual internal urethrotomy or stent placement. Refractoriness was defined by a stricture requiring repetitive treatments with a mean treatment interval of less than 4 months during a follow-up period of more than 12 months. The previous treatment records for urethral strictures are described in the Table. Two patients (patients 4 and 5) had received UroLume stents (American Medical Systems, Minnetonka, MN) 38 and 12 months earlier, respectively, but these patients experienced stricture recurrence as a result of ingrowing tissue hyperplasia through the stent at 22 and 6 months, respectively, after stent insertion. The UroLume stent was completely removed from patient 4 at 1 day before 188 Re-MAG3–filled balloon dilation, whereas the stent was incompletely removed from patient 5 at 10 months before 188Re-MAG3–filled balloon dilation. Overall, for all five patients, the mean treatment interval was 2.2 months for one session of surgical or interventional procedures (median, 1.5 months; range, 1.3–3.8 months). Preparation for 188Re-MAG3–filled Balloon Dilation Re is a high-energy -emitter with a maximum energy of 2.12 MeV. This isotope has a half-life of 17 hours and is available as a 188Re-perrhenate 188
solution from a tungsten W 188/188Re generator (Oak Ridge National Laboratory, Oak Ridge, TN). After the 188 Re-MAG3 solution was prepared from 188Re-perrhenate and MAG3 (Technescan; Mallinckrodt Medical, St. Louis, MO) with a synthesizer (11), the solution was concentrated to the desired radioactivity and volume. It was mixed with nonionic contrast medium (Ultravist 300; Schering, Berlin, Germany) to make a 30% contrast medium in a 188Re solution (9,10). On the basis of dosimetric data, the irradiation time was calculated to deliver 20 Gy or 30 Gy at a depth of 1 mm into the urethral wall from the balloon/ wall interface, depending on the actual radioactivity of the 188Re-MAG3 solution. Balloon Dilation Technique 188 Re-MAG3–filled balloon dilation was performed on an outpatient basis while patients were under moderate sedation with intravenously administered meperidine hydrochloride (Demerol; Keukdong Pharmaceuticals, Seoul, Korea). The patient was placed in a left anterior oblique position with his knees bent. After disinfection of the external urethral orifice with 0.05% chlorhexidine, the urethra was anesthetized topically with 10 mL of lubricating jelly containing 2% lidocaine. Immediately before balloon dilation, the site, severity, and length of the stricture were evaluated with retrograde urethrography. A 0.035-inch
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Treatment Interval† (months)
No.
Dose (Gy)
Before
After
1 4
20 20, 20, 20, 30
1.5 1.3
20 5
1 2
20 20, 30
1.3 3.8
19.0 6.5
1
30
3.0
3.0
guide wire (Radifocus M; Terumo, Tokyo, Japan) was inserted through the urethra across the stricture into the urinary bladder under fluoroscopic guidance. Then, an angioplasty balloon catheter (Cordis, Roden, The Netherlands) was passed over the guide wire to a position covering the stricture. The balloon catheters used were 10 mm in diameter and 4 cm long. The balloon was slowly inflated by manual pressure with diluted nonionic contrast medium (Ultravist 300) for 1 minute until the hourglassshaped deformity created by the stricture disappeared from the balloon contour. If the balloon could not be fully dilated with use of manual pressure, a conventional pressure-controlled inflation device was used to dilate the stricture. In cases in which full dilation of the stricture was not achieved even with the inflation device, a cutting balloon catheter (8 mm in diameter, 2 cm in length; Boston Scientific, Watertown, MA) was used to disrupt the tight strictures on the basis of our assumption that failure to adequately dilate the stricture would be predictive of recurrent stricture after 188Re-MAG3–filled balloon dilation. Immediately after conventional or cutting balloon dilation, the catheter was replaced with a new balloon catheter. For 188Re-MAG3–filled balloon dilation, a 188Re-MAG3–filled syringe and an inflation device were connected to the balloon with a three-way stopcock. After complete removal of
Effect and Complications
Follow-up (months)
No recurrent stricture, dysuria (2 d) Increased treatment interval, dysuria (1 week) at second 188Re BD No recurrent stricture Increases treatment interval, dysuria (3 weeks) at second 188Re BD Recurrent stricture
20 20
air from the balloon, the 188Re-MAG3 solution was manually injected into the balloon. Balloon inflation was maintained with a nominal pressure of 3 atm and was performed with the balloon center at the center of the stricture (Figs 1, 2). After the appropriate balloon inflation time, the 188Re-MAG3 solution was aspirated from the balloon catheter. The whole system was then removed and taken to the department of nuclear medicine for appropriate disposal. Follow-up We evaluated the patients’ conditions by means of a questionnaire that was adapted to the clinical signs and symptoms of recurrent urethral stricture at 1 week, every month for 3 months, and then every 6 months after 188 Re-MAG3–filled balloon dilation. The questionnaire contained questions about dysuria, hematuria, fever, and need for pain medicine. The patients were questioned by one author and advised to visit an outpatient clinic when they suspected a recurrence of dysuria similar to their condition before 188Re-MAG3–filled balloon dilation. Follow-up retrograde urethrography was scheduled at 1 month and 3 months and then every year after 188 Re-MAG3–filled balloon dilation to provide morphologic information about stricture recurrence. To assess the treatment efficacy of
19 13 9
Comments – Predilation with cutting balloon at fourth 188Re BD – Predilation with cutting balloon at second 188Re BD PTFE-covered stent for 1 week after failed 188Re BD
188
Re-MAG3–filled balloon dilation, we calculated the mean treatment interval between each 188Re-MAG3– filled balloon dilation and the next balloon dilation or any other interventional procedure carried out to treat the urethral stricture.
RESULTS 188
Re-MAG3–filled Balloon Dilation
The mean stricture length was 8 mm (range, 5–15 mm). We performed nine successful 188Re-MAG3–filled balloon dilations in the five patients, with an average of 1.8 procedures per patient (range, 1– 4). There were no procedure-related complications such as intolerable pain or balloon catheter rupture. Fluoroscopy demonstrated full dilation of the balloon catheters in all patients and no gaps between the 188 Re-MAG3–filled balloons and the urethral walls. Cutting balloon catheters had to be used before 188Re-MAG3–filled balloon dilation in two sessions (in patients 2 and 4) as a result of incomplete expansion of the conventional balloon catheters even with use of the pressure-controlled inflation device (Fig 2). With cutting balloon catheters, the stenotic portion could be successfully dilated fully without formation of a waist of the balloon. The applied irradiation dose was 20 Gy in six sessions and 30 Gy in three sessions at a depth of 1 mm into the
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Figure 1. Images from patient 1. (a) Retrograde urethrogram in left anterior oblique projection immediately before 188Re-MAG3–filled balloon dilation demonstrates a urethral stricture (arrow) near the external sphincter. There is a pouch-like contrast agent pooling (arrowheads) caused by urethral injury at the level of the external sphincter. (b) During 188Re-MAG3–filled balloon dilation, the balloon can be fully expanded (arrows). (c) Retrograde urethrogram in left anterior oblique projection immediately after 188Re-MAG3–filled balloon dilation reveals a significantly dilated lumen (arrow). (d) A retrograde urethrogram obtained 1 year after 188Re-MAG3–filled balloon dilation shows slightly reduced lumen (arrow) as a result of minimal stricture recurrence. However, the patient was free of symptoms.
urethral wall from the balloon/wall interface. Since June 2005, we have increased the irradiation dose from 20
Gy to 30 Gy because 20 Gy seemed to be less effective in some patients. For all nine sessions, the mean in-
flation time for 188Re-MAG3 application was 10.6 minutes (range, 6.5–17.0 min).
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Figure 2. Images from patient 4. (a) Retrograde urethrogram immediately before 188Re-MAG3–filled balloon dilation demonstrates restenosis (arrow) at the site of a UroLume urethral stent (arrowheads), which had been placed 38 months earlier. The first session of 188 Re-MAG3–filled balloon dilation had been performed 1 day after complete removal of the UroLume stent (not shown). (b– e) The second session of 188Re-MAG3–filled balloon dilation had to be performed because of recurrent dysuria 4 months later. A radiograph and retrograde urethrogram in left anterior oblique projection show a dilated lumen (arrow in c ) after cutting balloon dilation (arrows in b). Subsequently, 188Re-MAG3–filled balloon dilation (arrows in d) was performed and the lumen was fully dilated (arrow in e). (f) Left anterior oblique retrograde urethrogram obtained 3 months after second 188Re-MAG3–filled balloon dilation shows a slight restenosis (arrow). However, this patient was been free of dysuria until the end of the follow-up period of 9 months after the second 188 Re-MAG3–filled balloon dilation.
Follow-up There was no hematuria, fever, or need for pain medication after 188ReMAG3–filled balloon dilation in any patient. Three patients (patients 1, 2, and 4) experienced dysuria immediately after 188Re-MAG3–filled balloon dilation in three sessions. Although dysuria symptoms persisted for 2 days, 1 week, and 3 weeks, respectively, all patients managed to urinate by themselves. As a result of these symptoms reported by the first patients, we inserted Foley catheters immediately after 188Re-MAG3–filled balloon dilation to ease urination in two
patients (patients 2 and 5). The Foley catheter was kept in place for 2 weeks, and there was no immediate dysuria after catheter removal in these patients. During the mean follow-up period of 16.2 months (range, 9 –20 months) after initial 188Re-MAG3–filled balloon dilation, no further treatment was necessary in two patients (patients 1 and 3) (Fig 1), and further 188Re-MAG3– filled balloon dilation or stent placement was performed in the remaining three patients. Of these three patients, three additional sessions of 188ReMAG3–filled balloon dilation were
performed for stricture recurrence during the follow-up period of 20 months in one patient (patient 2). However, in this patient, the treatment interval increased from 1.3 months to 5 months after 188Re-MAG3–filled balloon dilation, so the patient has been satisfied with this treatment. In another patient (patient 4), one additional session of 188Re-MAG3–filled balloon dilation was necessary because of stricture recurrence 4 months after the initial balloon dilation (Fig 2). In the other patient (patient 5), a polytetrafluoroethylene-covered retrievable nitinol stent (Taewoong Medical,
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Ilsan, Korea) was inserted 3 months after 188Re-MAG3–filled balloon dilation because of stricture recurrence, although this stent was removed 1 week later because of stent migration. The patient refused further 188Re-MAG3– filled balloon dilation at that time and currently has dysuria similar to that he experienced before 188Re-MAG3–filled balloon dilation. The treatment interval ranged from 3 to 20 months for one session of 188ReMAG3–filled balloon dilation for all five patients. The mean and median treatment intervals increased from 2.2 months and 1.5 months, respectively, before 188Re-MAG3–filled balloon dilation to 10.7 months and 6.5 months, respectively, after 188Re-MAG3–filled balloon dilation.
DISCUSSION In the present study, we observed an increase of treatment interval or no stricture recurrence in four of five patients. After this procedure, the mean and median treatment intervals increased by a factor of more than four compared with the intervals before 188 Re-MAG3–filled balloon dilation. Moreover, 188Re-MAG3–filled balloon dilation in all five patients was performed while patients were under moderate sedation on an outpatient basis. Our results are preliminary because the patient population was very small. The improvements noted with 188 Re-MAG3–filled balloon dilation compared with conventional balloon dilation may have been caused by the ionizing irradiation in the former procedure. When it is considered that the success of endovascular irradiation to control recurrent arterial narrowing is based on the concept that restenosis is primarily an excessive healing phenomenon secondary to mechanical injury (12,13), the same treatment rationale can be applied to a urethral stricture secondary to trauma or anastomosis. Increased epithelial and submucosal thickness in canine urethras was observed after covered stent placement, which was reduced by 188 Re-MAG3–filled balloon dilation (9,10). Histologically, tissue hyperplasia consists of richly vascularized connective tissue with new capillary formation and numerous fibroblasts in the submucosa (9,14). Irradiation of
the human urethra may inhibit the cellular proliferative response by mechanisms similar to those observed during irradiation-induced suppression of the proliferative response in arterial cells (15,16). In the treatment of urethral strictures, 188Re-MAG3–filled balloon dilation has several advantages compared with intraurethral brachytherapy with a 192Ir source. First, -irradiation caused by 188Re has a low penetration depth, with a maximum of 11 mm, minimizing the exposure to patient and operator and decreasing the potential damage to adjacent normal tissue. By contrast, 192Ir, a ␥-emitter, is deeply penetrating and is not effectively shielded by standard lead aprons. Second, self-centering irradiation is possible with 188Re-MAG3– filled balloon dilation as a result of the properties of equidistant radiation from the balloon surface. By contrast, deviation of a catheter-based 192Ir source by as little as several millimeters from the center can lead to significant differences in dose distribution to the urethral wall (17,18). Third, compared with solid 192Ir sources, which use expensive afterloading devices, the 188Re-MAG3–filled balloon dilation system can be used with standard balloon dilation technology. Fourth, the target lesion in our study can be dilated with conventional or cutting balloon catheters before -irradiation. The mechanical dilation of the stenosed urethra can lacerate the strictured mucosa and possibly substitute for urethrotomy. We think laceration of the strictured mucosa before -irradiation is prerequisite for better results because elastic recoil predominate over irradiation effect in nonlacerated lumen. In our study, the chosen radiation dose was 20 Gy or 30 Gy at a depth of 1 mm into the tissue from the balloon surface. This dose was within the range of doses of intraurethral -irradiation used in previous studies, which ranged from 15 Gy to 40 Gy at a 1-mm tissue depth from the balloon surface, although the data were obtained in a canine urethral model (9,10) and transferred to the human setting. We avoided higher doses of 40 Gy because severe fibrosis and degeneration of the muscularis propria were reported when 48 –90 Gy at a 1-mm tissue depth were delivered with hol-
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mium Ho 166 –impregnated stents in a canine esophageal model (19). When it is taken into account that doses of 6 –16 Gy at a 1-cm tissue depth were used with a 192Ir source in the treatment of benign strictures of the urethra or bronchi (5,8,18,20), the radiation dose used in the present study, 20 –30 Gy at 1-mm tissue depth, can be considered low even though direct comparison of - and ␥-irradiation is not accurate. Patients treated with high-dose brachytherapy can experience irradiation-associated toxicities such as fever or epididymitis. In a previous report, such adverse events were reported in four of 17 patients (8). The three patients who experienced stricture recurrence after 188Re-MAG3– filled balloon dilation had a longer duration between the onset of urethral stricture and initial balloon dilation than did the two patients who did not experience stricture recurrence. In addition, the UroLume stent was incompletely removed from one patient, who experienced stricture recurrence 3 months after 188Re-MAG3–filled balloon dilation, which suggests that the remaining stent fragments may have continued to irritate the urethral mucosa or submucosa. Therefore, the milieu of the urethral tissue and its surroundings seem to be strongly associated with the clinical outcome. The adverse events of temporary dysuria in three patients in the present study suggest that congestion and edema of the urethral mucosa can occur and cause dysuria. In previous reports of 192Ir ␥-irradiation for urethral strictures (5,8), Foley catheters were kept in place for 1– 6 weeks to prevent edema-induced dysuria. After observing dysuria in three patients, we inserted Foley catheters for 2 weeks in the two patients treated subsequently. Our findings suggest that temporary Foley catheter placement should be performed after 188Re-MAG3–filled balloon dilation for urethral strictures. We assume that this kind of 188ReMAG3–filled balloon dilation might be applied to benign strictures of other nonvascular luminal organs such as the ureter, airway, or esophagus because the stricture mechanism and underlying histologic background would be similar. The major limitation of this study was its lack of urologic flowmetry in-
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formation. Urologic flowmetry gives an excellent indication of the urodynamic success of the endoluminal treatment. However, the patients were monitored in the department of urology in their local hospital. Therefore, timely urologic flowmetry was not performed. Our decision for repeat intervention was based on patients’ symptoms, primarily dysuria. We assessed the clinical success of the treatment by calculating the intervals between the successive treatment sessions. Another limitation of this study was the small number of patients. However, this study was performed to achieve an initial experience with 188 Re-MAG3–filled balloon dilation. For future trials, a randomized comparison with intraurethral ␥-irradiation for recurrent urethral strictures will be necessary. Last, there is a risk of balloon rupture with the risk of leakage and spillage of a -emitter into the urinary system as well into adjacent tissue in case of coincident urethral wall rupture. Utmost care, such as avoidance of excessive pressure, has to be taken to prevent balloon rupture. In case of balloon rupture, full hydration of the patient and stimulation of diuresis and urination for fast excretion of the radioisotope can minimize radiation hazard (9,21). In summary, the present data suggest that 188Re-MAG3–filled balloon dilation shows promise in preventing or delaying stricture recurrence in patients with recurrent urethral strictures. References 1. De Vocht TF, van Venrooij GE, Boon TA. Self-expanding stent insertion for urethral strictures: a 10-year follow-up. BJU Int 2003; 91:627–630. 2. Albers P, Fichtner J, Bruhl P, et al.
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