Cooled thermotherapy for the treatment of benign prostatic hyperplasia: durability of results obtained with the Targis System

ADULT UROLOGY

COOLED THERMOTHERAPY FOR THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA: DURABILITY OF RESULTS OBTAINED WITH THE TARGIS SYSTEM PAUL D. MILLER, CHRISTOF KASTNER, ERNEST W. RAMSEY,

AND

KEITH PARSONS

ABSTRACT Objectives. To evaluate the durability of benefit associated with cooled high-energy thermotherapy (cooled thermotherapy) using the Targis System with data extending to 5 years after treatment. Methods. At three centers in Canada and the United Kingdom, 150 patients with benign prostatic hyperplasia underwent cooled thermotherapy with the Targis System. This was an outpatient procedure performed without general or regional anesthesia. Patients were followed up at 1 and 6 weeks, 3, 6, and 12 months, and yearly to 5 years. Results. Patients were evaluated at 1, 2, 3, 4, and 5 years after treatment (n ⫽ 132, 111, 90, 77, and 59, respectively). At these intervals, the American Urological Association symptom scores improved by 11.7 (57%), 12.1 (58%), 11.5 (53%), 10.1 (47%), and 10.6 (47%) points (P ⬍0.0001 for each), the peak flow rates improved by a mean of 4.0 (57%), 4.0 (56%), 3.4 (48%), 3.3 (47%) and 2.4 (37%) mL/s (P ⬍0.0001 for each), and quality-of-life scores improved by 2.6, 2.6, 2.5, 2.3, and 2.3 points (P ⬍0.0001 for each). At least a 50% improvement in the American Urological Association symptom score was observed in 63% to 68% of patients available for follow-up at years 1, 2, and 3 and 50% and 51% of patients available for follow-up at years 4 and 5, respectively. Four patients required repeated microwave thermotherapy, 27 required subsequent invasive treatments, 1 permanent catheterization, 11 required alpha-blockers, and 1 antiandrogen therapy. Conclusions. Cooled thermotherapy with the Targis System produces durable improvements in symptoms, quality of life, and flow rates to at least 5 years after treatment. UROLOGY 61: 1160–1165, 2003. © 2003 Elsevier Inc.

A

number of innovative technologies have been introduced in recent years for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH). These new treatments generally involve the delivery of heat to the prostate, causing tissue destruction with the aim of relieving obstruction. Variations in transurethral resection of the prostate (TURP) have been introduced using lasers or loops. These remain “invasive” procedures, performed in a surgical suite under general or spinal anesthesia, and usually reFrom the Surrey and Sussex NHS Trust Hospital, Surrey, United Kingdom; University of Manitoba Health Sciences Centre, Winnipeg, Manitoba, Canada; and Royal Liverpool University Hospital, Liverpool, United Kingdom Reprint requests: Paul D. Miller, M.D., Department of Urology, East Surrey Hospital, Canada Avenue, Redhill RH1 5RH, United Kingdom Submitted: March 19, 2002, accepted (with revisions): January 21, 2003

1160

© 2003 ELSEVIER INC. ALL RIGHTS RESERVED

quire an overnight stay and delayed recovery. “Less invasive” procedures include transurethral microwave thermotherapy, transurethral needle ablation, interstitial laser coagulation, and high-intensity focused ultrasonography. High-intensity focused ultrasonography has required general or spinal anesthesia. Transurethral needle ablation and interstitial laser coagulation may be performed with urethral lidocaine and/or oral or intravenous analgesia, but intravenous sedation or prostate blocks have often been required. Cooled thermotherapy is performed as a single outpatient treatment using urethral lidocaine in combination with oral and/or intramuscular sedoanalgesia. Cooled thermotherapy has been used extensively worldwide with a variety of different thermotherapy devices. The Targis System is a second-generation microwave device that uses a dipolar, impedance-matched antenna that effectively delivers 0090-4295/03/$30.00 doi:10.1016/S0090-4295(03)00337-6

heat to the prostate while cooling to protect the adjacent urethra and bladder neck. We previously reported our 1-year1 and 3-year2 follow-up data with the Targis System. Those reports illustrated excellent short-term results for this minimally invasive treatment, but few data have been available on the long-term efficacy of the cooled high-energy thermotherapy procedure with the Targis System. We report our 5-year follow-up data on patients enrolled at three centers in Canada and the United Kingdom. MATERIAL AND METHODS The Targis (formerly T3) System is composed of a control unit containing the microwave generator, software, and coolant system and a procedure kit containing the three disposable components: microwave delivery system, rectal thermosensing unit, and coolant bag. A description of the components has been previously published.1 In the first international study with the Targis System, 150 men were enrolled in three investigational centers: University of Manitoba Health Sciences Centre (Winnipeg, Manitoba, Canada); East Surrey Hospital (East Surrey, UK); and Royal Liverpool University Hospital (Liverpool, UK). To be included in the study, patients had to be between 45 and 85 years of age, have BPH, and exhibit an American Urological Association (AUA) score of 9 or more, two peak flow rates each 12.0 mL/s or less, and a minimal voided volume of 125 mL. Patients were excluded from the study if they showed evidence of urinary tract infection, urinary retention, gross hematuria not due to BPH, prostate size greater than 100 cm3, urinary catheterization within 2 weeks preceding treatment, and any coexisting illnesses such as prostate or bladder cancer that could affect urogenital function. Use of alpha-blockers, antiandrogens, and 5-alpha reductase inhibitors was also prohibited before and during the study period. All patients underwent a 60-minute treatment performed in an outpatient setting without the presence of an anesthetist and without recourse to intensive patient monitoring. Follow-up visits were at 1 and 6 weeks and 3, 6, and 12 months after treatment. The study was later extended to include follow-up data collection at 2, 3, 4, and 5 years after treatment.

RESULTS One hundred fifty patients were enrolled in this study. The mean age at enrollment was 66 ⫾ 7 years (range 50 to 81). The mean prostate volume at enrollment was 40.4 ⫾ 18.1 cm3 (range 7.2 to 94.4). The mean prostate-specific antigen level at baseline was 3.9 ⫾ 3.2 ng/mL. Through 5 years of follow-up, 59 patients completed their evaluation, 11 patients missed their visit, 26 withdrew consent or were lost to followup, and 10 patients died of unrelated causes. Of the 150 patients, a total of 44 (29%) underwent additional BPH treatment at some point before 5 years. Of these 44 patients, 4 underwent repeated microwave treatment, 27 underwent alternative invasive treatment, 1 had a permanent catheter placed, 11 received alpha-blockers, and 1 received antiandrogen therapy. Figure 1 shows the Kaplan-Meier surUROLOGY 61 (6), 2003

FIGURE 1. Kaplan-Meier curve of freedom from alternative treatment.

vival curve for the cumulative percentage of patients free of retreatment to 5 years after therapy. Table I shows the paired results for the AUA symptom score, peak flow rate, and quality-of-life assessment at 1, 2, 3, 4, and 5 years of follow-up. Quality of life was measured by one question: “If you were to spend the rest of your life with your prostate symptoms just the way they are now, how would you feel about that?” Responses ranged from “delighted” to “terrible” (score 0 to 6). The AUA symptom score decreased significantly and remained stable during the 5 years of followup. One year after treatment, the AUA scores had improved by a mean of 11.7 points or 57% (P ⬍0.0001). This was maintained through years 2, 3, 4, and 5, with a mean improvement of 12.1 (58%), 11.5 (53%), 10.1 (47%), and 10.6 (47%), respectively (P ⬍0.0001 at each interval). Significant improvement (P ⬍0.001) was seen in all seven constituent questionnaire responses comprising the AUA symptom score. Peak flow rates improved by a mean of 4.0 mL/s (57%) at 1 year, 4.0 mL/s (56%) at 2 years, 3.4 mL/s (48%) at 3 years, 3.3 mL/s (47%) at 4 years, and 2.4 mL/s (37%) at 5 years. The improvement was statistically significant (P ⬍0.0001) at all intervals. The quality-of-life score at 1, 2, 3, 4, and 5 years improved by 2.6, 2.6, 2.5, 2.3, and 2.3 points, respectively (P ⬍0.0001 at all points). The improvement in symptom score, peak flow rate, and quality of life was independent of prostate volume and prostate-specific antigen level at baseline. Figure 2 shows the categorical percentage of improvement in AUA symptom score and peak flow rate plotted against the percentage of patients in each category, by follow-up interval. At least a 50% decrease in AUA symptom score was seen in between 63% and 68% of patients at years 1, 2, and 3, decreasing to 50% and 51% at years 4 and 5, respectively. At least an 80% decrease in symptom score was seen in approximately 25% of patients (range 23% to 27%) at each year of follow-up 1161

TABLE I. Improvements from baseline in AUA, peak flow, and quality of life Improvement From Baseline AUA* n Mean (SD) Peak flow (mL/s)* n Mean (SD) QOL* n Mean (SD)

Baseline

1 yr

2 yr

3 yr

4 yr

5 yr

150 20.0 (5.8)

132 11.7 (7.3)

111 12.1 (6.6)

89 11.5 (7.6)

77 10.1 (8.1)

57 10.6 (8.5)

141 8.3 (2.5)

115 4.0 (4.4)

93 4.0 (4.2)

76 3.4 (4.1)

57 3.3 (4.3)

49 2.4 (3.5)

150 4.2 (1.1)

130 2.6 (1.7)

111 2.6 (1.6)

90 2.5 (1.7)

77 2.3 (1.5)

59 2.3 (1.7)

KEY: AUA ⫽ American Urological Association; QOL ⫽ quality of life. * All paired comparisons are statistically significant (P ⬍0.0001).

through year 4, decreasing to 18% at year 5. At least a 50% increase in peak flow rate was seen in 31% to 47% of patients during the 5 years of follow-up and at least an 80% increase in peak flow rate was seen in 22% to 26% of patients. Table II shows a detailed assessment of quality of life. Before treatment, 70.0% scored from 4 to 6 (ie, were “mostly dissatisfied, unhappy, or felt terrible” about their symptoms). This decreased to 9.2%, 7.2%, 7.8%, 9.0%, and 8.5% at 1, 2, 3, 4, and 5 years of follow-up, respectively, and scores of 0 to 2 (ie, “delighted, pleased, or mostly satisfied” with their symptoms) increased to 76.9%, 77.5%, 75.6%, 70.5%, and 74.6% at 1, 2, 3, 4, and 5 years of follow-up, respectively. We also defined responders at 5 years on the basis of the change in AUA symptom score likely to be perceived as a change by patients.3 In this analysis, a baseline AUA score greater than 20 indicated severe symptoms and a baseline score from 9 to 19 points was considered moderate. For a patient with moderate symptoms, a decrease of 7 or more points would be perceived as a marked improvement, 3 to 6 points as moderate improvement, 1 to 2 points as slight improvement, and 0 or less as no improvement. For patients with severe symptoms, a decrease of 13 or more points would be perceived as marked improvement, 7 to 12 as moderate improvement, 3 to 6 as slight improvement, and 2 or less as no improvement. Twentyseven patients had moderate symptoms at baseline, 14 of whom (52%) had marked improvement, 7 (26%) moderate improvement, and 6 (22%) no improvement. Of 30 patients with severe symptoms at baseline, 18 (60%) had marked improvement, 8 (27%) moderate improvement, 2 (7%) slight improvement, and 2 (7%) no improvement. Of the 57 patients with data available at 5 years, 82% showed moderate or marked improvement, 32 of whom (56%) had marked improvement in symptoms. The early complications associated with treatment have been previously reported.1,2 Specifi1162

cally, post-treatment morbidity was transient and manageable. After gaining experience with the device and managing patient expectations, urinary tract infection, required pain medication, and posttreatment catheterization were minimized. Complications included a 4.6% rate of loss of ejaculate. In all, 14% of patients required a catheter for more than 7 days. This rate was reduced by the use of adjunctive alpha-blockade therapy.4 No adverse events occurred that were considered by the physician to be serious and related to treatment. COMMENT There is extensive worldwide experience with cooled thermotherapy, much more than with other “less invasive” techniques for the treatment of BPH. Cooled thermotherapy has been shown in numerous studies to be a safe outpatient procedure performed under local anesthesia with or without oral or intramuscular sedoanalgesia and with minimal morbidity. Generally, good improvement in symptoms and quality of life has resulted with modest improvement in flow rates. For most new BPH treatments, long-term data are lacking. Of these treatments, the most extensive long-term experience has been with cooled thermotherapy. Concerns have been raised regarding the durability of the results with microwave thermotherapy because of a high additional retreatment rate with devices using low-energy treatment regimens. A small study by Dahlstrand et al.5 reported that with the Prostatron 2.0 low-energy protocol, the additional treatment rates were 50% to 60% within 3 to 5 years. These additional treatments were generally surgery or medical therapy, with a few undergoing repeat microwave thermotherapy. The Targis System has been shown to achieve high intraprostatic temperatures, resulting in highenergy thermoablation. The antenna design minimizes rectal shutdowns, allowing constant heat delivery. Histologic studies have consistently shown UROLOGY 61 (6), 2003

FIGURE 2. Percentage of improvement in AUA symptom score and peak flow rate.

TABLE II. Frequency of responses to quality of life question Frequency of Responses Time Point (n)

Delighted

Pleased

Mostly Satisfied

Baseline (150) 1 yr (130) 2 yr (111) 3 yr (90) 4 yr (78) 5 yr (59)

0 30 22 20 13 11

1 36 36 25 20 13

4 34 28 23 22 20

(0) (23.1) (19.8) (22.2) (16.9) (18.6)

(0.7) (27.7) (32.4) (27.8) (26.0) (22.0)

(2.7) (26.2) (25.2) (25.6) (28.6) (33.9)

Mixed 40 18 17 15 16 10

(26.7) (13.9) (15.3) (16.7) (20.8) (17.0)

Mostly Dissatisfied 40 7 6 3 5 2

(26.7) (5.4) (5.4) (3.3) (6.5) (3.4)

Unhappy

Terrible

46 4 2 4 1 2

19 1 0 0 0 1

(30.7) (3.1) (1.8) (4.4) (1.3) (3.4)

(12.7) (0.8) (0) (0) (0) (1.7)

Data presented as number of patients, with the percentage in parentheses.

extensive circumferential coagulation necrosis of the prostate while preserving the urethra.6 Additional studies relating benefit to intraprostatic temperature have shown that improvement in symptoms and flow relate to higher temperatures.7 Our UROLOGY 61 (6), 2003

initial results reported with the Targis System have been supported by studies from other centers.8 –11 In the present series, symptom score improvement was approximately 53% to 58% at years 1 to 3, with slight drop off to 46% and 47% at years 4 and 5, 1163

respectively. Flow rate improvement was 4 mL/s at years 1 and 2 for 56% to 57% improvement. Some decrease occurred at years 3, 4, and 5, but the improvement was still highly significant. Quality-oflife improvement was well maintained out to 5 years. A limitation of this study was that the patient numbers decreased with follow-up owing to death, patients lost to follow-up, or patients undergoing alternative treatment. The results reported here only reflect the data collected up to these censoring events and, as such, represent to an extent the responders to treatment. Among noninvasive treatments for BPH, alphablockers remain a popular option. Djavan et al.,12 in a randomized study of 103 men with symptomatic BPH, compared the safety, efficacy, and retreatment rates associated with cooled high-energy thermotherapy with that of alpha-blockade therapy (terazosin). In their study, cooled thermotherapy was found to achieve not only superior longterm efficacy, but also a sevenfold decrease in alternative treatments after cooled thermotherapy (3 of 51 patients) compared with terazosin (21 of 52 patients). The cumulative percentage of patients in the terazosin arm receiving alternative treatment was 41% at 18 months compared with just 5.9% in the cooled thermotherapy arm (P ⬍0.0005). Of the 21 retreatments in the terazosin group, 19 were microwave therapy and two were TURP. All 3 patients seeking alternative treatment in the cooled thermotherapy group underwent TURP. In our study, the cumulative percentage (Kaplan-Meier curve) of patients receiving alternative treatment was 10% at 18 months and 33.9% at 5 years. CONCLUSIONS Cooled high-energy thermotherapy with the Targis System is a safe, durable, outpatient treatment for BPH, requiring no general or regional anesthesia and having minimal morbidity. Improvement in symptoms and quality of life are similar to that after more invasive treatments such as TURP and superior to medical therapy such as alphablockade. Most patients respond to treatment, and the benefit is durable for at least 5 years. The need for additional treatment is greater than that with TURP but significantly less than that with alphablockade. The Targis System may provide the best mix of durable efficacy, low morbidity, and acceptable risk of subsequent treatment compared with alpha-blockade and TURP for men with BPH. REFERENCES 1. Ramsey EW, Miller PD, and Parsons K: A novel transurethral microwave thermoablation system to treat benign 1164

prostatic hyperplasia: results of a prospective multicenter clinical trial. J Urol 158: 112–119, 1997. 2. Ramsey EW, Miller PD, and Parsons K: Transurethral microwave thermotherapy in the treatment of benign prostatic hyperplasia: results obtained with the Urologix T3 device. World J Urol 16: 96 –101, 1998. 3. Barry M, Williford W, Chang Y, et al: Benign prostatic hyperplasia specific health status measures in clinical research: how much change in the American Urological Association symptom index and the benign prostatic hyperplasia impact index is perceptible to patients? J Urol 154: 1770 – 1774, 1995. 4. Djavan B, Shariat S, Fakhari M, et al: Neoadjuvant and adjuvant alpha-blockade improves early results of high energy transurethral microwave thermotherapy for lower urinary tract symptoms of benign prostatic hyperplasia: a randomized, prospective clinical trial. Urology 53: 252–259, 1999. 5. Dahlstrand C, Walden M, and Patterson S: A cost-effectiveness analysis of TURP and TUMT for treatment of BPH: seven-year follow-up (abstract). J Endourol 13(suppl 1): A111, 1999. 6. Larson TR, Bostwick DG, and Corica A: Temperature correlated histopathologic changes following microwave thermoablation of obstructive tissue in patients with benign prostatic hyperplasia. Urology 47: 463–469, 1996. 7. Carter S, and Ogden C: Intraprostatic temperature versus clinical outcome in TUMT: is the response heat-dose dependent? J Urol 151: 416A, 1994. 8. Larson TR, Blute ML, Bruskewitz RC, et al: A high efficiency microwave thermoablation system for the treatment of benign prostatic hyperplasia: results of a randomized, shamcontrolled, prospective, double-blind, multicenter clinical trial. Urology 51: 731–742, 1998. 9. Thalmann GN, Graber SF, Bitton A, et al: Transurethral thermotherapy for benign prostatic hyperplasia significantly decreases infravesical obstruction: results in 134 patients after 1 year. J Urol 162: 387–393, 1999. 10. Djavan B, Roehrborn CG, Shariat S, et al: Prospective randomized comparison of high energy transurethral microwave thermotherapy versus ␣-blocker treatment of patients with benign prostatic hyperplasia. J Urol 161: 139 –143, 1999. 11. Francisca E, Kortmann B, Debruyne F, et al: High energy transurethral microwave thermotherapy (TUMT 2.5): results 4-years following treatment. J Endourol 13(suppl 1): A118, 1999. 12. Djavan B, Seitz C, Roehrborn CG, et al: Targeted transurethral microwave thermotherapy verse alpha-blockade in benign prostatic hyperplasia: outcomes at 18 months. Urology 57: 66 –70, 2001.

EDITORIAL COMMENT This was a three-center study in Canada and the United Kingdom of 150 patients who were initially treated with cooled thermotherapy using the Targis System. This cohort of patients was followed up prospectively using the traditional metrics to determine their response to therapy (eg, symptom score, peak flow rate, quality-of-life score). For all metrics, the 1-year values appear to be durable out to 5 years, and the authors offer this data as evidence that cooled thermotherapy produces durable improvements in symptoms, quality of life, and flow rates at 5 years after treatment. The authors, to their credit, point out that the major weakness of the study is that these are “responder” data. If one goes back to the Results section, initially 150 patients were treated, and at 5 years only 59 patients completed their evaluation. There were 44 patients who went on to alternative therapy, and 47 patients who were lost to follow-up. For the 44 patients who went on to alternative therapy, they use as the denominator the 150 patients to UROLOGY 61 (6), 2003