TARGETED TRANSURETHRAL MICROWAVE THERMOTHERAPY VERSUS ALPHA-BLOCKADE IN BENIGN PROSTATIC HYPERPLASIA: OUTCOMES AT 18 MONTHS

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1 ADULT UROLOGY TARGETED TRANSURETHRAL MICROWAVE THERMOTHERAPY VERSUS ALPHA-BLOCKADE IN BENIGN PROSTATIC HYPERPLASIA: OUTCOMES AT 18 MONTHS BOB DJAVAN, CHRISTIAN SEITZ, CLAUS G. ROEHRBORN, MESUT REMZI, MITRA FAKHARI, MATTHIAS WALDERT, ALI BASHARKHAH, BERNHARD PLANZ, MIKE HARIK, AND MICHAEL MARBERGER ABSTRACT Objectives. To compare directly the efficacy, safety, and durability of targeted transurethral microwave thermotherapy with that of alpha-blocker treatment for lower urinary tract symptoms of benign prostatic hyperplasia. Methods. In a randomized, controlled clinical trial, 52 patients with lower urinary tract symptoms due to benign prostatic hyperplasia received terazosin treatment and 51 underwent microwave treatment under topical anesthesia. The patient evaluation included the International Prostate Symptom Score, peak flow rate, and quality-of-life score before microwave treatment or initiation of terazosin treatment and at periodic intervals thereafter up to 18 months. Results. The mean International Prostate Symptom Score, peak flow rate, and quality-of-life score all improved significantly in both groups by 6 months. However, the magnitude of improvement was significantly greater in the microwave group than in the terazosin group. The significant between-group differences observed at 6 months in the mean International Prostate Symptom Score, peak flow rate, and quality-of-life score were fully maintained at 18 months, at which time the improvements in these three outcome measures were significantly greater (P ), by 35%, 22%, and 43%, respectively, in the microwave group than in the terazosin group. The actuarial rate of treatment failure at 18 months was significantly greater by sevenfold in the terazosin group. Adverse events were generally infrequent and readily manageable in both groups. Conclusions. Although the initial onset of terazosin action was more rapid, the longer term clinical outcomes of targeted microwave treatment were markedly superior. The more favorable results in patients who underwent microwave treatment were maintained for at least 18 months. UROLOGY 57: 66 70, , Elsevier Science Inc. Medical management with alpha-adrenergic receptor blocking agents is the most frequently adopted initial option for patients with lower urinary tract symptoms (LUTS) of benign prostatic hyperplasia (BPH). Alpha-blockade with prazosin analogues such as terazosin or the more recently introduced alpha 1A -adrenoceptor subtype-selective drug tamsulosin is effective in most From the Department of Urology, University of Vienna, Vienna, Austria; and Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas Reprint requests: Bob Djavan, M.D., Ph.D., Department of Urology, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria Submitted: June 23, 2000, accepted (with revisions): August 11, 2000 patients with BPH and LUTS and has a rapid onset. On the basis of a recent meta-analysis, these agents are similar in their effectiveness; however, their side-effect profiles differ. 1 The limitations of alphablocking agents are chiefly their side effects and the lack of efficacy in some patients. Transurethral microwave thermotherapy affords a minimally invasive alternative to medical management. The comparative merits of these two approaches to LUTS therapy have been reviewed elsewhere. 2 A single 1-hour outpatient microwave treatment session can result in long-lasting and substantial improvements in symptoms, flow rates, and quality of life (QOL). 3,4 For instance, in a recent study, 74%, 71%, and 79% of patients improved 50% or more in symptoms, peak urinary 2001, ELSEVIER SCIENCE INC /01/$ ALL RIGHTS RESERVED PII S (00)

2 flow rate (Qmax), and QOL score, respectively, by 12 months after microwave treatment. 5 The additional attractions of this therapeutic approach include the low morbidity and the ability to administer microwave treatment under topical anesthesia only. 6 The feasibility of effective microwave treatment in sessions as short as 30 minutes has recently been reported. 7 Also, patients with acute urinary retention due to BPH have been found to be responsive to microwave treatment. 8 A direct comparison of the safety and efficacy between alpha-blockade and microwave treatment has not previously been reported. However, a recent, randomized controlled trial demonstrated markedly superior clinical outcomes at 6 months in patients who underwent microwave therapy compared with those who received alpha-blocking agents. 9 Although the effects of microwave treatment have been shown to be durable for at least as long as 3 years, 10 it remained unclear whether the observed differences in outcome at 6 months between microwave and alpha-blocking therapy might be maintained with longer term follow-up. The present investigation, based on the 18-month follow-up of the patients in the recent randomized trial, was designed to address this question. MATERIAL AND METHODS PATIENTS The participants in this randomized controlled clinical trial at the University of Vienna consisted of 103 patients with moderate to severe LUTS due to BPH. For inclusion in the study, candidates must have been 45 to 85 years old and presented with an International Prostate Symptom Score (IPSS) of 9 or greater; a Qmax less than 12 ml/s with a voided volume of 150 ml or greater; and a prostatic urethral length of 30 to 50 mm as determined by transrectal ultrasound. Patients were excluded on the basis of a history of alpha-blocker usage within the 3 months before study entry, finasteride treatment, prostate surgery or other prostate procedure; a postvoid residual volume greater than 250 ml; neurogenic bladder; acute urinary retention; prostate cancer; prostatitis; bladder cancer; or a prostate volume greater than 100 cm 3. After providing informed written consent, the patients were randomly allocated to terazosin treatment (n 52) or targeted transurethral microwave treatment (n 51). DATA COLLECTION Before treatment, patients furnished their medical history and underwent a physical examination. The pretreatment assessment also included transrectal ultrasound imaging, serum prostate-specific antigen (PSA) assays, and uroflowmetry (Qmax). For IPSS determination, patients completed a selfadministered questionnaire, which included a question to establish the QOL score by the World Health Organization method. Follow-up evaluations of the IPSS, Qmax, and QOL score were conducted during the clinic visits at 2 weeks, 6 weeks, 3 months, 6 months, and 18 months after initiation of terazosin treatment or administration of microwave treatment. TERAZOSIN THERAPY The alpha-blocking regimen comprised 1 mg terazosin (Abbott Laboratories, North Chicago, Ill) daily for 3 days followed by 2 mg daily for 1 week and then 5 mg daily for 2 weeks. In patients attaining less than 35% IPSS improvement compared with baseline, the terazosin dose was increased to 10 mg daily. Terazosin therapy was continued throughout the remainder of the 18-month follow-up period. MICROWAVE TREATMENT Targeted thermoablation of obstructive prostatic tissue was performed using the Targis microwave system (Urologix, Minneapolis, Minn) under topical urethral anesthesia. Microwave power was delivered incrementally to achieve an intraurethral thermosensor temperature of 40 1 C. After the target temperature was reached, microwave power was applied continuously for 1 hour. After treatment, all microwave patients were catheterized for 24 hours, at which time they returned to the clinic for a voiding trial. Patients unable to void after 24 hours remained catheterized and were re-evaluated for the ability to void at 1 and 2 weeks after treatment. STATISTICAL ANALYSIS Data were analyzed using the Scientific Package for Social Sciences, version , statistical software (SPSS, Chicago, Ill). The mean IPSS, Qmax, and QOL score and the corresponding 95% confidence intervals (95% CIs) were calculated. Within-group and between-group differences were evaluated by repeated measures analysis of variance or Student s t test on a two-tailed basis. Differences in the percentages of patients achieving various cumulative improvement percentiles were assessed by the Mann-Whitney U test with last available data carried forward. Actuarial treatment failure rates were evaluated by Kaplan-Meier analysis, and significant between-group differences in failure rate were assessed by log-rank test. RESULTS The baseline patient age, prostate and transition zone volumes, circulating PSA concentration, IPSS, Qmax, and QOL score were similar between the two groups. The changes in the mean IPSS, Qmax, and QOL score throughout the study period are depicted in Figure 1. SYMPTOMS The mean IPSS improved significantly (P ) by 6 months in both treatment groups compared with baseline (Fig. 1). However, the magnitude of the improvement was greater in the microwave group. Thus, the mean IPSS at 6 months in the microwave group (6.8, 95% CI 6.2 to 7.5) was 38% lower (P ) than that in the terazosin group (11.0, 95% CI 10.2 to 11.9). Furthermore, 78% of the microwave group achieved a 50% or greater improvement in IPSS compared with 33% of the terazosin group (P ). The proportion of microwave patients with absolute IPSS improvements of 3 or greater (100%) or 4 or greater (100%) at the last follow-up visit 6 months or less after study entry was significantly larger UROLOGY 57 (1),

3 months of 35% was statistically significant (P ). PEAK FLOW RATE The Qmax increased significantly (P ) compared with the baseline in both groups by 6 months and remained stable thereafter (Fig. 1). The mean Qmax at 6 months in the microwave group (13.9 ml/s, 95% CI 13.2 to 14.6) was 19.8% higher than that in the terazosin group (11.6 ml/s, 95% CI 11.2 to 12.1). The proportion of microwave patients experiencing a 50% or greater Qmax increase at 6 months (65%) markedly exceeded (P ) that of terazosin recipients (10%). At the last follow-up visit 6 months or less after study entry, the proportion of microwave patients with absolute Qmax improvements of 3 ml/s or greater (86%) or 4 ml/s or greater (72%) was significantly higher (P ) than that of the terazosin group (36% and 12%, respectively). At 18 months, the mean Qmax remained similar to the 6-month value in both groups. In the microwave group, the mean Qmax at 18 months (13.8 ml/s, 95% CI 13.2 to 14.5) was 22% higher (P ) than that of terazosin patients (11.3 ml/s, 95% CI 10.9 to 11.7). QOL SCORE The pattern of change in the mean QOL score paralleled that in the mean IPSS (Fig. 1). After declining significantly in both groups by 6 months (P ), the mean QOL score remained near the 6-month level at 18 months. Significant betweengroup differences were, however, apparent at both 6 and 18 months. Thus, the mean microwave group QOL score at 6 months (1.3, 95% CI 1.0 to 1.5) and 18 months (1.3, 95% CI 1.0 to 1.9) was 38% and 43% lower (P ), respectively, than that of the terazosin group at 6 months (2.1, 95% CI 1.9 to 2.4) and 18 months (2.3, 95% CI 2.1 to 2.5). FIGURE 1. Mean (a) IPSS, (b) Qmax, and (c) QOL score in terazosin (closed circles) and microwave (open circles) patients before treatment and during follow-up. Numbers of observations (n) are shown by each data point. Error bars indicate 95% CI. P values are derived from between-group comparisons at the respective time points. (P and P 0.007, respectively) than that of terazosin patients (88% and 86%, respectively). At 18 months, the mean IPSS in both groups remained comparable to the 6-month values. The between-group difference in the mean IPSS at 18 TREATMENT FAILURE Terazosin therapy was considered a failure if the patients discontinued their medication because of either ineffectiveness or side effects. Microwave therapy was considered a failure if the patients required further LUTS therapy such as transurethral resection of the prostate. By 18 months, terazosin therapy had failed in 21 patients, in 13 patients because of ineffectiveness and in 8 because of side effects. Subsequent to terazosin failure, 19 of these patients underwent microwave treatment and 2 underwent transurethral resection of the prostate. Microwave therapy failed in 3 patients by 18 months who then underwent surgery. The actuarial rate of treatment failure at 18 months in the terazosin group (41%, 95% CI 29% to 56%) signif- 68 UROLOGY 57 (1), 2001

4 microwave treatment were urinary tract infection and loss of ejaculate. The cases of urinary tract infection were managed uneventfully by antibiotic medications, with no cases of persistent bacteriuria observed. Catheterization after microwave treatment was required for no longer than 24 hours in 90% of patients, and no microwave patient required catheterization for more than 2 weeks. FIGURE 2. Actuarial treatment failure rate, based on Kaplan-Meier analysis, in the terazosin (solid line) and microwave (dashed line) groups. P value corresponds to between-group difference by log-rank test. Numbers of patients at risk at the indicated time points are displayed above the abscissa. TABLE I. Adverse events Terazosin Group* Microwave Group* Adverse Event 6 mo 18 mo 6 mo 18 mo Dizziness Asthenia Headache Hypotension Nausea Postural dizziness Urinary tract infection Epididymitis Hemospermia Loss of ejaculate Urinary retention 1 wk in duration * Number of adverse events occurring between baseline and 6 months and between 6 and 18 months. icantly exceeded (P ) that in the microwave group (5.9%, 95% CI 2.0% to 17.0%) by approximately sevenfold (Fig. 2). ADVERSE EVENTS Most adverse events were encountered during the first 6 months, with fewer occurring in the interval from 6 to 18 months (Table I). The adverse events in the terazosin group from baseline to 6 months and from 6 months to 18 months totaled 17 and 6, respectively, compared with 7 and 5, respectively, for the microwave group. The most commonly occurring adverse events of terazosin were dizziness, asthenia, and headache; those for COMMENT The present data reveal that the superior clinical outcomes after microwave treatment compared with alpha-blockade previously demonstrated at 6 months 9 are fully maintained at 18 months. Significantly more favorable results at 18 months were observed in IPSS, Qmax, and QOL, and no evidence of a diminution in the between-group differences observed at 18 months compared with at 6 months was found. The magnitude of symptomatic improvement in the terazosin group was similar to that reported in prior investigations of alphablockade, and consequently the difference in improvement compared with microwave patients is unlikely to be due in any substantial part to inadequate terazosin dose titration. Adverse events in both groups were infrequent and readily manageable. The types of adverse events experienced by the two groups were distinct and nonoverlapping. The additional adverse events occurring in the 6 to 18-month interval were of comparable frequency in the terazosin and microwave groups. The limitations of the present study included the investigation of only a single alpha-blocking agent and the lack of a placebo or sham arm and placebo lead-in period. Nonetheless, in previous studies, marked differences have not been apparent in the magnitude of placebo effects in terazosin recipients 11,12 compared with that of sham effects in microwave patients. 3,4 Furthermore, improvements in the mean IPSS and Qmax with terazosin and microwave treatment have generally exceeded those of a placebo and sham procedure, respectively, by twofold to sevenfold. The treatment failure rate was significantly lower in the microwave group. This difference should, however, be interpreted with caution, since qualitatively different criteria were applied for scoring failure. Unlike terazosin recipients, microwave patients did not, for example, have the alternative of discontinuing treatment. Nevertheless, the sevenfold magnitude in the difference at 18 months was striking. Most early failures in the terazosin group were due to side effects; later failures were predominantly ascribable to a lack of efficacy. One advantage of terazosin, as previously described, 9 is its more rapid onset of action. Maximal UROLOGY 57 (1),

5 effects were manifested within 6 weeks compared with 6 months for microwave treatment. The earlier onset of action with alpha-blockade and the greater long-term efficacy of microwave treatment suggest the potential advantages of combining the two modalities, either sequentially or concurrently. This possibility has recently been investigated in a randomized controlled trial of 41 patients with BPH who underwent microwave treatment with or without neoadjuvant and adjuvant tamsulosin administration. The combination regimen resulted in significantly lower mean IPSSs at 2 weeks and 6 weeks than those of the microwave-only group. 13 Thus, neoadjuvant and adjuvant alpha-blockade combined with microwave treatment might promote early relief and more substantial long-term improvement. However, recent evidence suggests even greater early improvement after microwave treatment in patients receiving an intraurethral prostatic bridge-catheter compared with neoadjuvant and adjuvant tamsulosin administration. 14 CONCLUSIONS Terazosin treatment rapidly improves symptoms, voiding function, and QOL in patients with BPH and LUTS and may be preferred by some patients over a procedural intervention. Nevertheless, markedly superior outcomes are demonstrable by 6 months in patients receiving microwave treatment, and this superiority is fully maintained for at least as long as 18 months. This modality may be preferred by patients desiring a single definitive treatment conferring durable, substantial benefit. REFERENCES 1. Djavan B, and Marberger M: A meta-analysis on the efficacy and tolerability of 1 -adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol 36: 1 13, Djavan B, Larson TR, Blute ML, et al: Transurethral microwave thermotherapy: what role should it play versus medical management in the treatment of benign prostatic hyperplasia? Urology 52: , Larson TR, Blute ML, Bruskewitz RC, et al: A highefficiency microwave thermoablation system for the treatment of benign prostatic hyperplasia: results of a randomized, sham-controlled, prospective, double-blind, multicenter clinical trial. Urology 51: , Roehrborn CG, Preminger G, Newhall P, et al: Microwave thermotherapy for benign prostatic hyperplasia with the Dornier Urowave: results of a randomized, double-blind, multicenter, sham-controlled trial. Urology 51: 19 28, Djavan B, Bursa B, Basharkhah A, et al: Pretreatment prostate-specific antigen as an outcome predictor of targeted transurethral microwave thermotherapy. Urology 55: 51 57, Djavan B, Shariat S, Schäfer B, et al: Tolerability of high energy transurethral microwave thermotherapy with topical urethral anesthesia: results of a prospective, randomized, single-blinded clinical trial. J Urol 160: , Hammond GW: Targis microwave therapy, 60 minutes vs. 30 minute treatment: 1 year results. J Urol 163(suppl): 271, Djavan B, Seitz C, Ghawidel K, et al: High-energy transurethral microwave thermotherapy in patients with acute urinary retention due to benign prostatic hyperplasia. Urology 54: 18 22, 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: , 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: , Lepor H, Williford WO, Barry MJ, et al: The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med 335: , Roehrborn CG, Oesterling JE, Auerbach S, et al, and the HYCAT Investigator Group: The Hytrin Community Assessment Trial study: a one-year study of terazosin versus placebo in the treatment of men with symptomatic benign prostatic hyperplasia. Urology 47: , Djavan B, Shariat S, Fakhari M, et al: Neoadjuvant and adjuvant -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: , Djavan B, Fakhari M, Shariat S, et al: A novel intraurethral prostatic bridge catheter for prevention of temporary prostatic obstruction following high energy transurethral microwave thermotherapy in patients with benign prostatic hyperplasia. J Urol 161: , UROLOGY 57 (1), 2001