temporal resolution of urinary morbidity following prostate ...

Int. J. Radiation Oncology Biol. Phys., Vol. 47, No. 1, pp. 121–128, 2000 Copyright © 2000 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/00/$–see front matter

PII S0360-3016(99)00525-8

CLINICAL INVESTIGATION

Prostate

TEMPORAL RESOLUTION OF URINARY MORBIDITY FOLLOWING PROSTATE BRACHYTHERAPY GREGORY S. MERRICK, M.D.,*† WAYNE M. BUTLER, PH.D.,* JONATHAN H. LIEF, PH.D.,*‡ ANTHONY T. DORSEY, M.S.*

AND

*Schiffler Oncology Center, Wheeling Hospital, Wheeling, WV; †Division of Radiation Oncology & Biophysics, George Washington University Medical Center, Washington, DC; ‡Wheeling Jesuit University, Wheeling, WV Purpose: To report the short-term urinary morbidity for prostate brachytherapy patients without a preimplant history of a transurethral resection of the prostate gland and who received prophylactic and prolonged ␣-blockers. ␣-blockers may decrease radiation-induced urethritis and increase urinary flow. Multiple clinical and treatment parameters were evaluated to identify factors associated with increased acute urinary morbidity. Materials and Methods: One hundred seventy consecutive patients without a prior history of a transurethral resection of the prostate gland underwent transperineal ultrasound guided prostate brachytherapy for clinical T1c-T3a carcinoma of the prostate gland. For all patients, an ␣-blocker was initiated prior to implantation and continued at least until the international prostate symptom score (IPSS) returned to baseline levels. Clinical parameters evaluated for short-term urinary morbidity included patient age, clinical T stage, preimplant IPSS (obtained within 3 weeks of implantation), and prostate ultrasound volume. Treatment parameters included the utilization of neoadjuvant hormonal manipulation, the utilization of moderate dose external beam radiation therapy before implantation, the choice of isotope, the urethral dose, the total implant activity in millicuries, and a variety of dosimetric quality indicators (D90 and V100/V150/V200). Catheter dependency and the duration of ␣-blocker dependency was also evaluated. On average, 11.2 IPSS surveys were obtained for each patient. Results: One hundred fifty of the 170 patients (88.2%) had the urinary catheter permanently removed on day 0. Only one patient required an urinary catheter for > 5 days. Two patients (1.2%) required a subsequent transurethral resection of the prostate gland because of prolonged obstructive/irritative symptoms. To date, no patient has developed an urinary stricture or urinary incontinence. The IPS score on average peaked at 2 weeks following implantation. This score returned to within 1 point of the antecedent value at a median of 6 weeks and a mean of 13.3 weeks. At 26 and 50 weeks, 85% and 56% of the patients, respectively, continued with ␣-blockers. Of the clinical and treatment parameters evaluated for short-term urinary morbidity, only variants of the IPSS such as the maximum, maximum increase, and preimplant IPSS values correlated with time to return to the referent zone with p < 0.05. Conclusion: The return of the IPS score to baseline occurred more rapidly in our series than what has previously been reported. The 1.2% incidence of transurethral resections also compares favorably with the published literature. We believe these results may be due to maintaining the average urethral dose to approximately 115% of the prescribed dose and the prophylactic and long-term use of ␣-blockers. © 2000 Elsevier Science Inc. Prostate brachytherapy, Urinary morbidity,

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INTRODUCTION Over the past decade, transperineal ultrasound guided prostate brachytherapy has been increasingly utilized as definitive management for early stage carcinoma of the prostate gland. The results of prostate brachytherapy have been reported to be as favorable as the most positive radical prostatectomy series with a decreased incidence of urinary incontinence and sexual dysfunction (1–5). In addition, significant rectal injury is rare (6). A paucity of data, however, has been published regarding the short-term urinary morbidity following prostate brachytherapy. Almost all patients experience some degree of urinary irritative/obstruc-

tive symptomatology including urinary frequency, dysuria, urgency, interruption of the stream, incomplete voiding, straining, and nocturia; 3%–22% of patients develop acute urinary retention following prostate brachytherapy (4, 7–11). Terk et al. (7) were able to correlate the risk of urinary retention with the preimplant international prostate symptom score (IPSS). A recent controlled study concluded that peri-operative dexamethasone does not significantly alter short-term urinary morbidity (12). The IPSS was developed by the American Urological Association (AUA) in 1992 as a measure of symptomatic relief following prostatectomy for benign prostatic hypertrophy. The generated score resulted in excellent test-retest

Reprint requests to: Gregory S. Merrick, M.D., Schiffler Oncology Center, Wheeling Hospital, 1 Medical Park, Wheeling, WV

26003-6300; E-Mail: [email protected] Accepted for publication 23 November 1999. 121

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reliability and was sensitive to change (13). Recently, the reproducibility of the IPSS index was revalidated (14). Barry et al. (13) reported “the AUA symptom index as clinically sensible, reliable, valid and responsive. It is practical for use in practice and for inclusion in research protocols.” The IPSS index has also been proven a useful tool for evaluating urinary symptomatology following prostate brachytherapy (7). Herein, we report the short-term urinary morbidity for 170 consecutive prostate brachytherapy patients without a preimplant history of a transurethral resection of the prostate gland. ␣-blockers may decrease radiation-induced urethritis by relaxing urinary smooth muscle tone with a subsequent reduction in urinary flow resistance. In all patients, prophylactic ␣-blockers were initiated 2–3 weeks prior to implantation and continued until the IPSS declined at least as low as its preimplant value. Multiple clinical and treatment parameters were evaluated to identify factors associated with increased acute urinary morbidity.

MATERIALS AND METHODS One hundred seventy consecutive patients without a prior history of a transurethral resection of the prostate gland underwent transperineal ultrasound guided prostate brachytherapy from December 1997 through early April 1999 using either 125I or 103Pd for clinical T1c–T3a carcinoma of the prostate gland. The choice of isotope was dependent upon Gleason score. Because of well-documented inaccuracies in Gleason grading, all cases originating from outside institutions were reviewed prior to the formulation of a treatment plan (15). Calculation algorithms and seed parameters used in pre-plans and postoperative dosimetry were those recommended by the American Association of Physicists in Medicine (AAPM) Task Group 43 (TG-43) (16). Sixty-five patients were treated with 125I as monotherapy (145 Gy TG-43 prescribed minimum peripheral dose, mPD), 26 patients received 125I as a boost following moderate dose external beam radiation therapy (110 Gy TG-43 mPD), 8 patients received 103Pd as monotherapy (115 Gy mPD), and 71 patients received 103Pd as a boost (90 Gy mPD). Eighty patients also received neoadjuvant hormonal manipulation to include both an LHRH agonist and antiandrogen secondary to urinary obstructive symptomatology or unfavorable geometry. Moderate dose external beam radiation therapy consisted of 45 Gy to the prostate/ periprostatic region/seminal vesicles/first echelon lymph nodes in 1.8 Gy fractions utilizing high energy photons delivered via a multifield technique with shielding of the posterior half of the rectum via the lateral portals. All fields were treated daily. In 10 103Pd cases, 50.4 Gy in 1.8 Gy fractions was delivered to the above treatment volume prior to implantation. Our patient selection, pre-planning techniques, and intraoperative procedures have previously been

Volume 47, Number 1, 2000

described (6, 12, 17–20). Seven patients at the time of referral were already receiving an ␣-blocker as part of an antihypertensive regimen. For all other patients, an ␣-blocker was initiated 2–3 weeks prior to implantation and continued at least until the IPS score returned to baseline levels. The majority of the patients (156/170) received tamulosin HCl (Flomax, 0.4 – 0.8 mg daily, Nycomed-Amersham, Princeton, NJ). Ten patients received doxazosin mesylate (Cardura, 2–10 mg daily, Pfizer, Inc., New York, NY; Theragenics, Norcross, GA), and four patients received terazosin hydrochloride (Hytrin, 2–10 mg daily, Abbott, North Chicago, IL). Three of the ten doxazosin patients and all four of the terazosin patients had been receiving the ␣-blocker as part of an antihypertensive regimen. Within 2 h of implantation, a spiral CT scan was obtained at 5-mm thickness and 5-mm spacing extending 2-cm above and below the most superior and inferior implanted seeds for postoperative dosimetric evaluation. A urinary catheter and a 10-mm rectal obturator were in place for each patient for the identification of the urethra and anterior rectal mucosa, respectively (6). The actual dose distribution to the prostate/periprostatic region, urethra, and anterior rectal mucosa was generated via a dedicated treatment planning computer (Prowess-3000, SSGI, Chico, CA). In addition, values of the minimal dose received by 90% of the prostate volume (D90) and the percent prostate volume receiving 100%, 150%, and 200% of the prescribed minimal peripheral dose (V100, V150, and V200, respectively) were determined for each patient (18). Urethral dose was defined as a point-dose at the geometric center of the urinary catheter. The average urethral dose was defined as the average of the point-dose on all CT slices passing through the prostate and the maximal urethral dose as the maximal dose on a single CT slice. All prostate volumes and relevant urethral and rectal surfaces including those on the pre-planning ultrasound and postimplant CT were determined by one investigator (GSM). Clinical parameters evaluated for short-term urinary morbidity included patient age, clinical T stage, preimplant IPSS (obtained within 3 weeks of implantation), and prostate ultrasound volume. Treatment parameters evaluated included the utilization of neoadjuvant hormonal manipulation, the utilization of moderate dose external beam radiation therapy before implantation, the choice of isotope (125I versus 103Pd), the urethral dose, the total implant activity in millicuries, the D90, and V100/ V150/V200. Catheter dependency and the duration of ␣-blocker dependency were also evaluated. Serial IPSS surveys were obtained up to 16 times for each patient for a total of 1922 questionnaires according to the schedule in Table 1. The minimum IPSS follow-up for this study group was 8 weeks, the maximum was 80 weeks (mean ⫽ 38.5 weeks, median ⫽ 37.3 weeks) with a mean of 11.2 questionnaires per patient. The number of days between the implant date and the survey date was rounded for some analyses to the nearest scheduled week (the number of respondents at each scheduled point in Table 1 is less than the complete study group of 170 because of

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Table 1. I-PSS survey schedule and results Week

Number of respondents*

Mean IPSS

Mean IPSS difference†

Proportion unreturned§

Proportion on ␣-blockers

1 2 3 4 6 8 12 16 20 26 32 38 44 50 65 80

161 165 158 165 160 167 168 151 143 119 94 89 73 64 34 12

11.99 12.67 12.04 11.99 10.80 10.10 8.72 7.98 6.78 6.17 5.60 5.00 4.00 4.61 4.09 5.17

6.28 6.96 6.44 6.31 5.14 4.44 2.98 2.33 1.24 0.65 0.10 ⫺0.38 ⫺0.79 ⫺0.16 ⫺0.62 1.92

0.788 0.700 0.606 0.553 0.471 0.382 0.340 0.302 0.222 0.158 0.120 0.061 0.050 0.038 0.025 0.013

0.994 0.994 1.000 0.994 0.994 0.988 0.994 0.987 0.944 0.849 0.745 0.670 0.548 0.563 0.529 0.750

Total

1923

* n ⫽ 170, but IPSS surveys were not obtained from all patients in each time interval. † Mean of the difference between IPSS and antecedent IPSS for individual patients. § Proportion of respondents who have not returned to the reference zone of ⫾ 1 of antecedent IPSS.

patient unavailability and other factors). Statistical analyses were performed using SPSS 9.0 software (SPSS Inc., Chicago, IL), which included Kaplan-Meier analysis of the progression of IPSS values and uni- and multivariate analyses to correlate various study parameters.

RESULTS Table 2 details the clinical and treatment parameters of the evaluated patient population. The urinary catheter was removed on the day of implantation in 150 of the 170

Table 2. Patient and treatment characteristics of 170 subjects Parameter

Number

Mean

SD

Median

Age at implant Prostate serum antigen (ng/mL) Gleason score Antecedent I-PSS Ultrasound volume (cm3) Planning volume (cm3) Clinical stage: T1c T2a T2b T2c T3a Patients implanted with isotope: 103 Pd Total activity (mCi) Needles used Seeds implanted 125 I Total activity (mCi) Needles used Seeds implanted Patients treated with: External beam radiation Neo-adjuvant hormones V100 (% volume) V150 (% volume) V200 (% volume) D90 (% 嗱 mPD) Max urethral dose (% 嗱 mPD) Average urethral dose (% 嗱 mPD)

170

66.60 9.15 6.68 5.69 34.94 57.61

6.95 6.39 0.97 3.82 10.03 13.37

68.44 7.40 7.00 5.00 34.30 57.00

147.86 29.99 127.1 45.90 31.82 138.6

27.13 3.30 19.3 18.61 3.08 19.8

146.72 30 129 46.02 32 138

93.6 48.0 23.4 107.1 131.4 112.2

4.6 13.0 6.6 9.0 19.9 12.6

95.0 46.9 21.7 106.8 128.9 110.8

66 38 47 16 3 79 91

97 80

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Fig. 1. The number of patients whose urinary catheter was removed in different time periods after prostrate brachytherapy. Eighty-eight percent of patients were catheter free on day 0, and all but one patient were catheter free by day 5.

implanted patients (88.2%). The pie chart in Fig. 1 illustrates that 10 of the 170 patients (6%) required a urinary catheter for ⬎ 2 days, and 5 of these patients (3%) required a catheter beyond 3 days. One patient was catheter-dependent for ⬎ 5 days (5 months). This patient, and one other, subsequently underwent a transurethral resection of the prostate gland (at 5 and 8 months, respectively, following implantation) for persistent urinary obstructive/irritative symptoms. To date, no patient in our series has developed an urinary stricture or urinary incontinence. Each patient was considered free of morbidity as soon as the difference between the subsequent IPSS and the pretreatment antecedent IPSS was not greater than 1. The mean of the differences between antecedent IPSS and subsequent IPSS is plotted in Fig. 2 with the reference zone of ⫾ 1 from the baseline IPSS highlighted. The IPS score on average peaked at 2 weeks following implantation and then subsided

Fig. 2. Resolution of urinary morbidity as measured by the mean (n from Table 1) of the difference between the subsequent IPSS values and the preimplant IPSS value. The area between the dotted reference lines includes the population average IPSS value beginning about 22 weeks after implant.

Fig. 3. Kaplan-Meier plot of the proportion of patients whose IPSS has not returned to within one point of their preimplant IPSS. Although the time axis is labeled in weeks, the data is actually plotted in elapsed days between implant and the date the IPSS survey was taken. Circled data points correspond to the time of their last survey for patients who had not returned to the reference level by the close of this study.

following a roughly exponential decline into the reference zone. The cohort mean IPSS entered the reference zone (i.e., returned within one point of the antecedent value) 22 weeks after implant, despite the fact that about 20% of the respondents had not returned to the reference zone at that time. For every time period reported, there were some patients who had not returned to within 1 point of the antecedent IPSS, but beyond 22 weeks, the large majority who were well within the reference zone kept the group mean also within the reference zone. At 80 weeks, with only 12 respondents in the cohort, the statistics are less robust since 11/12 are in the reference zone but the average IPSS difference is distorted by the one patient with continued marked IPSS elevation. The Kaplan-Meier analysis of individual patient outcomes is plotted in Fig. 3 and shows the proportion of the patient population whose IPSS had returned to within ⫾ 1 point of the antecedent score vs. the time after implant. Small stepwise declines in the graph are noted as a function of days from implant when the questionnaire was completed rather than the more coarse time intervals targeted in Table 1. The shortest time interval from implant to survey completion was 6 days, and at 7 days, 21% of respondents had returned to within 1 point of their antecedent score. The statistical analysis estimates time-to-occurrence in the presence of cases where the categorical event has not yet occurred by taking into account the time since implant of those 15 patients who have been monitored but have not yet returned to the antecedent level. The median time until return was 6 weeks (42 days) and the Kaplan-Meier analysis analysis determined that the mean was 13.3 weeks (93 days). This large difference between the median and mean times of return to within ⫾ 1 of the antecedent IPSS


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Table 3. Factors evaluated as possible contributors to short term urinary morbidity Correlation coefficients and p values for return to within ⫾ 1 point of preimplant IPSS value 6 weeks (n ⫽ 170) Parameter Age at implant Prostate serum antigen Clinical stage Catheter out Antecedent IPSS Maximum IPSS Max. IPSS increase External beam Adjuvant therapy Ultrasound volume Planning volume No. needles used No. seeds implanted Total seed activity: Isotope Prescribed mPD Max. urethral dose Mean urethral dose D90 V100 V150 V200

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I Pd

103

13 weeks (n ⫽ 166)

50 weeks (n ⫽ 156)

corr

p

corr

p

corr

p

0.166 ⫺0.048 ⫺0.029 ⫺0.081 0.214 ⫺0.385 ⫺0.541 ⫺0.032 ⫺0.056 ⫺0.096 ⫺0.110 ⫺0.058 ⫺0.088

0.030 0.537 0.710 0.292 0.005 ⬍0.001 ⬍0.001 0.677 0.472 0.211 0.153 0.449 0.256

⫺0.124 ⫺0.018 ⫺0.031 ⫺0.096 0.268 ⫺0.366 ⫺0.549 0.009 ⫺0.089 ⫺0.079 ⫺0.091 ⫺0.032 ⫺0.061

0.112 0.820 0.692 0.219 ⬍0.001 ⬍0.001 ⬍0.001 0.912 0.257 0.310 0.243 0.683 0.434

⫺0.053 0.077 ⫺0.027 ⫺0.136 0.076 ⫺0.130 ⫺0.192 0.065 ⫺0.153 0.087 0.126 0.054 0.113

0.513 0.336 0.739 0.091 0.344 0.106 0.016 0.419 0.056 0.283 0.117 0.507 0.159

⫺0.158 ⫺0.128 0.004 0.071 ⫺0.023 0.051 0.075 0.004 0.050 0.006

0.134 0.260 0.139 0.360 0.768 0.785 0.330 0.955 0.516 0.941

0.000 ⫺0.114 0.114 0.036 0.027 0.059 0.072 0.139 0.107 0.032

1.000 0.325 0.142 0.642 0.733 0.450 0.358 0.073 0.171 0.686

0.098 ⫺0.041 ⫺0.032 ⫺0.046 0.092 0.031 ⫺0.009 0.099 0.075 0.038

0.657 0.734 0.687 0.567 0.252 0.702 0.912 0.218 0.350 0.641

indicates that there is a small group of patients whose IPSS remains elevated for a long period of time. All patients received ␣-blockers for a minimum of 3 months following implantation. Table 1 shows the proportion of patients on ␣-blockers during the course of the study. At 26 weeks following implantation, 85% were ␣-blocker dependent and at 50 weeks 56% continued using ␣-blockers. As mentioned previously, the statistics are not robust at 80 weeks, and of the 12 patients in the survey group, 9 were ␣-blocker dependent. Prior to implant, 1 of these 9 presented was using the medication as part of an antihypertensive regimen, and he was continued on it. Table 3 details the clinical and treatment parameters evaluated for short-term urinary morbidity. Only various permutations of the IPSS correlated with time to return to the reference zone. These include the patient’s maximum IPSS, the maximum increase of IPSS and antecedent IPSS. The latter quantity (p ⱕ 0.01 at 6, 13, and 50 weeks) is negatively correlated with time to return to the reference zone indicating that patients in our series with a relatively low preimplant IPSS returned slower than did patients with a higher preimplant IPSS. Age at implant was statistically significant (p ⫽ 0.03) at 6 weeks, but not with additional follow-up. None of the other clinical or treatment parameters evaluated, including clinical T stage, prostate ultrasound volume, the utilization of neoadjuvant hormonal manipulation, moderate dose external beam radiation therapy, the choice of isotope, the urethral dose, the total implant activity in millicuries, or the D90,V100/ V150/V200 were

statistically significant via either univariate or multivariate analysis. In addition, the approximate 20% of patients with prolonged IPSS elevation and the 56% of patients who were ␣-blocker dependent at 50 weeks were not significantly different from those patients with rapid normalization of the IPSS or the ␣-blocker independent patients in terms of clinical or treatment parameters. DISCUSSION Over the past decade, prostate brachytherapy has been increasingly utilized as definitive management for early stage carcinoma of the prostate gland. The results of prostate brachytherapy have been reported to be as favorable as the most positive radical prostatectomy series with a decreased incidence of urinary incontinence and sexual dysfunction (1–5). A paucity of data, however, has been published regarding the short-term urinary morbidity following prostate brachytherapy. Almost all patients experience some degree of urinary irritative/obstructive symptomatology following the procedure. In addition, 3%–22% of patients develop acute urinary retention following implantation requiring an indwelling catheter (4, 7, 8 –11). The IPSS was developed by the AUA in 1992 as a measure of symptom relief following prostatectomy for benign prostatic hypertrophy. Reports by Barry et al. (13) and Barnboym et al. (14) documented the reliability of serial IPSS determinations. In addition, Barry et al. (13) reported that the index was sensitive to change as witnessed by a significant im-

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provement in urinary obstructive symptomatology following transurethral resection for benign prostatic hypertrophy. Barry et al. (13) concluded that “the AUA symptom index is clinically sensible, reliable, valid and responsive. It is practical for use in practice and for inclusion in research protocols.” The initial study evaluating IPSS scores (13) reported that the survey was unable to describe general symptomatology using individual scores as well as utilizing the sum of the seven responses. Desai et al. (21) confirmed the superiority of the total IPS score over individual responses in determining patient assessment following prostate brachytherapy. These findings are important in the interpretation of our results because individual scores are not available for all IPSS determinations. Terk et al. (7) were able to correlate the risk of urinary retention following prostate brachytherapy with the preimplant IPS score. The risk of urinary retention for preimplant IPSS scores ⬍ 10, 10 –19, and ⬎ 20 were 2%, 11%, and 29%, respectively. Our data was unable to confirm a greater risk of urinary retention with higher preimplant IPSS scores. However, 88.8% of our preimplant scores were ⬍ 11 (mean ⫽ 5.7). In addition, all of our patients received prophylactic ␣-blockers that continued for a minimum of 3 months following implantation. In the report by Terk et al., (7), ␣-blockers were utilized only at the time of urinary retention and discontinued when the obstruction resolved. In the study by Terk et al., (7), the overall incidence of prolonged urinary retention was 5.6% (14 of 251 patients). The median time to the onset of urinary retention was 1 day (range 1–51 days). All but 1 of the 14 patients developed urinary retention within 2 weeks of implantation. Of the 14 patients who developed prolonged urinary retention, 6 (2.4% of all patients) required a transurethral resection of the prostate gland without subsequent urinary incontinence. The follow-up of those 6 patients ranged from 6 –32 months. The remaining 8 patients required an intermittent or indwelling catheter for a median of 28 days. Wallner et al. (4) reported that 8 of 92 patients (8.7%) required a transurethral resection of the prostate gland for urinary obstructive symptomatology following prostate brachytherapy. Three of those 8 patients developed some degree of urinary incontinence. As illustrated in Fig. 1, only one patient in our series required a urinary catheter longer than 5 days, and no patient developed urinary retention after day 1. Two of our 170 patients (1.2%) required a subsequent transurethral resection of the prostate gland at 5 and 8 months following implantation. To date, none of these sequential 170 patients has developed an urinary stricture requiring dilatation or urinary incontinence. Terk et al. (7) also reported a 37% incidence of urinary retention in patients implanted with 103 Pd with preimplant IPSS scores ⬎ 10 following neoadjuvant hormonal manipulation. In our series, 11 patients underwent implantation with 103Pd with preimplant IPSS scores ⬎ 10 following neoadjuvant hormonal manipulation; 9 of those 11 patients had the urinary catheter permanently removed on day 0 and all had the catheter removed by day


4 (data not shown). In contrast to the report from Terk et al. (7), however, all of those 11 patients had received a moderate dose of external beam radiation therapy, whereas the Mount Sinai patients were treated with implant alone. Desai et al. (21) reported the mean IPSS peaked at 1 month at a value of 14 from a baseline of 6. The IPSS scores remained elevated for 12 months and gradually returned to a baseline of 7 from 12–24 months. Lee et al. (22) followed 46 consecutive prostate brachytherapy patients for 3 months. IPSS determinations were obtained prior to implantation and at 1 and 3 months following brachytherapy and the mean values were 8.1, 19.7, and 15.3, respectively. The authors made no mention of ␣-blocker usage. In our series, the IPSS peaked at 2 weeks at a value of 12.7 from a mean antecedent value of 5.7. Our 1 and 3 month values were 12.0 and 8.7, respectively. Return of subsequent IPSS scores to baseline were observed at a mean and median of 13 and 6 weeks, respectively. Despite similar preimplant IPSS values, our prophylactic and prolonged usage of ␣-blockers may potentially explain the time-course difference in the resolution of urinary morbidity. In the report by Desai et al. (21), the prolonged elevation of IPSS scores correlated with total implant activity and dose volume factors (the V80/90/ 95/100 and D70/90/100/150), but not the dose to the urethra. In contrast, the present study found no correlation between the return of the IPS score to its antecedent value and the total implant activity, dose volume factors or dose (average or maximal) to the urethra. Wallner et al. (23) reported that urinary morbidity was associated with a maximal urethral dose ⬎ 400 Gy. In the present study, the average maximal urethral dose for 125I was 133% of mPD: 193 Gy (TG-43) for 65 monotherapy patients and 190 Gy (TG-43) for 26 combined modality therapy patients, where the dose includes 45 Gy of external beam radiation therapy. No patient received a maximal urethral dose ⬎ 400 Gy. This may explain the absence of urethral dose as a predictor of urinary morbidity in our series. In addition, Wallner et al. (23) reported that larger prostates had significantly more longterm morbidity, and the effect of prostate size was independent of urethral dose. In a subsequent report from Memorial Sloan Kettering Cancer Center, Zelefsky et al. (9) reported that the incidence of late grade II toxicity was similar for patients with prostate glands less than or greater than 60 cm3. In our series, prostate size did not predict short-term urinary morbidity. One hundred eighteen (69.4%) of our glands were ⱕ 40 cm3 and 157 were ⱕ 50 cm3 at implantation. Only 13 (7.6%) of all glands were ⬎ 50 cm3 at the time of implantation. Because our series is enriched with smaller glands, our results indicating an absence of size effects on urinary morbidity remain tentative when applied to glands of 50 cm3 or larger. In our series we also evaluated the effect of patient age, clinical stage, the utilization of moderate dose external beam radiation therapy, the choice of isotope, the utilization of preimplant neoadjuvant hormonal manipulation, and multiple dosimetric quality parameters (D90/V100/V150/V200). As detailed in Table 3, various expressions of the IPSS such as antecedent value, maximal


value and maximum increase in IPSS show a clear and statistically significant correlation with the resolution of urinary morbidity at each important time interval. Of the remaining evaluated treatment and clinical parameters, age at implant was statistically significant at predicting urinary morbidity, but this parameter was significant only at 6 weeks following implantation. To the best of our knowledge, this report represents the first series of prostate brachytherapy patients evaluated for urinary morbidity utilizing prophylactic and prolonged ␣-blockers. ␣-blockers may decrease radiation-induced urethritis by relaxing urinary smooth muscle tone with a subsequent reduction in urinary flow resistance. Previously, Kleinberg et al. (24) reported the acute urinary morbidity for 31 patients undergoing prostate brachytherapy at Memorial Sloan Kettering Cancer Center from 1988 to 1991. Eight patients received terazosin (2–10 mg daily) for urinary obstructive/irritative symptomatology. Significant improvement in urinary symptomatology was noted in seven of the eight patients. In a study of 51 patients evaluated 6 months after brachytherapy, Arterbery et al. (25) reported that 93% of their patients had used an ␣-blocker for an average of 6 weeks. Seventy-five percent of those patients reported an improvement in urinary symptoms while receiving the ␣-blockers. Zelefsky et al. (26) recently reported the results of 3D conformal external beam radiation therapy for 743 consecutive patients. Fifty-two patients experienced late grade II urinary toxicity. Thirty-three of the 52 patients (64%) noted significant resolution or improvement in urinary symptoms following the initiation of an ␣-blocker. In an update of the Memorial Sloan Kettering prostate brachytherapy series, Zelefsky et al. (9) reported that 31% (45 patients) required ␣-blockers 1 year following brachytherapy. In those 45 patients, the median duration of grade II symptomatology was 23 months (range 12–70 months).

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Wallner et al. (4) reported that 14% of all patients remain ␣-blocker dependent at 24 months. Although these numbers are lower than ours (56% at 50 weeks), the Memorial Sloan Kettering results do not report detailed serial IPSS determinations for their evaluated patients, and as such, the time course of normalization of urinary morbidity via IPSS scores cannot be ascertained from their results. The median duration of grade II urinary symptomatology in our patients is not yet discernible. The true utility of ␣-blockers in prostate brachytherapy will be determined only by a randomized trial. We intend to follow these 170 patients prospectively for a total of 5 years and to report a follow-up evaluation. CONCLUSIONS One hundred fifty (88.2%) of the 170 patients in our series had the urinary catheter permanently removed on day 0, and 169 (99.4%) by day 5 following implantation. The mean patient IPSS values peaked at 2 weeks and returned to antecedent values on average at 13 weeks, with a median of 6 weeks. This return is significantly more rapid than what has previously been reported. The 1.2% incidence of transurethral resections also compares favorably with the published literature. Multivariate analysis indicated that patient age (but only at 6 weeks), antecedent IPSS, maximum IPSS increase, and maximum IPSS predicted for prolonged urinary morbidity. We believe these results may be due to maintaining the average urethral dose to approximately 115% of the prescribed dose and the prophylactic and long-term use of ␣-blockers. In addition to biochemical results, future studies must continue to address urinary, rectal, and sexual morbidity to determine the impact of this treatment modality on the quality of life of prostate brachytherapy patients.

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