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Factors influencing risk of acute urinary retention after TRUS-guided permanent prostate seed implantation
Int. J. Radiation Oncology Biol. Phys., Vol. 52, No. 2, pp. 453– 460, 2002 Copyright © 2002 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/02/$–see front matter
PII S0360-3016(01)02658-X
CLINICAL INVESTIGATION
Prostate
FACTORS INFLUENCING RISK OF ACUTE URINARY RETENTION AFTER TRUS-GUIDED PERMANENT PROSTATE SEED IMPLANTATION JUANITA CROOK, M.D.,* MICHAEL MCLEAN, M.D.,* CHARLES CATTON, M.D.,* IVAN YEUNG, PH.D.,† JOHN TSIHLIAS, M.D.,‡ AND MELANIA PINTILIE, M.SC.§ Departments of *Radiation Oncology and §Biostatistics, and ‡Division of Urology, University Health Network, Princess Margaret Hospital, Toronto, Ontario, Canada; †Department of Radiation Physics, Princess Margaret Hospital, Toronto, Ontario, Canada Purpose: To look for factors predictive of acute urinary retention (AUR) after permanent seed prostate brachytherapy. Methods and Materials: From March 1999 to February 2001, 150 permanent seed prostate implants were performed at Princess Margaret Hospital (Stage T1c, n ⴝ 113; T2a, n ⴝ 37; mean prostate-specific antigen level 5.9 ng/mL, prescription dose 145 Gy per Task Group No. 43). ␣-Blockers were used routinely after implantation. Dosimetry was based on the 1-month postimplant CT scan. The International Prostate Symptom Score (IPSS) and catheterization were recorded at 1 month and 3 months and then every 3 months. The following variables were examined: age, baseline IPSS, prior androgen ablation, prostate transrectal ultrasound volume, number of seeds, D90, V100, V200, and urethral dose. Results: Twenty patients (13%) experienced AUR. No difference was seen in the mean D90 (149 Gy vs. 152 Gy, p ⴝ 0.6), V100 (90% vs. 91%, p ⴝ 0.6), V200 (23% vs. 25% p ⴝ 0.4), IPSS (6.4 vs. 5.9, p ⴝ 0.8), or maximal urethral dose (204 Gy vs. 210 Gy, p ⴝ 0.5). The prostate volume was significantly larger in men with AUR (39.8 cm3 vs. 34.3 cm3, p ⴝ 0.003), and the mean number of seeds was higher (112 vs. 103, p ⴝ 0.006). Of the 20 patients experiencing AUR, 11 (55%) had received prior antiandrogen therapy to downsize their prostates vs. 35 (27%) of the 130 who did not have AUR (p ⴝ 0.02). Multivariate analysis showed prostate volume and prior hormone use to be independent predictors of AUR. Conclusions: Implant quality as determined by D90, V100, V200, and urethral dose did not predict AUR. Prostate size was the major determinant of AUR. For any given prostate size, prior androgen ablation increased the risk of AUR. Men with larger prostates should be aware of the increased risk when contemplating brachytherapy. © 2002 Elsevier Science Inc. Prostate brachytherapy,
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INTRODUCTION
counseling patients who are trying to make a treatment choice. We report the experience at the Princess Margaret Hospital/University Health Network with 150 permanent seed implants.
Permanent seed prostate brachytherapy is becoming an increasingly popular option in the management of clinically localized prostate cancer. It is estimated that in 2001, ⬎50% of American Medicare patients with newly diagnosed localized prostate cancer will have been treated with brachytherapy. By 2005, 50% of all appropriate newly diagnosed cases will receive brachytherapy (1). This option is often perceived as having a better side effect profile than radical prostatectomy. Nonetheless, a significant proportion of men will experience prolonged urinary dysfunction. Acute urinary retention (AUR) rates generally range from 5% to 15% and may result in a prolonged period of catheterization, intermittent self-catheterization, a suprapubic tube, or even a transurethral resection, if persistent. This can have a major impact on quality of life for the individual. The ability to predict more severe urinary toxicity would be beneficial in
METHODS AND MATERIALS Permanent radioactive seed implantation as management for early-stage localized prostate cancer was approved and funded by the Ministry of Health in the Province of Ontario in February 1999. Provincial evidence-based guidelines (2) developed by the Cancercare Ontario Provincial Guidelines Group (genitourinary division) restrict the availability to appropriately selected patients (Stage T1c/T2a, Gleason score ⱕ6, prostate-specific antigen [PSA] level ⬍10 ng/ mL). From March 1999 to February 2001, 150 men were treated with 125I permanent seed implantation at the Prin-
Reprint requests to: Juanita Crook, M.D., Princess Margaret Hospital, 610 University Ave., Toronto, Ontario M5G 2M9 Canada.
Received Jun 12, 2001, and in revised form Aug 24, 2001. Accepted for publication Sep 4, 2001. 453
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cess Margaret Hospital/University Health Network in Toronto, Canada. Patient population The mean patient age was 66 years (range 49 – 83). Exceptions to the guideline criteria were rare. Tumor stage was T1c in 113 and T2a in 37 patients. The mean PSA level was 5.9 ng/mL (median 5.7, range 0.6 –16). The median Gleason score was 6 (mean 5.8). Outside pathologic findings were centrally reviewed and upgraded to Gleason 7 for 6 patients after the implant. Otherwise, all Gleason scores were ⱕ6. Given the favorable risk profiles, additional staging, such as bone scans or CT scans, was not required. All patients completed an International Prostate Symptom Score (IPSS) questionnaire (3) at the first consultation. Those with scores ⱖ7 were further investigated with voiding studies to measure the flow rate and postvoid residual volume. The mean baseline IPSS was 5.9 (median 6, range 0 –19). Prostate volume was confirmed by transrectal ultrasonography (TRUS), and those patients with prostate volumes ⬎50 cm3 were treated with 2– 4 months of androgen deprivation using a combination of nonsteroidal antiandrogens and depot luteinizing hormone-releasing hormone. Of the 150 patients, 46 (31%) had a short course of prior androgen ablative therapy. The mean prostate volume before hormone administration was 60 cm3 but ranged to 89 cm3. The mean and median prostate volume at the time of implantation for the entire group was 35 cm3, and for those requiring downsizing with androgen ablation, it was also 35 cm3. Technique All implants were preplanned with TRUS mapping of the prostate according to the Seattle technique, as previously described by Prestidge et al. (4). A pubic arch evaluation was undertaken by TRUS as part of the mapping procedure. Planning was accomplished using MMS software (MultiMedical Systems), using a modified peripheral loading distribution of radioactivity (5, 6). The dosimetric parameters aimed for a V150 of 45–50% of the prostate and a V200 of 12–15%. The maximal urethral dose was planned to be ⬍150% of the prescribed dose (i.e., ⬍220 Gy). All implants were transperineal, guided by both template and TRUS. 125I (Oncoseed, Nycomed Amersham) seeds were placed into the prostate using preloaded needles according to the preplan. Sagittal TRUS images were used to verify all needles destined for the base of the prostate. Fluoroscopy was used after each row of needles had been inserted to verify the relative depths of insertion. The mean activity per seed was 0.317 mCi (range 0.27– 0.37). The prescribed dose to cover the planning target volume was 145 Gy (Task Group No. 43) (7). The median number of seeds per patient was 103 (range 67–140). All implants but two were performed under general anesthesia. Cystoscopy was routinely performed at implant completion to check for loose seeds in the bladder and to evacuate any clots. The first 50 patients were encouraged to
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spend 1 night in the hospital for observation. Most of the more recent implants were performed as outpatient procedures. Patients were discharged without a catheter after a voiding trial. All patients were prescribed an ␣-blocker such as terazosin, doxazosin, or tamsulosin for a minimum of 3 months. Routine steroids were not used. Quality assurance Patients returned 4 weeks after brachytherapy for assessment. All patients underwent a chest X-ray to look for migratory seeds in the lungs, serum PSA determination, orthogonal pelvic simulator films for manual seed identification, and CT of the prostate (3-mm slices). A urethral catheter was inserted at the time of the CT scan to help in urethral identification. For the first 98 patients, the prostate was contoured on the CT scan with the help of the TRUS preplan images. Since September 2000, all patients have also undergone MRI of the prostate (n ⫽ 52). The prostate was contoured on the MRI after MRI/CT fusion using Picker AcQsim multimodality technology. Seeds were identified using CT images and MMS software, but manually verified. Implant quality (8) was evaluated in terms of the V100 (percentage of prostate receiving the prescribed 145 Gy), D90 (dose in Gray received by 90% of the prostate), V200 (percentage of prostate receiving twice the prescribed dose), and maximal and average urethral doses. Follow-up After the 1-month assessment, patients were seen at 3 and 6 months, and then, alternating with their referring urologist, at 6-month intervals. The PSA and IPSS evaluations were collected every 3 months. AUR was defined as any need for catheterization after brachytherapy. No patient who required a catheter at any time was excluded. Those patients who had had a routine catheter inserted postoperatively were not counted as having been in retention unless they had been unable to void after removal of the catheter. Statistical analysis The technical and clinical factors (except for the prior use of hormonal therapy) were compared between the 2 groups (AUR vs. no AUR) using the Wilcoxon rank-sum test with the normal approximation. A nonparametric approach was chosen because of uncertainty whether the data followed a normal distribution. Prior use of hormonal therapy was tested as a variable using the Fisher exact test. Logistic regression analysis was used to test the impact of more than one variable on the occurrence of AUR (9). RESULTS The median follow-up was 13 months (range 3–27). The rate of urinary retention requiring catheterization after implantation was 13% (20 of 150). The time of onset was variable, but most occurred soon after implantation, 6 within the first 24 h, 9 between Days 2 and 7, and 2 in the second week. The remaining 3 were late onset at 2, 5, and
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Fig. 1. Median IPSS with respect to interval after brachytherapy.
5 months. Two of these men continued intermittent selfcatheterization for 18 months. The third was catheterized for severe urinary symptoms, but was not in retention, and the catheter was removed after 4 days. The mean duration of catheterization for those men who have recovered spontaneous voiding was 5 weeks (median 2). Five patients (3%) were still catheter dependent at a median time of 8 months (range 3–18). Four of the 5 had had prior androgen ablation for downsizing the prostate from a mean of 71 cm3 to a mean of 43 cm3. Three required intermittent self-catheterization at last follow-up (at 8, 12, and 18 months). Two were gradually improving. One patient had a suprapubic tube at 6 months, and 1 had an indwelling catheter at 3 months. No patient has yet undergone postimplant transurethral resection of the prostate (TURP).
The IPSS after brachytherapy peaked at 1–3 months, began to fall by 6 months, and returned to baseline by 12 months (Fig. 1). Patient factors The contribution of patient factors to AUR after implantation is summarized in Table 1. Neither age nor baseline IPSS was predictive of subsequent urinary retention after implantation. The mean baseline IPSS for those with urinary retention was 6.4 vs. 5.9 for those without retention. However, all those with scores ⱖ7 underwent detailed voiding studies to rule out any significant obstructive uropathy. Androgen ablation was routinely used to reduce the prostate size before implantation for those men with prostates ⬎50 cm3 or with evidence of pubic arch obstruction. Of the
Table 1. Mean values for possible factors contributing to AUR after brachytherapy
Age (y) IPSS score Prior HT Prostate volume (cm3) Seeds (n) V100 (%) V150 (%) D90 (Gy) V200 (%) Average urethral dose (Gy) Maximal urethral dose‡ (Gy)
AUR
No AUR
p*
66.5 6.4 11/20 39.8 112 90 52 149 23 157 204
64.8 5.9 35/130 34.3 103 91 53 152 25 167 210
0.5 0.8 0.018† 0.003 0.006 0.6 0.5 0.6 0.4 NS 0.5
Abbreviations: AUR ⫽ acute urinary retention; IPSS ⫽ International Prostate Symptom Score; HT ⫽ hormonal therapy; V100 ⫽ percentage of prostate receiving full 145-Gy prescribed dose; V150 ⫽ percentage of prostate receiving 150% of prescribed dose (or 220 Gy); D90 ⫽ dose in Gray received by 90% of prostate; V200 ⫽ percentage of prostate receiving twice the prescribed dose. * Univariate analysis using Wilcoxon rank-sum test. † Proportion with prior hormones based on Fisher’s exact test. ‡ Urethra identified by urinary catheter on 1-month postimplant CT scan.
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Fig. 2. Relationship of prostate volume (in cubic centimeters) to number of seeds. The 2 outliers were the first and second cases planned.
20 men with urinary retention after implantation, 11 (55%) had had prior hormonal therapy, compared with 35 (27%) of the 130 without postimplant retention (p ⫽ 0.018). The AUR rate of men requiring downsizing before implantation was 24% compared with 8.7% of those who presented with an acceptable prostate size. The prostate volume was larger at the time of implantation in the group who developed urinary retention, 39.8 cm3 vs. 34.3 cm3 for those without retention (p ⫽ 0.003). Physical factors The physical factors are summarized in Table 1. The mean D90 for the 150 patients was 151 Gy, the mean V100 was 91% (median 93%), and mean V200 was 24%. The mean and median maximal urethral dose was 209 Gy, and the mean of the average urethral dose per patient was 165 Gy (range 103–208). None of these dosimetric factors was predictive of urinary retention after implantation. The number of seeds per implant was predictive; it was 103 for those without urinary retention vs. 112 for those with it (p ⫽ 0.006). The number of seeds is, however, proportional to the prostate volume at the time of planning (Fig. 2), given the narrow range of seed activity (0.27– 0.37 mCi/seed) and a consistent planning policy. In multivariate analysis, both prostate volume at the time of implant and prior hormonal therapy remained significant, with p values of 0.0033 and 0.0073, respectively. A fitted curve (Fig. 3) showing the risk of urinary retention according to prostate volume for those patients with and without prior hormonal therapy revealed a distinct separation of the curves. Those requiring a short course of androgen ablation
to reduce prostate size before brachytherapy were 4 times more likely to have AUR (odds ratio ⫽ 4, 95% confidence interval 1.5–11). DISCUSSION The popularity of prostate brachytherapy is partially attributable to a perceived favorable toxicity profile. Some degree of urinary morbidity related to urethritis and prostatitis is common in the postimplant period. Symptoms tend to peak at about 2 months (10), with maximal IPSS at 1 month (11), but improve with time, as do function and bother scores (12). Severe long-term urinary morbidity is reported in 3–12%. Health-related quality of life returns to near baseline by 3 months (13), and patients’ overall satisfaction is high at 6 months. The use of ␣-blockers routinely after brachytherapy is common (14, 15) and precludes grading of urinary toxicity by systems such as that suggested by Gelblum et al. (16) or Brown et al. (17) (Table 2). The most distressing adverse event is AUR requiring catheterization. Often this is only a brief setback, and spontaneous voiding is quickly reestablished. However, the occasional patient will require a prolonged period of intermittent self-catheterization, a suprapubic tube, or TURP (15, 16, 25). This clearly can have a major impact on the patient’s quality of life. In the present series, 13% of men required catheterization at some point beyond the 24-h postimplant period. For those men who resumed spontaneous voiding, the median duration of catheterization was 2 weeks (mean 5). However, 5 men remained catheter dependent at 3–18 months. Clarification of the factors predispos-
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Fig. 3. Risk of urinary retention according to prostate volume for men with and without prior hormonal therapy: observed values, fitted model, and 95% confidence intervals. The multivariate analysis consisted of logistic regression in which the outcome variable was whether the patient had AUR and the explanatory variables were volume and prior hormone use. Because the value for any 1 patient was either 1 or 0 (retention or no retention), no data points occur between these y-axis values. Figure 3 shows the dependency, as prescribed by the equation obtained in the model fitting, of the probability of AUR for any particular prostate volume with and without prior hormones. In this way, the average probability of AUR for a volume of 40 cm3 was 10% if no prior hormonal therapy was given and 32% for the same volume after downsizing. The vertical bars show the 95% confidence interval for the above numbers.
ing to AUR after brachytherapy would be useful in counseling patients for whom lifestyle and quality of life are often important deciding factors in their treatment decision. AUR is reported in 2–33% (Table 3). Most resolve with medical management, so that eventual TURP is required in only 1– 6%. The various potential predictive factors can be divided into pretreatment factors such as patient age, baseline urinary function as evaluated by IPSS or American Urologic Association score, prior use of hormonal therapy, and prostate volume. Predictive factors in this category can be used in counseling patients before their treatment decision. Posttreatment or technical factors would include the number of needles and number of seeds used and various dosimetric parameters such as V100, D90, V200, and urethral dose. Knowledge of the predictive factors in this group can be used in defining planning parameters to minimize risk.
Prostate volume Gelblum et al. (16) reported only a 2.2% rate of AUR in 600 patients, but a 5% TURP rate. Prostate volume (⬎35 cm3) predicted for a higher incidence of Grade 2 toxicity, but not retention or TURP. Han et al. (18) reviewed the outcome of 160 consecutive brachytherapy patients by means of a patient questionnaire to determine the incidence of emergency room visits, catheterization, and hospitalization. Thirty-three percent of patients required catheterization, 11% were still catheterized at 1 month, and 3 patients (2%) were at 12 months. Prostate volume was an independent predictor of AUR, with a relative risk of 17 (confidence interval: 13–18) for prostates 40 cm3 compared with 20 cm3. Lee et al. (14) found a 12% AUR rate for 91 patients. Significant factors for urinary retention were the number of
Table 2. Modified RTOG grading system Grade 0 Grade 1 Grade 2 Grade 3
No change Frequency or nocturia; dysuria, urgency, or bladder spasm requiring no or minimal intervention, such as pyridium Frequency with urgency and nocturia requiring alpha-blocker therapy Obstructive symptoms requiring an in-dwelling catheter or posttreatment TURP
Abbreviations: RTOG ⫽ Radiation Therapy Oncology Group; TURP ⫽ transurethral resection of the prostate. Data from Geblum et al. (16) and Brown et al. (17).
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Table 3. Summary of published rates of AUR following prostate brachytherapy Predictive factors for AUR Author
Year
Patients (n)
AUR (%)
Volume
Brown et al. (17) Present series Ciezki et al. (32) Friedland et al. (33) Gelblum et al. (16) Han et al. (16) Lee et al. (14) Merrick et al. (15) Storey et al. (34) Terk et al. (25) Thomas et al. (27) Wang et al. (35)* Zelefsky et al. (36)
2000 2001 2001
87 150 194
6 13 10.8
X X*
2001 1999 2000 2000 2000 1999 1998 2000 2000 1999
457 693 160 91 170 206 251 50 33 245
8.4 2.2 33 12 6 11 5.6 12 35 3
Total activity
IPSS
Prior HT
TURP (%)
X
X
X X 5
X X† 1.2 X‡ X‡
X
X
2.5
Abbreviations as in Tables 1 and 2. All prostates ⬎50 cm3. * prostate length † also number of needles and postimplant CT volume. ‡ Univariate only, dropped out on multivariate analysis.
needles (p ⬍0.038), prostate volume (p ⬍0.048), planning ultrasound target volume (p ⬍0.02), and postimplant CT volume (p ⬍0.021). Only univariate analysis was undertaken. Clearly, the number of needles related to the gland volume, just as the number of seeds reflected the prostate volume in the present series. Postimplant prostate volume is an interesting factor, as larger volumes may well reflect prolonged prostatic edema after implantation. However, the assessment of prostate volume by CT can be subjective and is prone to considerable interobserver variation (19, 20). Prostate volumes evaluated on CT scan are typically significantly larger than those determined by MRI or TRUS (21–24). Evaluation by MRI or TRUS would be necessary to be confident about any association. Terk et al. (25) reported a 5.6% retention rate for 251 patients. The median time to spontaneous voiding was 4 weeks. In univariate analysis, the TRUS prostate volume was predictive of AUR, with a rate of 4.4% for volumes ⬍50 cm3 and 16% for larger volumes (p ⫽ 0.02). However, in multivariate analysis, this factor dropped out, leaving only pretreatment IPSS and prior hormone use as significant. In contrast to the present series and the findings of Lee et al. (14), Brown et al. (17) found that the 6% rate of AUR for 87 patients was related to the total activity implanted and the number of sources, but not to the prostate volume or any dosimetric parameters. Merrick et al. (26) and Thomas et al. (27) reported on the influence of the transitional zone (TZ) volume as opposed to total prostate volume for predicting urinary morbidity and retention after brachytherapy. Thomas et al. found an AUR rate of 12% in 50 patients that, in univariate analysis, was dependent on total prostate volume, number of seeds, and TZ volume. In multivariate analysis, only the TZ volume
was predictive. For TZ volumes ⬍50 cm3, the AUR was 0%, for those 50 – 60 cm3, it was 33%, and if the TZ volume was ⬎60 cm3, the retention rate was 71%. In contrast, Merrick et al. (26) found that the TZ index (prostate volume/TZ volume) correlated with the time for normalization of IPSS and the maximal IPSS, but not with the need for catheterization. However, the mean TZ volume in the series of Merrick et al. was 7 cm3, much smaller than the range of TZ volumes found to be predictive in the series of Thomas et al. (27). Baseline bladder function The report by Gelblum et al. (16) on 600 patients had a very low incidence of urinary retention (2.2%) but a 5% incidence of postimplant TURP. The duration of Grade 2 toxicity was related to the preimplant IPSS, with a score ⬎7 predictive of a higher rate of Grade 2 toxicity at 60 days (59% vs. 32%, p ⫽ 0.001). The mean preimplant IPSS for the 28 men requiring TURP was 13. Terk et al. (25) also found the preimplant IPSS to be predictive of urinary retention. In their series of 251 patients, 29% required catheterization if their baseline IPSS was ⬎20 compared with 2% if it was ⬍10. The pretreatment IPSS remained significant in the multivariate analysis (p ⫽ 0.029). In the present series, all men with an IPSS ⱖ7 underwent detailed voiding studies. Those with findings of significant obstruction (maximal flow rates ⬍10 mL/s) or postvoid residual urine volumes (⬎60 cm3) were counseled of their increased risk of becoming catheter dependent for an indefinite period after brachytherapy and consequently frequently chose alternate therapy. This careful screening of all candidates with preexisting lower urinary tract symptoms introduced an obvious selection bias when assessing the
Risk of AUR after TRUS-guided prostate seed implantation
utility of the IPSS questionnaire in predicting for urinary retention after brachytherapy. The published evidence (16, 25) that an elevated IPSS predicted for more severe urinary symptoms after brachytherapy was indeed the basis of our policy. Our findings do not refute the usefulness of the IPSS questionnaire in this setting, but rather suggest that if there is no urodynamic evidence of significant flow impairment, those patients with an elevated IPSS have the same risk of postimplant retention as those who score more favorably. It may not be necessary to exclude such patients from brachytherapy on the basis of a high IPSS alone. Prior androgen ablation Androgen ablation is frequently used before brachytherapy to reduce the size of prostates that have a TRUS volume ⬎50 – 60 cm3 (22, 28). Larger prostates are technically difficult to implant, largely because of pubic arch interference, and are also associated with more severe urinary symptoms in the immediate postimplant period, with more Grade 2 and 3 toxicity (14, 18, 20, 25). Frazier et al. (29) found a mean prostate volume reduction of 29% after 3 months of androgen deprivation in a series of 60 patients. Nine of 13 patients whose prostates were still too large after 3 months showed a further 20% reduction with an additional 3 months of androgen ablation. Similarly, Stone et al. (30) reported an average 35% volume decrease when patients were treated with 3 months of androgen ablation before implantation. Most patients received the hormonal therapy because of unfavorable tumor factors (PSA ⬎10 ng/mL, Gleason score ⱖ7, or Stage T2b disease or greater). Glands ⬍40 cm3 reduced by an average of 29% and those ⬎40 cm3 reduced by 41%. In the present series, androgen ablation was used to reduce the prostate size in 31% of patients. The mean gland size for those who did not require prior downsizing was 35 cm3; the preimplant/posthormone volume for those benefiting from a short course of androgen ablation was identical at 35 cm3. Unfortunately, despite the volume reduction, the prior hormone group remained at an increased risk of postimplant urinary retention, 24% compared with 8.7% for those not requiring downsizing. Other investigators have reported the influence of prior
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androgen ablation. In the report by Terk et al. (25) of 251 patients, 114 were implanted with 103Pd and 137 with 125I. Palladium was used for unfavorable tumor factors or if the patient had had prior hormonal therapy. A total of 90 patients had the combination of hormones and palladium. In this subgroup, those who had a persistent IPSS ⬎10 after 3 months of androgen ablation had a 37% risk of urinary retention after implant. In multivariate analysis, the combination of hormonal therapy and palladium predicted for urinary retention. The two factors could not be analyzed separately nor could the influence of prior hormonal therapy be examined for those patients treated with 125I. Other factors No dosimetric factors consistently predicted for AUR. The V150 was reported by Gelblum et al. not to be predictive of urinary toxicity. Wallner et al. (31) reported urethral doses ⬎400 Gy to be associated with increased Grade 2–3 urinary morbidity. With modified peripheral loading, one aims to keep the urethral dose to ⬍150%, and in the present series, the mean maximal urethral dose was 210 Gy. Merrick et al. (15) reported that in 170 patients, of whom only 1 required a catheter for ⬎5 days, the average urethral dose was 115% of the prescribed dose. Although it is not evident from the present series, it is possible that a lower planned urethral dose would decrease the risk of retention. CONCLUSIONS AUR is the most common adverse event after permanent seed, low-dose-rate prostate brachytherapy. Prior knowledge of an individual’s relative risk of AUR would be useful in counseling patients before the procedure. In this series of 150 consecutive implants, prostate volume and the use of prior hormonal therapy to downsize the prostate were independent predictors of AUR. The systematic use of the IPSS questionnaire to screen patients and to direct those with significant lower urinary tract symptoms for detailed urodynamic studies permitted us to implant those patients with higher scores without an increased incidence of AUR. We are currently looking at the component parts of the overall volume (transitional zone vs. peripheral zone) to see whether this predictive capacity can be further refined.
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6. Merrick GS, Butler WM, Lief JH, et al. Prostatic conformal brachytherapy: 125I/103Pd postoperative dosimetric analysis. Radiat Oncol Invest 1997;5:305–313. 7. Nath R, Anderson LL, Luxton G, et al. Dosimetry of interstitial brachytherapy sources: Recommendations of the American Association of Physicists in Medicine—TG-43. Med Phys 1995;22:209 –234. 8. Nag S, Bice W, DeWyngaert K, et al. The American Brachytherapy Society recommendations for permanent prostate brachytherapy postimplant dosimetric analysis. Int J Radiat Oncol Biol Phys 2000;46:221–230. 9. Hosmer DW, Lameshow S. Applied logistic regression. New York: John Wiley & Sons; 1998.
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10. Krumholtz JS, Michalski JM, Sundram CP, et al. Healthrelated quality of life and morbidity in patients receiving brachytherapy for clinically localized prostate cancer. J Endourol 2000;14:371–374. 11. Lee WR, McQuellon RP, McCullough DL. A prospective analysis of patient-reported quality of life after prostate brachytherapy. Semin Urol Oncol 2000;18:147–151. 12. Brandeis JM, Litwin MS, Burnison CM, et al. Quality of life outcomes after brachytherapy for early stage prostate cancer. J Urol 2000;163:851– 857. 13. Lee WR, McQuellon RP, Harris-Henderson K, et al. A preliminary analysis of health-related quality of life in the first year after permanent source interstitial brachytherapy (PIB) for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2000;46:77– 81. 14. Lee N, Wuu C, Brody R, et al. Factors predicting for postimplantation urinary retention after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000;48:1457–1460. 15. Merrick GS, Butler WM, Lief JH, et al. Temporal resolution of urinary morbidity following prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000;47:121–128. 16. Gelblum DY, Potters L, Ashley R, et al. Urinary morbidity following ultrasound-guided transperineal seed implantation. Int J Radiat Oncol Biol Phys 1999;45:59 – 67. 17. Brown D, Colonias A, Miller R, et al. Urinary morbidity with a modified peripheral loading technique of transperineal 125I prostate implantation. Int J Radiat Oncol Biol Phys 2000;47: 353–360. 18. Han BH, Demel KC, Wallner K, et al. Patient reported shortterm complications after prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000;48:150. 19. Bice WS, Prestidge BR, Friedland JL, et al. Centralized multiinstitutional postimplant analysis for prostate brachytherapy. Int J Radiat Oncol Biol Phys 1998;41:921–927. 20. Dubois DF, Prestidge BR, Hotchkiss LA, et al. Intraobserver and interobserver variability of MR imaging and CT-derived prostate volumes after transperineal interstitial permanent prostate brachytherapy. Radiology 1998;207:785–789. 21. Kagawa K, Lee WR, Schulteiss TE, et al. Initial clinical assessment of CT-MRI image fusion software in localization of the prostate for 3D conformal radiation therapy. Int J Radiat Oncol Biol Phys 1997;38:319 –325. 22. Nag S, Beyer D, Friedland J, et al. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999;44:789 –799. 23. Narayana V, Robertson PL, Sandler H, et al. Impact of differences in ultrasound and computed tomography volumes on treatment planning of permanent prostate implants. Int J Radiat Oncol Biol Phys 1997;37:1181–1185.
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24. Rasch C, Barillot I, Remeijer P, et al. Definition of the prostate in CT and MRI: A multi-observer study. Int J Radiat Oncol Biol Phys 1999;43:57– 66. 25. Terk MD, Stock RG, Stone NN. Identification of patients at increased risk for prolonged urinary retention following radioactive seed implantation of the prostate. J Urol 1998;160: 1379 –1382. 26. Merrick GS, Butler WM, Galbreath RW, et al. Relationship between the transition zone index of the prostate gland and urinary morbidity after brachytherapy. Urology 2001;57:524 – 529. 27. Thomas MD, Cormack R, Tempany CM, et al. Identifying the predictors of acute urinary retention following magnetic-resonance-guided prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000;47:905–908. 28. Potters L, Torre T, Ashley R, et al. Examining the role of neoadjuvant androgen deprivation in patients undergoing prostate brachytherapy. J Clin Oncol 2000;18:1187–1192. 29. Frazier A, Kaufman N, Rosemberg S, et al. Prostate volume induced by neoadjuvant androgen ablation in preparation for permanent radioactive seed implantation. Radiother Oncol 2000;55:77. 30. Stone NN, Stock RG. Neoadjuvant hormonal therapy improves the outcomes of patients undergoing radioactive seed implantation for localized prostate cancer. Mol Urol 1999;3: 239 –244. 31. Wallner K, Roy J, Harrison L. Dosimetry guidelines to minimize urethral and rectal morbidity following transperineal I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 1995;32:465– 471. 32. Ciezki JP, Angermeier K, Ulchaker J, et al. The effect of anatomic and dosimetric variables on urinary obstruction following permanent Iodine-125 prostate brachytherapy. J Brachytherapy Intl 2001;17:49. 33. Friedland JL, Tsao A, Pow-Sang JM, et al. Urinary retention following prostate brachytherapy. J Brachytherapy Intl 2001; 17:48. 34. Storey MR, Landgren RC, Cottone JL, et al. Transperineal 125 Iodine implantation for treatment of clinically localized prostate cancer: 5-year tumour control and morbidity. Int J Radiat Oncol Biol Phys 1999;43:565–570. 35. Wang H, Wallner K, Sutlief S, et al. Transperineal brachytherapy in patients with large prostate glands. Int J Cancer 2000;90:199 –205. 36. Zelefsky MJ, Wallner KE, Ling CC, et al. Comparison of the 5-year outcome and morbidity of three-dimensional conformal radiotherapy versus transperineal permanent Iodine-125 implantation for early-stage prostatic cancer. J Clin Oncol 1999; 17:517–522.
PII S0360-3016(01)02658-X
CLINICAL INVESTIGATION
Prostate
FACTORS INFLUENCING RISK OF ACUTE URINARY RETENTION AFTER TRUS-GUIDED PERMANENT PROSTATE SEED IMPLANTATION JUANITA CROOK, M.D.,* MICHAEL MCLEAN, M.D.,* CHARLES CATTON, M.D.,* IVAN YEUNG, PH.D.,† JOHN TSIHLIAS, M.D.,‡ AND MELANIA PINTILIE, M.SC.§ Departments of *Radiation Oncology and §Biostatistics, and ‡Division of Urology, University Health Network, Princess Margaret Hospital, Toronto, Ontario, Canada; †Department of Radiation Physics, Princess Margaret Hospital, Toronto, Ontario, Canada Purpose: To look for factors predictive of acute urinary retention (AUR) after permanent seed prostate brachytherapy. Methods and Materials: From March 1999 to February 2001, 150 permanent seed prostate implants were performed at Princess Margaret Hospital (Stage T1c, n ⴝ 113; T2a, n ⴝ 37; mean prostate-specific antigen level 5.9 ng/mL, prescription dose 145 Gy per Task Group No. 43). ␣-Blockers were used routinely after implantation. Dosimetry was based on the 1-month postimplant CT scan. The International Prostate Symptom Score (IPSS) and catheterization were recorded at 1 month and 3 months and then every 3 months. The following variables were examined: age, baseline IPSS, prior androgen ablation, prostate transrectal ultrasound volume, number of seeds, D90, V100, V200, and urethral dose. Results: Twenty patients (13%) experienced AUR. No difference was seen in the mean D90 (149 Gy vs. 152 Gy, p ⴝ 0.6), V100 (90% vs. 91%, p ⴝ 0.6), V200 (23% vs. 25% p ⴝ 0.4), IPSS (6.4 vs. 5.9, p ⴝ 0.8), or maximal urethral dose (204 Gy vs. 210 Gy, p ⴝ 0.5). The prostate volume was significantly larger in men with AUR (39.8 cm3 vs. 34.3 cm3, p ⴝ 0.003), and the mean number of seeds was higher (112 vs. 103, p ⴝ 0.006). Of the 20 patients experiencing AUR, 11 (55%) had received prior antiandrogen therapy to downsize their prostates vs. 35 (27%) of the 130 who did not have AUR (p ⴝ 0.02). Multivariate analysis showed prostate volume and prior hormone use to be independent predictors of AUR. Conclusions: Implant quality as determined by D90, V100, V200, and urethral dose did not predict AUR. Prostate size was the major determinant of AUR. For any given prostate size, prior androgen ablation increased the risk of AUR. Men with larger prostates should be aware of the increased risk when contemplating brachytherapy. © 2002 Elsevier Science Inc. Prostate brachytherapy,
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INTRODUCTION
counseling patients who are trying to make a treatment choice. We report the experience at the Princess Margaret Hospital/University Health Network with 150 permanent seed implants.
Permanent seed prostate brachytherapy is becoming an increasingly popular option in the management of clinically localized prostate cancer. It is estimated that in 2001, ⬎50% of American Medicare patients with newly diagnosed localized prostate cancer will have been treated with brachytherapy. By 2005, 50% of all appropriate newly diagnosed cases will receive brachytherapy (1). This option is often perceived as having a better side effect profile than radical prostatectomy. Nonetheless, a significant proportion of men will experience prolonged urinary dysfunction. Acute urinary retention (AUR) rates generally range from 5% to 15% and may result in a prolonged period of catheterization, intermittent self-catheterization, a suprapubic tube, or even a transurethral resection, if persistent. This can have a major impact on quality of life for the individual. The ability to predict more severe urinary toxicity would be beneficial in
METHODS AND MATERIALS Permanent radioactive seed implantation as management for early-stage localized prostate cancer was approved and funded by the Ministry of Health in the Province of Ontario in February 1999. Provincial evidence-based guidelines (2) developed by the Cancercare Ontario Provincial Guidelines Group (genitourinary division) restrict the availability to appropriately selected patients (Stage T1c/T2a, Gleason score ⱕ6, prostate-specific antigen [PSA] level ⬍10 ng/ mL). From March 1999 to February 2001, 150 men were treated with 125I permanent seed implantation at the Prin-
Reprint requests to: Juanita Crook, M.D., Princess Margaret Hospital, 610 University Ave., Toronto, Ontario M5G 2M9 Canada.
Received Jun 12, 2001, and in revised form Aug 24, 2001. Accepted for publication Sep 4, 2001. 453
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cess Margaret Hospital/University Health Network in Toronto, Canada. Patient population The mean patient age was 66 years (range 49 – 83). Exceptions to the guideline criteria were rare. Tumor stage was T1c in 113 and T2a in 37 patients. The mean PSA level was 5.9 ng/mL (median 5.7, range 0.6 –16). The median Gleason score was 6 (mean 5.8). Outside pathologic findings were centrally reviewed and upgraded to Gleason 7 for 6 patients after the implant. Otherwise, all Gleason scores were ⱕ6. Given the favorable risk profiles, additional staging, such as bone scans or CT scans, was not required. All patients completed an International Prostate Symptom Score (IPSS) questionnaire (3) at the first consultation. Those with scores ⱖ7 were further investigated with voiding studies to measure the flow rate and postvoid residual volume. The mean baseline IPSS was 5.9 (median 6, range 0 –19). Prostate volume was confirmed by transrectal ultrasonography (TRUS), and those patients with prostate volumes ⬎50 cm3 were treated with 2– 4 months of androgen deprivation using a combination of nonsteroidal antiandrogens and depot luteinizing hormone-releasing hormone. Of the 150 patients, 46 (31%) had a short course of prior androgen ablative therapy. The mean prostate volume before hormone administration was 60 cm3 but ranged to 89 cm3. The mean and median prostate volume at the time of implantation for the entire group was 35 cm3, and for those requiring downsizing with androgen ablation, it was also 35 cm3. Technique All implants were preplanned with TRUS mapping of the prostate according to the Seattle technique, as previously described by Prestidge et al. (4). A pubic arch evaluation was undertaken by TRUS as part of the mapping procedure. Planning was accomplished using MMS software (MultiMedical Systems), using a modified peripheral loading distribution of radioactivity (5, 6). The dosimetric parameters aimed for a V150 of 45–50% of the prostate and a V200 of 12–15%. The maximal urethral dose was planned to be ⬍150% of the prescribed dose (i.e., ⬍220 Gy). All implants were transperineal, guided by both template and TRUS. 125I (Oncoseed, Nycomed Amersham) seeds were placed into the prostate using preloaded needles according to the preplan. Sagittal TRUS images were used to verify all needles destined for the base of the prostate. Fluoroscopy was used after each row of needles had been inserted to verify the relative depths of insertion. The mean activity per seed was 0.317 mCi (range 0.27– 0.37). The prescribed dose to cover the planning target volume was 145 Gy (Task Group No. 43) (7). The median number of seeds per patient was 103 (range 67–140). All implants but two were performed under general anesthesia. Cystoscopy was routinely performed at implant completion to check for loose seeds in the bladder and to evacuate any clots. The first 50 patients were encouraged to
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spend 1 night in the hospital for observation. Most of the more recent implants were performed as outpatient procedures. Patients were discharged without a catheter after a voiding trial. All patients were prescribed an ␣-blocker such as terazosin, doxazosin, or tamsulosin for a minimum of 3 months. Routine steroids were not used. Quality assurance Patients returned 4 weeks after brachytherapy for assessment. All patients underwent a chest X-ray to look for migratory seeds in the lungs, serum PSA determination, orthogonal pelvic simulator films for manual seed identification, and CT of the prostate (3-mm slices). A urethral catheter was inserted at the time of the CT scan to help in urethral identification. For the first 98 patients, the prostate was contoured on the CT scan with the help of the TRUS preplan images. Since September 2000, all patients have also undergone MRI of the prostate (n ⫽ 52). The prostate was contoured on the MRI after MRI/CT fusion using Picker AcQsim multimodality technology. Seeds were identified using CT images and MMS software, but manually verified. Implant quality (8) was evaluated in terms of the V100 (percentage of prostate receiving the prescribed 145 Gy), D90 (dose in Gray received by 90% of the prostate), V200 (percentage of prostate receiving twice the prescribed dose), and maximal and average urethral doses. Follow-up After the 1-month assessment, patients were seen at 3 and 6 months, and then, alternating with their referring urologist, at 6-month intervals. The PSA and IPSS evaluations were collected every 3 months. AUR was defined as any need for catheterization after brachytherapy. No patient who required a catheter at any time was excluded. Those patients who had had a routine catheter inserted postoperatively were not counted as having been in retention unless they had been unable to void after removal of the catheter. Statistical analysis The technical and clinical factors (except for the prior use of hormonal therapy) were compared between the 2 groups (AUR vs. no AUR) using the Wilcoxon rank-sum test with the normal approximation. A nonparametric approach was chosen because of uncertainty whether the data followed a normal distribution. Prior use of hormonal therapy was tested as a variable using the Fisher exact test. Logistic regression analysis was used to test the impact of more than one variable on the occurrence of AUR (9). RESULTS The median follow-up was 13 months (range 3–27). The rate of urinary retention requiring catheterization after implantation was 13% (20 of 150). The time of onset was variable, but most occurred soon after implantation, 6 within the first 24 h, 9 between Days 2 and 7, and 2 in the second week. The remaining 3 were late onset at 2, 5, and
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Fig. 1. Median IPSS with respect to interval after brachytherapy.
5 months. Two of these men continued intermittent selfcatheterization for 18 months. The third was catheterized for severe urinary symptoms, but was not in retention, and the catheter was removed after 4 days. The mean duration of catheterization for those men who have recovered spontaneous voiding was 5 weeks (median 2). Five patients (3%) were still catheter dependent at a median time of 8 months (range 3–18). Four of the 5 had had prior androgen ablation for downsizing the prostate from a mean of 71 cm3 to a mean of 43 cm3. Three required intermittent self-catheterization at last follow-up (at 8, 12, and 18 months). Two were gradually improving. One patient had a suprapubic tube at 6 months, and 1 had an indwelling catheter at 3 months. No patient has yet undergone postimplant transurethral resection of the prostate (TURP).
The IPSS after brachytherapy peaked at 1–3 months, began to fall by 6 months, and returned to baseline by 12 months (Fig. 1). Patient factors The contribution of patient factors to AUR after implantation is summarized in Table 1. Neither age nor baseline IPSS was predictive of subsequent urinary retention after implantation. The mean baseline IPSS for those with urinary retention was 6.4 vs. 5.9 for those without retention. However, all those with scores ⱖ7 underwent detailed voiding studies to rule out any significant obstructive uropathy. Androgen ablation was routinely used to reduce the prostate size before implantation for those men with prostates ⬎50 cm3 or with evidence of pubic arch obstruction. Of the
Table 1. Mean values for possible factors contributing to AUR after brachytherapy
Age (y) IPSS score Prior HT Prostate volume (cm3) Seeds (n) V100 (%) V150 (%) D90 (Gy) V200 (%) Average urethral dose (Gy) Maximal urethral dose‡ (Gy)
AUR
No AUR
p*
66.5 6.4 11/20 39.8 112 90 52 149 23 157 204
64.8 5.9 35/130 34.3 103 91 53 152 25 167 210
0.5 0.8 0.018† 0.003 0.006 0.6 0.5 0.6 0.4 NS 0.5
Abbreviations: AUR ⫽ acute urinary retention; IPSS ⫽ International Prostate Symptom Score; HT ⫽ hormonal therapy; V100 ⫽ percentage of prostate receiving full 145-Gy prescribed dose; V150 ⫽ percentage of prostate receiving 150% of prescribed dose (or 220 Gy); D90 ⫽ dose in Gray received by 90% of prostate; V200 ⫽ percentage of prostate receiving twice the prescribed dose. * Univariate analysis using Wilcoxon rank-sum test. † Proportion with prior hormones based on Fisher’s exact test. ‡ Urethra identified by urinary catheter on 1-month postimplant CT scan.
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Fig. 2. Relationship of prostate volume (in cubic centimeters) to number of seeds. The 2 outliers were the first and second cases planned.
20 men with urinary retention after implantation, 11 (55%) had had prior hormonal therapy, compared with 35 (27%) of the 130 without postimplant retention (p ⫽ 0.018). The AUR rate of men requiring downsizing before implantation was 24% compared with 8.7% of those who presented with an acceptable prostate size. The prostate volume was larger at the time of implantation in the group who developed urinary retention, 39.8 cm3 vs. 34.3 cm3 for those without retention (p ⫽ 0.003). Physical factors The physical factors are summarized in Table 1. The mean D90 for the 150 patients was 151 Gy, the mean V100 was 91% (median 93%), and mean V200 was 24%. The mean and median maximal urethral dose was 209 Gy, and the mean of the average urethral dose per patient was 165 Gy (range 103–208). None of these dosimetric factors was predictive of urinary retention after implantation. The number of seeds per implant was predictive; it was 103 for those without urinary retention vs. 112 for those with it (p ⫽ 0.006). The number of seeds is, however, proportional to the prostate volume at the time of planning (Fig. 2), given the narrow range of seed activity (0.27– 0.37 mCi/seed) and a consistent planning policy. In multivariate analysis, both prostate volume at the time of implant and prior hormonal therapy remained significant, with p values of 0.0033 and 0.0073, respectively. A fitted curve (Fig. 3) showing the risk of urinary retention according to prostate volume for those patients with and without prior hormonal therapy revealed a distinct separation of the curves. Those requiring a short course of androgen ablation
to reduce prostate size before brachytherapy were 4 times more likely to have AUR (odds ratio ⫽ 4, 95% confidence interval 1.5–11). DISCUSSION The popularity of prostate brachytherapy is partially attributable to a perceived favorable toxicity profile. Some degree of urinary morbidity related to urethritis and prostatitis is common in the postimplant period. Symptoms tend to peak at about 2 months (10), with maximal IPSS at 1 month (11), but improve with time, as do function and bother scores (12). Severe long-term urinary morbidity is reported in 3–12%. Health-related quality of life returns to near baseline by 3 months (13), and patients’ overall satisfaction is high at 6 months. The use of ␣-blockers routinely after brachytherapy is common (14, 15) and precludes grading of urinary toxicity by systems such as that suggested by Gelblum et al. (16) or Brown et al. (17) (Table 2). The most distressing adverse event is AUR requiring catheterization. Often this is only a brief setback, and spontaneous voiding is quickly reestablished. However, the occasional patient will require a prolonged period of intermittent self-catheterization, a suprapubic tube, or TURP (15, 16, 25). This clearly can have a major impact on the patient’s quality of life. In the present series, 13% of men required catheterization at some point beyond the 24-h postimplant period. For those men who resumed spontaneous voiding, the median duration of catheterization was 2 weeks (mean 5). However, 5 men remained catheter dependent at 3–18 months. Clarification of the factors predispos-
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Fig. 3. Risk of urinary retention according to prostate volume for men with and without prior hormonal therapy: observed values, fitted model, and 95% confidence intervals. The multivariate analysis consisted of logistic regression in which the outcome variable was whether the patient had AUR and the explanatory variables were volume and prior hormone use. Because the value for any 1 patient was either 1 or 0 (retention or no retention), no data points occur between these y-axis values. Figure 3 shows the dependency, as prescribed by the equation obtained in the model fitting, of the probability of AUR for any particular prostate volume with and without prior hormones. In this way, the average probability of AUR for a volume of 40 cm3 was 10% if no prior hormonal therapy was given and 32% for the same volume after downsizing. The vertical bars show the 95% confidence interval for the above numbers.
ing to AUR after brachytherapy would be useful in counseling patients for whom lifestyle and quality of life are often important deciding factors in their treatment decision. AUR is reported in 2–33% (Table 3). Most resolve with medical management, so that eventual TURP is required in only 1– 6%. The various potential predictive factors can be divided into pretreatment factors such as patient age, baseline urinary function as evaluated by IPSS or American Urologic Association score, prior use of hormonal therapy, and prostate volume. Predictive factors in this category can be used in counseling patients before their treatment decision. Posttreatment or technical factors would include the number of needles and number of seeds used and various dosimetric parameters such as V100, D90, V200, and urethral dose. Knowledge of the predictive factors in this group can be used in defining planning parameters to minimize risk.
Prostate volume Gelblum et al. (16) reported only a 2.2% rate of AUR in 600 patients, but a 5% TURP rate. Prostate volume (⬎35 cm3) predicted for a higher incidence of Grade 2 toxicity, but not retention or TURP. Han et al. (18) reviewed the outcome of 160 consecutive brachytherapy patients by means of a patient questionnaire to determine the incidence of emergency room visits, catheterization, and hospitalization. Thirty-three percent of patients required catheterization, 11% were still catheterized at 1 month, and 3 patients (2%) were at 12 months. Prostate volume was an independent predictor of AUR, with a relative risk of 17 (confidence interval: 13–18) for prostates 40 cm3 compared with 20 cm3. Lee et al. (14) found a 12% AUR rate for 91 patients. Significant factors for urinary retention were the number of
Table 2. Modified RTOG grading system Grade 0 Grade 1 Grade 2 Grade 3
No change Frequency or nocturia; dysuria, urgency, or bladder spasm requiring no or minimal intervention, such as pyridium Frequency with urgency and nocturia requiring alpha-blocker therapy Obstructive symptoms requiring an in-dwelling catheter or posttreatment TURP
Abbreviations: RTOG ⫽ Radiation Therapy Oncology Group; TURP ⫽ transurethral resection of the prostate. Data from Geblum et al. (16) and Brown et al. (17).
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Table 3. Summary of published rates of AUR following prostate brachytherapy Predictive factors for AUR Author
Year
Patients (n)
AUR (%)
Volume
Brown et al. (17) Present series Ciezki et al. (32) Friedland et al. (33) Gelblum et al. (16) Han et al. (16) Lee et al. (14) Merrick et al. (15) Storey et al. (34) Terk et al. (25) Thomas et al. (27) Wang et al. (35)* Zelefsky et al. (36)
2000 2001 2001
87 150 194
6 13 10.8
X X*
2001 1999 2000 2000 2000 1999 1998 2000 2000 1999
457 693 160 91 170 206 251 50 33 245
8.4 2.2 33 12 6 11 5.6 12 35 3
Total activity
IPSS
Prior HT
TURP (%)
X
X
X X 5
X X† 1.2 X‡ X‡
X
X
2.5
Abbreviations as in Tables 1 and 2. All prostates ⬎50 cm3. * prostate length † also number of needles and postimplant CT volume. ‡ Univariate only, dropped out on multivariate analysis.
needles (p ⬍0.038), prostate volume (p ⬍0.048), planning ultrasound target volume (p ⬍0.02), and postimplant CT volume (p ⬍0.021). Only univariate analysis was undertaken. Clearly, the number of needles related to the gland volume, just as the number of seeds reflected the prostate volume in the present series. Postimplant prostate volume is an interesting factor, as larger volumes may well reflect prolonged prostatic edema after implantation. However, the assessment of prostate volume by CT can be subjective and is prone to considerable interobserver variation (19, 20). Prostate volumes evaluated on CT scan are typically significantly larger than those determined by MRI or TRUS (21–24). Evaluation by MRI or TRUS would be necessary to be confident about any association. Terk et al. (25) reported a 5.6% retention rate for 251 patients. The median time to spontaneous voiding was 4 weeks. In univariate analysis, the TRUS prostate volume was predictive of AUR, with a rate of 4.4% for volumes ⬍50 cm3 and 16% for larger volumes (p ⫽ 0.02). However, in multivariate analysis, this factor dropped out, leaving only pretreatment IPSS and prior hormone use as significant. In contrast to the present series and the findings of Lee et al. (14), Brown et al. (17) found that the 6% rate of AUR for 87 patients was related to the total activity implanted and the number of sources, but not to the prostate volume or any dosimetric parameters. Merrick et al. (26) and Thomas et al. (27) reported on the influence of the transitional zone (TZ) volume as opposed to total prostate volume for predicting urinary morbidity and retention after brachytherapy. Thomas et al. found an AUR rate of 12% in 50 patients that, in univariate analysis, was dependent on total prostate volume, number of seeds, and TZ volume. In multivariate analysis, only the TZ volume
was predictive. For TZ volumes ⬍50 cm3, the AUR was 0%, for those 50 – 60 cm3, it was 33%, and if the TZ volume was ⬎60 cm3, the retention rate was 71%. In contrast, Merrick et al. (26) found that the TZ index (prostate volume/TZ volume) correlated with the time for normalization of IPSS and the maximal IPSS, but not with the need for catheterization. However, the mean TZ volume in the series of Merrick et al. was 7 cm3, much smaller than the range of TZ volumes found to be predictive in the series of Thomas et al. (27). Baseline bladder function The report by Gelblum et al. (16) on 600 patients had a very low incidence of urinary retention (2.2%) but a 5% incidence of postimplant TURP. The duration of Grade 2 toxicity was related to the preimplant IPSS, with a score ⬎7 predictive of a higher rate of Grade 2 toxicity at 60 days (59% vs. 32%, p ⫽ 0.001). The mean preimplant IPSS for the 28 men requiring TURP was 13. Terk et al. (25) also found the preimplant IPSS to be predictive of urinary retention. In their series of 251 patients, 29% required catheterization if their baseline IPSS was ⬎20 compared with 2% if it was ⬍10. The pretreatment IPSS remained significant in the multivariate analysis (p ⫽ 0.029). In the present series, all men with an IPSS ⱖ7 underwent detailed voiding studies. Those with findings of significant obstruction (maximal flow rates ⬍10 mL/s) or postvoid residual urine volumes (⬎60 cm3) were counseled of their increased risk of becoming catheter dependent for an indefinite period after brachytherapy and consequently frequently chose alternate therapy. This careful screening of all candidates with preexisting lower urinary tract symptoms introduced an obvious selection bias when assessing the
Risk of AUR after TRUS-guided prostate seed implantation
utility of the IPSS questionnaire in predicting for urinary retention after brachytherapy. The published evidence (16, 25) that an elevated IPSS predicted for more severe urinary symptoms after brachytherapy was indeed the basis of our policy. Our findings do not refute the usefulness of the IPSS questionnaire in this setting, but rather suggest that if there is no urodynamic evidence of significant flow impairment, those patients with an elevated IPSS have the same risk of postimplant retention as those who score more favorably. It may not be necessary to exclude such patients from brachytherapy on the basis of a high IPSS alone. Prior androgen ablation Androgen ablation is frequently used before brachytherapy to reduce the size of prostates that have a TRUS volume ⬎50 – 60 cm3 (22, 28). Larger prostates are technically difficult to implant, largely because of pubic arch interference, and are also associated with more severe urinary symptoms in the immediate postimplant period, with more Grade 2 and 3 toxicity (14, 18, 20, 25). Frazier et al. (29) found a mean prostate volume reduction of 29% after 3 months of androgen deprivation in a series of 60 patients. Nine of 13 patients whose prostates were still too large after 3 months showed a further 20% reduction with an additional 3 months of androgen ablation. Similarly, Stone et al. (30) reported an average 35% volume decrease when patients were treated with 3 months of androgen ablation before implantation. Most patients received the hormonal therapy because of unfavorable tumor factors (PSA ⬎10 ng/mL, Gleason score ⱖ7, or Stage T2b disease or greater). Glands ⬍40 cm3 reduced by an average of 29% and those ⬎40 cm3 reduced by 41%. In the present series, androgen ablation was used to reduce the prostate size in 31% of patients. The mean gland size for those who did not require prior downsizing was 35 cm3; the preimplant/posthormone volume for those benefiting from a short course of androgen ablation was identical at 35 cm3. Unfortunately, despite the volume reduction, the prior hormone group remained at an increased risk of postimplant urinary retention, 24% compared with 8.7% for those not requiring downsizing. Other investigators have reported the influence of prior
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androgen ablation. In the report by Terk et al. (25) of 251 patients, 114 were implanted with 103Pd and 137 with 125I. Palladium was used for unfavorable tumor factors or if the patient had had prior hormonal therapy. A total of 90 patients had the combination of hormones and palladium. In this subgroup, those who had a persistent IPSS ⬎10 after 3 months of androgen ablation had a 37% risk of urinary retention after implant. In multivariate analysis, the combination of hormonal therapy and palladium predicted for urinary retention. The two factors could not be analyzed separately nor could the influence of prior hormonal therapy be examined for those patients treated with 125I. Other factors No dosimetric factors consistently predicted for AUR. The V150 was reported by Gelblum et al. not to be predictive of urinary toxicity. Wallner et al. (31) reported urethral doses ⬎400 Gy to be associated with increased Grade 2–3 urinary morbidity. With modified peripheral loading, one aims to keep the urethral dose to ⬍150%, and in the present series, the mean maximal urethral dose was 210 Gy. Merrick et al. (15) reported that in 170 patients, of whom only 1 required a catheter for ⬎5 days, the average urethral dose was 115% of the prescribed dose. Although it is not evident from the present series, it is possible that a lower planned urethral dose would decrease the risk of retention. CONCLUSIONS AUR is the most common adverse event after permanent seed, low-dose-rate prostate brachytherapy. Prior knowledge of an individual’s relative risk of AUR would be useful in counseling patients before the procedure. In this series of 150 consecutive implants, prostate volume and the use of prior hormonal therapy to downsize the prostate were independent predictors of AUR. The systematic use of the IPSS questionnaire to screen patients and to direct those with significant lower urinary tract symptoms for detailed urodynamic studies permitted us to implant those patients with higher scores without an increased incidence of AUR. We are currently looking at the component parts of the overall volume (transitional zone vs. peripheral zone) to see whether this predictive capacity can be further refined.
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24. Rasch C, Barillot I, Remeijer P, et al. Definition of the prostate in CT and MRI: A multi-observer study. Int J Radiat Oncol Biol Phys 1999;43:57– 66. 25. Terk MD, Stock RG, Stone NN. Identification of patients at increased risk for prolonged urinary retention following radioactive seed implantation of the prostate. J Urol 1998;160: 1379 –1382. 26. Merrick GS, Butler WM, Galbreath RW, et al. Relationship between the transition zone index of the prostate gland and urinary morbidity after brachytherapy. Urology 2001;57:524 – 529. 27. Thomas MD, Cormack R, Tempany CM, et al. Identifying the predictors of acute urinary retention following magnetic-resonance-guided prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000;47:905–908. 28. Potters L, Torre T, Ashley R, et al. Examining the role of neoadjuvant androgen deprivation in patients undergoing prostate brachytherapy. J Clin Oncol 2000;18:1187–1192. 29. Frazier A, Kaufman N, Rosemberg S, et al. Prostate volume induced by neoadjuvant androgen ablation in preparation for permanent radioactive seed implantation. Radiother Oncol 2000;55:77. 30. Stone NN, Stock RG. Neoadjuvant hormonal therapy improves the outcomes of patients undergoing radioactive seed implantation for localized prostate cancer. Mol Urol 1999;3: 239 –244. 31. Wallner K, Roy J, Harrison L. Dosimetry guidelines to minimize urethral and rectal morbidity following transperineal I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 1995;32:465– 471. 32. Ciezki JP, Angermeier K, Ulchaker J, et al. The effect of anatomic and dosimetric variables on urinary obstruction following permanent Iodine-125 prostate brachytherapy. J Brachytherapy Intl 2001;17:49. 33. Friedland JL, Tsao A, Pow-Sang JM, et al. Urinary retention following prostate brachytherapy. J Brachytherapy Intl 2001; 17:48. 34. Storey MR, Landgren RC, Cottone JL, et al. Transperineal 125 Iodine implantation for treatment of clinically localized prostate cancer: 5-year tumour control and morbidity. Int J Radiat Oncol Biol Phys 1999;43:565–570. 35. Wang H, Wallner K, Sutlief S, et al. Transperineal brachytherapy in patients with large prostate glands. Int J Cancer 2000;90:199 –205. 36. Zelefsky MJ, Wallner KE, Ling CC, et al. Comparison of the 5-year outcome and morbidity of three-dimensional conformal radiotherapy versus transperineal permanent Iodine-125 implantation for early-stage prostatic cancer. J Clin Oncol 1999; 17:517–522.