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Analysis of Urinary Function Using Validated Instruments and Uroflowmetry After Primary and Salvage Prostate Cryoablation
Outcomes Analysis of Urinary Function Using Validated Instruments and Uroflowmetry After Primary and Salvage Prostate Cryoablation Masaki Kimura, Vladimir Mouraviev, Matvey Tsivian, Daniel M. Moreira, Janice M. Mayes, and Thomas J. Polascik OBJECTIVES METHODS
RESULTS
CONCLUSIONS
To evaluate changes in urinary function after cryoablation for clinically localized prostate cancer and to investigate risk factors that predict changes in urinary function after surgery. Among the patients who underwent primary or salvage cryoablation between January 2002 and May 2008, 74 patients (50 primary and 24 salvage) with both a preoperative and postoperative urinary function domain score and uroflowmetry were included in this study. The mean age was 66.8 ⫾ 7.5 years and the mean follow-up period was 42.5 ⫾ 20.3 months. The changes in postoperative urinary function were evaluated on the basis of several categorized groups, including surgical method, preoperative urinary symptoms, and prostate volume. Of 74 patients, 2 (2.7%) presented with mild stress incontinence after cryoablation. No patient presented with persistent urinary retention or urethral fistula. When comparing postoperative International Prostate Symptom Score (IPSS) and bother index scores with preoperative scores, it was found that on average IPSS and bother index recovered 12 and 18 months after cryoablation, respectively, and continued to improve after recovery. Only salvage cryoablation correlated with deteriorating urinary function in a logistic regression model (P ⫽ .032). However, it was noted that the patients with preoperative moderate to severe urinary symptoms and larger prostate volume showed improvement of urinary function after cryoablation. No associations were found between worsened urinary function and prostate volume, comorbidities (hypertension, obesity, and diabetes), or sexual function. Cryoablation is a minimally invasive surgery for localized prostate cancer. This study is the first to demonstrate the ability of cryoablation in terms of maintaining and potentially improving urinary function using validated instruments and uroflowmetry assessments. UROLOGY 76: 1258 –1265, 2010. © 2010 Elsevier Inc.
I
n the 1960s, the first report of prostate cryoablation was published by Gonder et al;1 however, the imprecision and immature technology resulted in unpromising oncological outcome and morbidity rates. Presently, because of improved and more developed cryotechnology, cryoablation has become an established minimally invasive surgery for localized prostate cancer (PCa) in both the primary and salvage setting.2-4 Third-generation cryoablation, driven by the Joule-Thomson effect using argon– helium gas, 17-gauge cryoneedles, and real-time ultrasound guided imaging has significantly improved both oncological and morbidity outcomes after surgery.2,5,6 Currently, patients are given multiple therapeutic options for treating localized PCa, which may further complicate the decision-making process. Regarding localized From the Division of Urologic Surgery, Department of Surgery, Duke Prostate Center, Duke University Medical Center, Durham, North Carolina Reprint requests: Thomas J. Polascik, M.D., Duke University Medical Center, Box 2804 Yellow Zone Durham, NC 27710. E-mail: [email protected] Submitted: August 15, 2009, accepted (with revisions): September 29, 2009
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© 2010 Elsevier Inc. All Rights Reserved
PCa, factors other than oncologic outcome may apply when making a treatment choice. Ideally, physicians can guide patients toward appropriate curative treatment modalities with minimum morbidity, taking into account the patient’s risk tolerance.7 Thus, both physicians and patients need to understand the risks and benefits of therapy choices, because an aggressive treatment can bring higher morbidity and regret.8 With the exception of erectile dysfunction, cryoablation—a minimally invasive surgery for localized PCa— can provide lower complication rates.5,9,10 After cryoablation, there are several potential forms of associated morbidity: perineal pain, urinary tract infection, urethral stricture, urethral fistula, voiding dysfunction including lower urinary tract symptoms (LUTS), incontinence, retention, and diminished sexual function.11,12 Using a urethral warming catheter and monitoring temperatures during the procedure with a thermosensor dramatically reduced the incidence of urinary complications seen with first- and second-generation cryoablation devices.13 0090-4295/10/$36.00 doi:10.1016/j.urology.2009.09.062
In this study, we evaluate urinary function longitudinally by using validated instruments and uroflowmetry after cryoablation from several perspectives. Additionally, risk factors associated with deteriorating urinary function after ablation were analyzed with several preoperative variables.
MATERIAL AND METHODS Patient Selection, Assessment, and Follow-Up Between January 2002 and October 2008, a total of 74 patients with complete records regarding urinary function were included in this study. The mean follow-up period was 42.5 ⫾ 20.3 months. All patients with biopsy-proven PCa underwent cryoablation as primary or salvage therapy. All primary patients were diagnosed with T1c or T2 disease according to the American Joint Committee on Cancer classification (2002 staging system). Urinary function was evaluated using the International Prostate Symptom Score (IPSS), bother index (BI), uroflometry, and measurement of postvoid residual (PVR), preoperatively and postoperatively. The mean time period for preoperative measurement of uroflowmetry (peak flow rate) and PVR was 9.2 ⫾ 10.5 months after surgery. The PVR was determined by ultrasonography. Postoperative temporary incontinence was defined as stress or urge incontinence requiring any protective pad within 5 weeks of surgery. Persistent incontinence was defined as prolonged incontinence after 5 weeks from surgery. Postoperative temporary urinary retention was defined as the need to reinsert the catheter after its removal within 5 weeks of surgery. Additionally, persistent retention was defined as requiring long-term (⬎3 weeks) suprapubic or Foley catheter placement after 5 weeks from surgery. An informed consent was obtained from all patients.
Cryoablation Procedure The procedure was performed by a single surgeon (T.J.P.). All patients underwent a dual freeze-thaw cycle using argon gas (third-generation cryotechnology) with 17-gauge cryoneedles (SeedNet, Galil, Plymouth Meeting, PA). For the cryoablation procedure, the patient is placed in a lithotomy position under general anesthesia and a Foley catheter is placed. Using transrectal ultrasound guidance, 17-gauge cryoprobes were sequentially placed through a brachy template into the prostate by standard protocol. Appropriate needle positioning is verified by ultrasound image in both the sagittal and the transverse dimensions; a thermocouple is placed at the level of the urinary sphincter as well as in Denonvillier’s fascia. Cystoscopy is performed to ensure the cryotherapy needles did not violate the urethra, and a urethral warming catheter is subsequently placed to maintain a temperature of approximately 42°C during the procedure. The urinary sphincter is maintained at temperatures ⬎0°C, and freezing is stopped when the iceball reaches the anterior rectal wall and the posterior prostatic capsule is at least ⫺20°C. A dual freeze-thaw cycle is used. After the final passive thaw, the urethral warming catheter remains in situ for an additional 20 minutes. All cryoprobes are then removed and a Foley catheter is placed. The patient is discharged and a voiding trial is performed within 1-2 weeks.
Analysis of Urinary Function and Predictive Factors For subjective and objective assessment of urinary function regarding cryoablation, IPSS, BI, and uroflometry—including UROLOGY 76 (5), 2010
peak flow rate, voided volume, and PVR—were measured preoperatively and postoperatively. Deterioration of urinary function was defined when the category of total IPSS score (ie, mild [IPSS 0-7], moderate [IPSS 8-19], and severe [IPSS 20-35])14 changed to a higher category at the last follow-up time point as compared with preoperative IPSS categories. Several variables were analyzed including age, clinical stage, surgery type (primary or salvage), administration of hormonal therapy, prostate volume measured by TRUS, catheterization period, prostatespecific antigen (PSA) nadia, preoperative PSA, IPSS, BI, peak flow, PVR, International Index of Erectile Function 5, LUTS, incontinence, medical comorbidities (hypertension and diabetes), and body mass index were analyzed to determine predictive factors.
Statistical Analysis Student t test and the Mann–Whitney test were used to compare continual variables, whereas the 2 and Fisher’s exact test were used to compare categorical variables. A Wilcoxon signedrank test was used for comparing preoperative and postoperative IPSS, BI, peak flow, and PVR. For univariate and multivariate analysis, logistic regression was used to determine correlated factors involving any change in urinary function, and P ⬍.05 was considered statistically significant. All statistical analyses were performed using STATA software (StataCorp 2007. Stata Statistical Software: Release 10. College Station, TX: StataCorp LP).
RESULTS Baseline Characteristics The baseline characteristics of this cohort are summarized in Table 1. Of the 74 patients, only 2 (2.7%) presented with prolonged mild stress incontinence after cryoablation. No patients presented with persistent urinary retention or urethral fistula. A total of 11 primary patients were subjected to temporary hormonal therapy (within 3 months of cryotherapy) and 11 salvage patients were exposed to temporary hormonal therapy at the time of radiation therapy, which was discontinued before surgery. A total of 16 patients were subjected to medications for benign prostate hyperplasia such as ␣-blocker therapy or anticholinergic therapy before surgery. Changes of Urinary Function After Cryoablation The mean IPSS scores of the overall cohort at 0 (baseline), 6, 12, 18, 24, and 36 months were 8.5, 10.0, 7.6, 6.9, 6.6, and 6.5, respectively, and the corresponding scores for mean BI were 1.9, 2.1, 3.2, 1.8, 1.3, and 1.4, respectively. The changes in IPSS and BI after cryoablation are detailed in Figure 1A. When comparing posttreatment IPSS with preoperative scores, the mean IPSS minimally worsened at 6 months after surgery; however, it continued to improve beyond 12 months. Although the mean BI worsened from 6 to 12 months when compared with preoperative scores, it improved 18 months after surgery. Regarding uroflowmetry, Table 2 summarized the changes of peak flow and PVR within several categories. No significant difference of the mean peak flow between pre- and post-treatment was found in the 1259
Table 1. Demographic and baseline characteristics of patients
Variable Age (y) Mean ⫾ SD Median (range) Preoperative PSA (ng/mL) Mean ⫾ SD Median (range) Clinical stage, n (%) T1c T2 BPH medications, n (%) Yes No Hormonal Tx, n (%) Yes No Prostate volume (cm3) Mean ⫾ SD Median (range) Catheterization period (d) Mean ⫾ SD Median (range) Preoperative IPSS Mean ⫾ SD Median (range) Preoperative BI Mean ⫾ SD Median (range) Preoperative IIEF5 Mean ⫾ SD Median (range) HTN, n (%) Yes No DM, n (%) Yes No BMI, n (%) ⬍25 25-30 ⱖ30
Entire Cohort
Primary
Salvage
74
50
24
66.8 ⫾ 7.5 67.0 (50-83) 5.77 ⫾ 4.28 4.95 (0.1-19.9)
68.4 ⫾ 7.0 68.5 (54-83) 5.74 ⫾ 3.67 5.0 (0.3-19.8)
63.5 ⫾ 7.6 64.0 (50-82) 5.85 ⫾ 5.41 4.55 (0.1-19.9)
P .008 .470 .394
48 (75.0) 16 (25.0)
38 (77.6) 11 (22.4)
10 (66.7) 5 (33.3)
16 (22.6) 58 (78.4)
12 (24.0) 38 (76.0)
4 (16.7) 20 (83.3)
22 (29.7) 52 (70.3)
11 (22.0) 39 (78.0)
11 (45.8) 13 (54.2)
.558 .036
25.1 ⫾ 11.0 22.8 (8.1-68.7)
28.4 ⫾ 11.0 27.1 (10.8-68.7)
18.3 ⫾ 7.3 16.7 (8.1-37.5)
9.8 ⫾ 4.8 9 (2-29)
9.5 ⫾ 4.4 9.0 (5-27)
10.4 ⫾ 7.3 8.5 (2-29)
8.5 ⫾ 6.5 7.5 (0-33)
8.2 ⫾ 6.0 7.0 (0-24)
9.2 ⫾ 7.6 9.5 (0-33)
1.9 ⫾ 1.4 2 (0-6)
1.9 ⫾ 1.5 2 (0-6)
1.7 ⫾ 1.1 2 (0-4)
7.4 ⫾ 6.7 5 (1-24)
6.5 ⫾ 6.4 4 (1-24)
9.3 ⫾ 7.0 7.5 (1-24)
⬍.001 .387 .702 .734 .762 .382
44 (59.5) 30 (40.5)
28 (56.0) 22 (44.0)
16 (66.7) 8 (33.3)
18 (24.3) 56 (75.7)
13 (26.0) 37 (74.0)
5 (20.1) 19 (79.2)
9 (13.4) 28 (41.8) 30 (44.8)
9 (19.5) 20 (43.5) 17 (37.0)
0 (0.0) 8 (38.1) 13 (61.9)
.628 .034
SD ⫽ standard deviation; PSA ⫽ prostate-specific antigen; BPH ⫽ benign prostate hyperplasia; Tx ⫽ treatment; IPSS ⫽ International Prostate Symptom Score; BI ⫽ bother index; IIEF-5 ⫽ International Index of Erectile Function; HTN ⫽ hypertension; DM ⫽ diabetes mellitus; BMI ⫽ body mass index.
entire cohort (P ⫽ .154). Although, the corresponding mean PVR improved from 61.3 ⫾ 81.6 to 46.8 ⫾ 40.5 mL, there is no statistical difference between pre- and postoperative PVR (P ⫽ .415). Risk Factor Analysis Table 3 summarizes univariate and multivariate analysis regarding factors potentially influencing changes in urinary function after cryoablation. Of 74 patients, 16 (22%) changed to a higher urinary symptomatic category as compared with their preoperative baseline category. In univariate analysis, salvage cryoablation (P ⫽ .006), lower prostate volume (P ⫽ .034), and longer catheterization period after cryoablation (P ⫽ .030) were correlated with worsened urinary function regarding total IPSS. However, medical comorbidities (hypertension: 1260
P ⫽ .395, obesity: P ⫽ .594, and diabetes: P ⫽ .559), preoperative urinary function (IPSS: P ⫽ .126, BI: P ⫽ 0.372, peak flow: P ⫽ .419, and PVR: P ⫽ .960), and sexual function (International Index of Erectile Function: P ⫽ .253) did not demonstrate any correlation with worsened urinary function after cryoablation. In multivariate analysis, only salvage cryoablation remained statistically significant (P ⫽ .032). Changes in Urinary Function With Primary and Salvage Cryoablation When comparing between primary and salvage cryoablation regarding IPSS and BI scores, salvage cryoablation demonstrated a worsened postoperative IPSS and BI score than primary cryoablation. The changes in IPSS and BI in relation to primary or salvage cryoablation are UROLOGY 76 (5), 2010
Figure 1. (A) Changes in mean International Prostate Symptom Score (IPSS) and mean bother index (BI) score after prostate cryoablation in entire cohort. The numbers of evaluated patients at the each time point ranged from 29 to 74. (B) Changes in mean IPSS and BI score after primary and salvage prostate cryoablation. (C) Changes in mean IPSS and BI score after prostate cryoablation regarding patients with preoperative mild urinary symptoms (IPSS 0-7) and moderate to severe urinary symptoms (IPSS ⱖ 8). (D) Changes in mean IPSS and BI score after prostate cryoablation regarding patients with smaller prostate volume (⬍30 mL) and larger prostate volume (ⱖ30 mL). * indicates P ⬍.05 between subcategories.
UROLOGY 76 (5), 2010
1261
.294 .037
.445 .112
.153 .217
.415
P
Table 3. Univariate and multivariate analysis of risk factors influencing urinary function after cryoblation
1262
⫹0.4 ⫺39.4 Pre-symptom scores were categorized by mild (IPSS 0-7) and moderate-severe (IPSS ⱖ 8) categories. PVR ⫽ postvoiding residual urine; Pre⫺ ⫽ preoperative; mod ⫽ moderate; PV ⫽ prostate volume.
49.8 ⫾ 74.1 79.7 ⫾ 91.2 ⫺3.8 ⫹2.4 16.4 ⫾ 10.2 16.6 ⫾ 11.1 20.2 ⫾ 10.9 14.2 ⫾ 9.1 50 (67.6) 24 (32.4)
.421 .717
50.2 ⫾ 39.6 40.3 ⫾ 42.5
⫺14.0 ⫺16.2 57.7 ⫾ 65.9 65.8 ⫾ 99.2 ⫺2.8 ⫹0.9 15.7 ⫾ 10.2 18.3 ⫾ 9.5 18.5 ⫾ 12.7 17.4 ⫾ 11.1 38 (51.4) 36 (48.6)
.100 .165
43.7 ⫾ 35.1 49.6 ⫾ 45.3
⫺25.9 ⫹7.2 73.5 ⫾ 92.1 38.2 ⫾ 51.2 ⫹1.7 ⫺7.6 18.3 ⫾ 10.7 13.7 ⫾ 9.4 16.6 ⫾ 9.9 21.3 ⫾ 12.2 50 (67.6) 24 (32.4)
.436 .028
47.6 ⫾ 42.2 45.4 ⫾ 38.1
⫺14.5 46.8 ⫾ 40.5 61.3 ⫾ 81.6 .154 ⫺1.6 16.4 ⫾ 10.4 18.0 ⫾ 10.6
All patients Case type Primary Salvage Pre-symptoms Mild Mod-severe PV (cm3) ⬍30 ⱖ30
74
P Category
Number (%)
Pre (Mean ⫾ SD) Peak Flow (mL/s) Post (Mean ⫾ SD) Differential Pre (Mean ⫾ SD)
Table 2. Changes in peak flow and PVR after cryoablation
PVR (mL) Post (Mean ⫾ SD)
Differential
Variables
OR
95% CI
P
Age Clinical stage (T1c vs T2) Case type (primary vs salvage) Hormonal therapy Prostate volume Catheterization period Preoperative PSA PSA Nadia Preoperative IPSS Preoperative BI Preoperative peak flow rate Preoperative PVR Preoperative IIEF5 Incontinence HTN DM BMI ⬍25 25-30 ⱖ30
0.97 1.44 5.23
Univariate 0.90-1.05 0.38-5.54 1.61-17.00
.416 .592 .006
1.58 0.93 1.15 0.89 0.17 0.93 0.82 1.02
0.49-5.04 0.86-0.99 1.01-1.30 0.76-1.07 0.01-3.12 0.82-1.02 0.52-1.28 0.97-1.09
.445 .034 .030 .224 .230 .126 .372 .419
1.00 0.95 2.39 1.67 0.66
0.99-1.01 0.86-1.04 0.75-7.60 0.51-5.41 0.16-2.64
.960 .253 .140 .395 .559
Ref 1.29 1.53
— 0.27-6.28 0.32-7.30
— .749 .594
Age Case type (primary vs salvage) Prostate volume Preoperative IIEF5 DM
1.00 5.37
Multivariate 0.91-1.09 1.16-24.92
.979 .032
0.96 0.91 0.85
0.89-1.04 0.89-1.02 0.19-3.89
.372 .104 .839
OR ⫽ odds ratio; CI ⫽ confidence interval; PVR ⫽ postvoiding residual urine; LUTS ⫽ lower urinary tract symptoms; HTN ⫽ hypertension; DM ⫽ diabetes mellitus.
detailed in Figure 1B. The mean IPSS at 6, 12, and 18 months were statistically different (P ⬍.001, .007, and .032, respectively) between surgical groups, as were the mean BI at 6 and 12 months (P ⫽ .002 and ⬍.001, respectively). However, at 18 months the mean BI returned toward baseline and did not show a significant difference between surgical groups (P ⫽ .133). With regard to changes of peak flow rate and PVR, peak flow rate improved and PVR reduced postoperatively in primary patients. On the contrary, salvage patients had a worsening peak flow rate and increasing PVR postoperatively. However, both groups did not show any statistical difference between pre- and postoperative scores with respect to peak flow rate and PVR (Table 2). Changes in Urinary Function Regarding Preoperative Urinary Symptoms The changes in IPSS and BI based on preoperative urinary symptom level (mild: IPSS 0-7 vs moderate to severe: IPSS ⱖ 8) are detailed in Figure 1C. When comparing changes in urinary function between these groups, the patients with moderate to severe symptoms showed more improvement after cryoablation than the patients with mild symptoms. The mean IPSS at 6, 12, UROLOGY 76 (5), 2010
and 18 months were statistically different (P ⬍.001, .007, and .032, respectively); however, there was no difference at 24 and 36 months (P ⫽ .066 and .642, respectively) between each subcategories. The mean BI until 12 months was statistically different between each group; however, at 18, 24, and 36 months the mean BI of the moderate to severe patients had improved and come close to the score of those patients with mild symptoms, which did not show a significant difference between each group (P ⫽ .834, .100, and .714, respectively). With regard to changes of peak flow and PVR, the patients with moderate to severe urinary symptoms had an improved flow rate and reduced PVR after surgery; however, both groups did not show any statistically significant difference between preand postoperative score (Table 2).
Changes in Urinary Function Regarding Prostate Volume The IPSS score of patients with a larger prostate volume are detailed in Figure 1D. Patients with prostate volume ⱖ30 or ⬍30 mL were categorized into a larger prostate volume group and smaller prostate group, respectively. The IPSS score of patients with a larger prostate volume had a temporary deterioration at 6 months compared with patients with a smaller prostate volume (P ⫽ .005); however, it recovered to baseline at 18 months (P ⫽ .394) and continued to improve, finally showing better improvement than those who had a smaller prostate volume. In terms of the BI score, the larger prostate group had deteriorated from 6 to 12 months temporally compared with the smaller prostate group (P ⫽ .041 and .013, respectively); however, it recovered at 18 months (P ⫽ .876) and continued to improve. Regarding the comparison of mean peak flow and PVR based on prostate volume pre- and postoperatively, there seemed to be a trend among patients who had larger prostate volume (ⱖ30 mL) to have an improved peak flow rate and reduced PVR (Table 2). In particular, when comparing pre- and postoperative PVR, the volumes significantly decreased postoperatively in the larger prostate volume group (P ⫽ .037).
COMMENT Cryoablation is recognized as an established minimally invasive procedure for the treatment of localized PCa in both the primary and salvage setting.3,5,6 Although several reports detailing oncologic outcomes of cryoablation have been published; there are not many series reporting quality of life (QOL) (eg, urinary function and sexual function) after cryoablation using improved third-generation technology. To our knowledge, this is the first study evaluating urinary function after prostate cryoablation using both uroflowmetry and validated QOL instruments. Outcomes from the Cryo On-Line Data registry reported that among the 1198 consecutive patients who underwent primary cryoablation, 3.6% of patients develUROLOGY 76 (5), 2010
oped urinary retention, 2.1% underwent transurethral resection of the prostate to remove sloughed tissue, and 4.8% developed incontinence with a pad rate of 2.9%.15 Although this is the largest pooled cryoablation multicenter series to date, this study does not report detailed and longitudinal urinary function analyzed using objective and subjective pre- and postoperative data. Ismail et al16 also reported on 100 patients who underwent salvage cryoablation. In this study, 13% of patients developed incontinence, 2% had urinary retention, and 1% had a urethral fistula post-cryoablation. In our study of 74 patients, 6 patients (8.1%) developed temporary urinary retention and no patients required TURP or had persistent urinary retention. Additionally, 7 patients (9.5%) had temporary incontinence with 2 patients (2.7%) having prolonged mild stress incontinence after cryoablation. No patient presented with a recto-urethral fistula. Seemingly, our urinary function morbidity was comparable with other contemporary cryotherapy series, indicating a relatively safe and standardized procedure. Using the American Urological Association Symptom Score (AUASS) to analyze urinary function deterioration after cryoablation, DiBlasio et al17 demonstrated that a lower preoperative PSA and higher biopsy Gleason sum were associated with a higher postoperative AUASS (P ⫽ .008 and .002, respectively) among a cohort of 78 consecutive patients. In addition, a larger prostate volume showed a trend toward worsening LUTS and higher postoperative AUASS outcomes (P ⫽ .070). Interestingly, our data did not demonstrate a positive correlation between deterioration of urinary function and prostate volume (odds ratio,0.96; P ⫽ .372). Conversely, the postoperative urinary function of the patients with moderate to severe symptoms and a larger prostate volume kept improving during the observation period. Additionally, univariate and multivariate analysis of our results may imply that patients with poor preoperative urinary function, pre-existing comorbidities (diabetes, hypertension, and obesity), and a large prostate volumes are amenable to be treated with cryoablation while maintaining urinary function. Regarding differences in QOL between primary and salvage cryoablation, Anastasiadis et al7 reported on 131 consecutive patients who underwent primary and salvage cryoablation using QOL questionnaires. In this study, primary cryotherapy patients fared significantly better in terms of physical and social functioning as compared with salvage cryoablation patients. Moreover, urinary symptoms were significantly more severe in the salvage group. Our study can support these results considering only salvage cryoablation was a risk factor in multivariate analysis. Additionally, the peak flow analysis between pre- and postsalvage cryoablation identified a statistically significant decrease (P ⫽ .028), which could be due to fibrosis in the posterior urethra because of cryoablation of the radiated prostate. 1263
Few published articles report on the longitudinal analyses of changes in IPSS, BI, and uroflowmetry after cryoablation. In a brachytherapy setting, there are several series analyzing urinary QOL including IPSS and uroflowmetry longitudinally, which demonstrated the changes of urinary function after brachytherapy during the entire follow-up period.18-21 Our results of both subjective (IPSS, BI) and objective data (uroflowmetry) revealed an improvement in urinary function after cryoablation within the entire cohort. In particular, urinary function of patients with moderate to severe urinary symptoms or a larger prostate volume improved sufficiently after cryoablation so as to have almost equal, if not better, scores at the end of the follow-up period than the patients with mild symptoms and a smaller prostate volume at preoperative point (Fig. 1C,1D). In addition, our results demonstrated that patients who had stable or improved urinary function after cryoablation had a significantly higher preoperative IPSS and BI score (eg, those with preoperative LUTS compared with patients who had worsened urinary function after surgery. These results suggest that if patients have good voiding function or low urinary symptoms preoperatively, cryoablation will likely not lead to further improvement in urinary function. However, for those patients who had preoperative LUTS (higher IPSS and BI), cryoablation improved urinary function after surgery, thus potentially offering efficacy as therapy for both LUTS and PCa. We assume this phenomenon was derived from the treatment efficacy of cryoablation, based on destroying prostate tissue and shrinking the prostate gland postprocedure thereby improving LUTS. This study has several limitations. First, this is a retrospective report of a prospective database involving a single center; thus, physician-assessed morbidities may induce more subjective factors than in a randomized, blinded study. Second, a formal urodynamics evaluation, which is the gold standard to assess flow and obstruction, was not indicated nor performed. The limitation of uroflowmetry in distinguishing between poor detrusor function and bladder outlet obstruction are previously published.22 Third, our cohort is relatively small (n ⫽ 74), especially in the salvage patients (n ⫽ 24), with intermediate follow-up (mean 42.5 ⫾ 20.3 months). However, we believe that the follow-up in this report is sufficiently long enough to assess any changes in urinary function, because most patients recovered by 12 months and showed further improvement at 18 months. Despite these limitations, our data may suggest that cryoablation is an appropriate, minimally invasive surgery in terms of preserving and potentially improving urinary function after surgery. This could facilitate decision-making for patients who desire to maintain urinary QOL when considering definitive therapy for localized PCa. To better understand the urinary effect of this procedure, further study is needed with longer follow-up and a larger number of patients. 1264
CONCLUSIONS Third-generation cryo-technology is a minimally invasive modality for the treatment of localized PCa in a primary and salvage setting. This study is the first report suggesting that cryoablation can preserve and might improve urinary function during the observation period, even if patients had moderate to severe urinary symptoms or a larger prostate volume preoperatively. Additionally, our results revealed that only the salvage setting is a predictive factor for worsening urinary function after cryoablation; however, there was no correlation with preoperative urinary function, prostate volume, and preexisting comorbidities. Thus, cryoablation is an ideal approach for preserving and potentially improving urinary function in the primary setting for patients who desire minimal surgical morbidity. References 1. Gonder MJ, Soanes WA, Shulman S. Cryosurgical treatment of the prostate. Invest Urol. 1966;3:372-378. 2. Hubosky SG, Fabrizio MD, Schellhammer PF, et al. Single center experience with third-generation cryosurgery for management of organ-confined prostate cancer: critical evaluation of short-term outcomes, complications, and patient quality of life. J Endourol. 2007;21:1521-1531. 3. Ng CK, Moussa M, Downey DB, et al. Salvage cryoablation of the prostate: followup and analysis of predictive factors for outcome. J Urol. 2007;178:1253-57 [discussion: 1257]. 4. Polascik TJ, Mayes JM, Mouraviev V. From whole-gland to targeted cryoablation for the treatment of unilateral or focal prostate cancer. Oncol Williston Park. 2008;22:900-906 [discussion: 906-907: 914]. 5. Bahn DK, Lee F, Badalament R, et al. Targeted cryoablation of the prostate: 7-year outcomes in the primary treatment of prostate cancer. Urology. 2002;60:3-11. 6. Polascik TJ, Nosnik I, Mayes JM, et al. Short-term cancer control after primary cryosurgical ablation for clinically localized prostate cancer using third-generation cryotechnology. Urology. 2007;70: 117-121. 7. Anastasiadis AG, Sachdev R, Salomon L, et al. Comparison of health-related quality of life and prostate-associated symptoms after primary and salvage cryotherapy for prostate cancer. J Cancer Res Clin Oncol. 2003;129:676-682. 8. Schroeck FR, Krupski TL, Sun L, et al. Satisfaction and regret after open retropubic or robot-assisted laparoscopic radical prostatectomy. Eur Urol. 2008;54:785-793. 9. Chin JL, Ng CK, Touma NJ, et al. Randomized trial comparing cryoablation and external beam radiotherapy for T2C-T3B prostate cancer. Prostate Cancer Prostatic Dis. 2008;11:40-45. 10. Chin JL, Pautler SE, Mouraviev V, et al. Results of salvage cryoablation of the prostate after radiation: identifying predictors of treatment failure and complications. J Urol. 2001;165:1937-1941 [discussion: 1941-1942]. 11. Han KR, Cohen JK, Miller RJ, et al. Treatment of organ confined prostate cancer with third generation cryosurgery: preliminary multicenter experience. J Urol. 2003;170:1126-1130. 12. Onik GM, Cohen JK, Reyes GD, et al. Transrectal ultrasoundguided percutaneous radical cryosurgical ablation of the prostate. Cancer. 1993;72:1291-1299. 13. Cohen JK, Miller RJ. Thermal protection of urethra during cryosurgery of prostate. Cryobiology. 1994;31:313-316. 14. Barry MJ, Fowler FJ Jr, O’Leary MP, et al. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol. 1549-57;148 [discussion: 1564, 1992].
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15. Jones JS, Rewcastle JC, Donnelly BJ, et al. Whole gland primary prostate cryoablation: initial results from the cryo on-line data registry. J Urol. 2008;180:554-558. 16. Ismail M, Ahmed S, Kastner C, et al. Salvage cryotherapy for recurrent prostate cancer after radiation failure: a prospective case series of the first 100 patients. BJU Int. 2007;100:760-764. 17. DiBlasio CJ, Derweesh IH, Malcolm JB, et al. Contemporary analysis of erectile, voiding, and oncologic outcomes following primary targeted cryoablation of the prostate for clinically localized prostate cancer. Int Braz J Urol. 2008;34:443-450. 18. Meyer JP, Bell CR, Elwell C, et al. Brachytherapy for prostate cancer: is the pretreatment prostate volume important? BJU Int. 2008;102:1585-1588.
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19. Aaltomaa SH, Kataja VV, Lahtinen T, et al. Eight years experience of local prostate cancer treatment with permanent I 125 seed brachytherapy—morbidity and outcome results. Radiother Oncol. 2009;91:213-216. 20. Bottomley D, Ash D, Al-Qaisieh B, et al. Side effects of permanent I 125 prostate seed implants in 667 patients treated in Leeds. Radiother Oncol. 2007;82:46-49. 21. Gutman S, Merrick GS, Butler WM, et al. Severity categories of the International prostate symptom score before, and urinary morbidity after, permanent prostate brachytherapy. BJU Int. 2006;97: 62-68. 22. Ather MH, Memon A. Uroflowmetry and evaluation of voiding disorders. Tech Urol. 1998;4:111-117.
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RESULTS
CONCLUSIONS
To evaluate changes in urinary function after cryoablation for clinically localized prostate cancer and to investigate risk factors that predict changes in urinary function after surgery. Among the patients who underwent primary or salvage cryoablation between January 2002 and May 2008, 74 patients (50 primary and 24 salvage) with both a preoperative and postoperative urinary function domain score and uroflowmetry were included in this study. The mean age was 66.8 ⫾ 7.5 years and the mean follow-up period was 42.5 ⫾ 20.3 months. The changes in postoperative urinary function were evaluated on the basis of several categorized groups, including surgical method, preoperative urinary symptoms, and prostate volume. Of 74 patients, 2 (2.7%) presented with mild stress incontinence after cryoablation. No patient presented with persistent urinary retention or urethral fistula. When comparing postoperative International Prostate Symptom Score (IPSS) and bother index scores with preoperative scores, it was found that on average IPSS and bother index recovered 12 and 18 months after cryoablation, respectively, and continued to improve after recovery. Only salvage cryoablation correlated with deteriorating urinary function in a logistic regression model (P ⫽ .032). However, it was noted that the patients with preoperative moderate to severe urinary symptoms and larger prostate volume showed improvement of urinary function after cryoablation. No associations were found between worsened urinary function and prostate volume, comorbidities (hypertension, obesity, and diabetes), or sexual function. Cryoablation is a minimally invasive surgery for localized prostate cancer. This study is the first to demonstrate the ability of cryoablation in terms of maintaining and potentially improving urinary function using validated instruments and uroflowmetry assessments. UROLOGY 76: 1258 –1265, 2010. © 2010 Elsevier Inc.
I
n the 1960s, the first report of prostate cryoablation was published by Gonder et al;1 however, the imprecision and immature technology resulted in unpromising oncological outcome and morbidity rates. Presently, because of improved and more developed cryotechnology, cryoablation has become an established minimally invasive surgery for localized prostate cancer (PCa) in both the primary and salvage setting.2-4 Third-generation cryoablation, driven by the Joule-Thomson effect using argon– helium gas, 17-gauge cryoneedles, and real-time ultrasound guided imaging has significantly improved both oncological and morbidity outcomes after surgery.2,5,6 Currently, patients are given multiple therapeutic options for treating localized PCa, which may further complicate the decision-making process. Regarding localized From the Division of Urologic Surgery, Department of Surgery, Duke Prostate Center, Duke University Medical Center, Durham, North Carolina Reprint requests: Thomas J. Polascik, M.D., Duke University Medical Center, Box 2804 Yellow Zone Durham, NC 27710. E-mail: [email protected] Submitted: August 15, 2009, accepted (with revisions): September 29, 2009
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© 2010 Elsevier Inc. All Rights Reserved
PCa, factors other than oncologic outcome may apply when making a treatment choice. Ideally, physicians can guide patients toward appropriate curative treatment modalities with minimum morbidity, taking into account the patient’s risk tolerance.7 Thus, both physicians and patients need to understand the risks and benefits of therapy choices, because an aggressive treatment can bring higher morbidity and regret.8 With the exception of erectile dysfunction, cryoablation—a minimally invasive surgery for localized PCa— can provide lower complication rates.5,9,10 After cryoablation, there are several potential forms of associated morbidity: perineal pain, urinary tract infection, urethral stricture, urethral fistula, voiding dysfunction including lower urinary tract symptoms (LUTS), incontinence, retention, and diminished sexual function.11,12 Using a urethral warming catheter and monitoring temperatures during the procedure with a thermosensor dramatically reduced the incidence of urinary complications seen with first- and second-generation cryoablation devices.13 0090-4295/10/$36.00 doi:10.1016/j.urology.2009.09.062
In this study, we evaluate urinary function longitudinally by using validated instruments and uroflowmetry after cryoablation from several perspectives. Additionally, risk factors associated with deteriorating urinary function after ablation were analyzed with several preoperative variables.
MATERIAL AND METHODS Patient Selection, Assessment, and Follow-Up Between January 2002 and October 2008, a total of 74 patients with complete records regarding urinary function were included in this study. The mean follow-up period was 42.5 ⫾ 20.3 months. All patients with biopsy-proven PCa underwent cryoablation as primary or salvage therapy. All primary patients were diagnosed with T1c or T2 disease according to the American Joint Committee on Cancer classification (2002 staging system). Urinary function was evaluated using the International Prostate Symptom Score (IPSS), bother index (BI), uroflometry, and measurement of postvoid residual (PVR), preoperatively and postoperatively. The mean time period for preoperative measurement of uroflowmetry (peak flow rate) and PVR was 9.2 ⫾ 10.5 months after surgery. The PVR was determined by ultrasonography. Postoperative temporary incontinence was defined as stress or urge incontinence requiring any protective pad within 5 weeks of surgery. Persistent incontinence was defined as prolonged incontinence after 5 weeks from surgery. Postoperative temporary urinary retention was defined as the need to reinsert the catheter after its removal within 5 weeks of surgery. Additionally, persistent retention was defined as requiring long-term (⬎3 weeks) suprapubic or Foley catheter placement after 5 weeks from surgery. An informed consent was obtained from all patients.
Cryoablation Procedure The procedure was performed by a single surgeon (T.J.P.). All patients underwent a dual freeze-thaw cycle using argon gas (third-generation cryotechnology) with 17-gauge cryoneedles (SeedNet, Galil, Plymouth Meeting, PA). For the cryoablation procedure, the patient is placed in a lithotomy position under general anesthesia and a Foley catheter is placed. Using transrectal ultrasound guidance, 17-gauge cryoprobes were sequentially placed through a brachy template into the prostate by standard protocol. Appropriate needle positioning is verified by ultrasound image in both the sagittal and the transverse dimensions; a thermocouple is placed at the level of the urinary sphincter as well as in Denonvillier’s fascia. Cystoscopy is performed to ensure the cryotherapy needles did not violate the urethra, and a urethral warming catheter is subsequently placed to maintain a temperature of approximately 42°C during the procedure. The urinary sphincter is maintained at temperatures ⬎0°C, and freezing is stopped when the iceball reaches the anterior rectal wall and the posterior prostatic capsule is at least ⫺20°C. A dual freeze-thaw cycle is used. After the final passive thaw, the urethral warming catheter remains in situ for an additional 20 minutes. All cryoprobes are then removed and a Foley catheter is placed. The patient is discharged and a voiding trial is performed within 1-2 weeks.
Analysis of Urinary Function and Predictive Factors For subjective and objective assessment of urinary function regarding cryoablation, IPSS, BI, and uroflometry—including UROLOGY 76 (5), 2010
peak flow rate, voided volume, and PVR—were measured preoperatively and postoperatively. Deterioration of urinary function was defined when the category of total IPSS score (ie, mild [IPSS 0-7], moderate [IPSS 8-19], and severe [IPSS 20-35])14 changed to a higher category at the last follow-up time point as compared with preoperative IPSS categories. Several variables were analyzed including age, clinical stage, surgery type (primary or salvage), administration of hormonal therapy, prostate volume measured by TRUS, catheterization period, prostatespecific antigen (PSA) nadia, preoperative PSA, IPSS, BI, peak flow, PVR, International Index of Erectile Function 5, LUTS, incontinence, medical comorbidities (hypertension and diabetes), and body mass index were analyzed to determine predictive factors.
Statistical Analysis Student t test and the Mann–Whitney test were used to compare continual variables, whereas the 2 and Fisher’s exact test were used to compare categorical variables. A Wilcoxon signedrank test was used for comparing preoperative and postoperative IPSS, BI, peak flow, and PVR. For univariate and multivariate analysis, logistic regression was used to determine correlated factors involving any change in urinary function, and P ⬍.05 was considered statistically significant. All statistical analyses were performed using STATA software (StataCorp 2007. Stata Statistical Software: Release 10. College Station, TX: StataCorp LP).
RESULTS Baseline Characteristics The baseline characteristics of this cohort are summarized in Table 1. Of the 74 patients, only 2 (2.7%) presented with prolonged mild stress incontinence after cryoablation. No patients presented with persistent urinary retention or urethral fistula. A total of 11 primary patients were subjected to temporary hormonal therapy (within 3 months of cryotherapy) and 11 salvage patients were exposed to temporary hormonal therapy at the time of radiation therapy, which was discontinued before surgery. A total of 16 patients were subjected to medications for benign prostate hyperplasia such as ␣-blocker therapy or anticholinergic therapy before surgery. Changes of Urinary Function After Cryoablation The mean IPSS scores of the overall cohort at 0 (baseline), 6, 12, 18, 24, and 36 months were 8.5, 10.0, 7.6, 6.9, 6.6, and 6.5, respectively, and the corresponding scores for mean BI were 1.9, 2.1, 3.2, 1.8, 1.3, and 1.4, respectively. The changes in IPSS and BI after cryoablation are detailed in Figure 1A. When comparing posttreatment IPSS with preoperative scores, the mean IPSS minimally worsened at 6 months after surgery; however, it continued to improve beyond 12 months. Although the mean BI worsened from 6 to 12 months when compared with preoperative scores, it improved 18 months after surgery. Regarding uroflowmetry, Table 2 summarized the changes of peak flow and PVR within several categories. No significant difference of the mean peak flow between pre- and post-treatment was found in the 1259
Table 1. Demographic and baseline characteristics of patients
Variable Age (y) Mean ⫾ SD Median (range) Preoperative PSA (ng/mL) Mean ⫾ SD Median (range) Clinical stage, n (%) T1c T2 BPH medications, n (%) Yes No Hormonal Tx, n (%) Yes No Prostate volume (cm3) Mean ⫾ SD Median (range) Catheterization period (d) Mean ⫾ SD Median (range) Preoperative IPSS Mean ⫾ SD Median (range) Preoperative BI Mean ⫾ SD Median (range) Preoperative IIEF5 Mean ⫾ SD Median (range) HTN, n (%) Yes No DM, n (%) Yes No BMI, n (%) ⬍25 25-30 ⱖ30
Entire Cohort
Primary
Salvage
74
50
24
66.8 ⫾ 7.5 67.0 (50-83) 5.77 ⫾ 4.28 4.95 (0.1-19.9)
68.4 ⫾ 7.0 68.5 (54-83) 5.74 ⫾ 3.67 5.0 (0.3-19.8)
63.5 ⫾ 7.6 64.0 (50-82) 5.85 ⫾ 5.41 4.55 (0.1-19.9)
P .008 .470 .394
48 (75.0) 16 (25.0)
38 (77.6) 11 (22.4)
10 (66.7) 5 (33.3)
16 (22.6) 58 (78.4)
12 (24.0) 38 (76.0)
4 (16.7) 20 (83.3)
22 (29.7) 52 (70.3)
11 (22.0) 39 (78.0)
11 (45.8) 13 (54.2)
.558 .036
25.1 ⫾ 11.0 22.8 (8.1-68.7)
28.4 ⫾ 11.0 27.1 (10.8-68.7)
18.3 ⫾ 7.3 16.7 (8.1-37.5)
9.8 ⫾ 4.8 9 (2-29)
9.5 ⫾ 4.4 9.0 (5-27)
10.4 ⫾ 7.3 8.5 (2-29)
8.5 ⫾ 6.5 7.5 (0-33)
8.2 ⫾ 6.0 7.0 (0-24)
9.2 ⫾ 7.6 9.5 (0-33)
1.9 ⫾ 1.4 2 (0-6)
1.9 ⫾ 1.5 2 (0-6)
1.7 ⫾ 1.1 2 (0-4)
7.4 ⫾ 6.7 5 (1-24)
6.5 ⫾ 6.4 4 (1-24)
9.3 ⫾ 7.0 7.5 (1-24)
⬍.001 .387 .702 .734 .762 .382
44 (59.5) 30 (40.5)
28 (56.0) 22 (44.0)
16 (66.7) 8 (33.3)
18 (24.3) 56 (75.7)
13 (26.0) 37 (74.0)
5 (20.1) 19 (79.2)
9 (13.4) 28 (41.8) 30 (44.8)
9 (19.5) 20 (43.5) 17 (37.0)
0 (0.0) 8 (38.1) 13 (61.9)
.628 .034
SD ⫽ standard deviation; PSA ⫽ prostate-specific antigen; BPH ⫽ benign prostate hyperplasia; Tx ⫽ treatment; IPSS ⫽ International Prostate Symptom Score; BI ⫽ bother index; IIEF-5 ⫽ International Index of Erectile Function; HTN ⫽ hypertension; DM ⫽ diabetes mellitus; BMI ⫽ body mass index.
entire cohort (P ⫽ .154). Although, the corresponding mean PVR improved from 61.3 ⫾ 81.6 to 46.8 ⫾ 40.5 mL, there is no statistical difference between pre- and postoperative PVR (P ⫽ .415). Risk Factor Analysis Table 3 summarizes univariate and multivariate analysis regarding factors potentially influencing changes in urinary function after cryoablation. Of 74 patients, 16 (22%) changed to a higher urinary symptomatic category as compared with their preoperative baseline category. In univariate analysis, salvage cryoablation (P ⫽ .006), lower prostate volume (P ⫽ .034), and longer catheterization period after cryoablation (P ⫽ .030) were correlated with worsened urinary function regarding total IPSS. However, medical comorbidities (hypertension: 1260
P ⫽ .395, obesity: P ⫽ .594, and diabetes: P ⫽ .559), preoperative urinary function (IPSS: P ⫽ .126, BI: P ⫽ 0.372, peak flow: P ⫽ .419, and PVR: P ⫽ .960), and sexual function (International Index of Erectile Function: P ⫽ .253) did not demonstrate any correlation with worsened urinary function after cryoablation. In multivariate analysis, only salvage cryoablation remained statistically significant (P ⫽ .032). Changes in Urinary Function With Primary and Salvage Cryoablation When comparing between primary and salvage cryoablation regarding IPSS and BI scores, salvage cryoablation demonstrated a worsened postoperative IPSS and BI score than primary cryoablation. The changes in IPSS and BI in relation to primary or salvage cryoablation are UROLOGY 76 (5), 2010
Figure 1. (A) Changes in mean International Prostate Symptom Score (IPSS) and mean bother index (BI) score after prostate cryoablation in entire cohort. The numbers of evaluated patients at the each time point ranged from 29 to 74. (B) Changes in mean IPSS and BI score after primary and salvage prostate cryoablation. (C) Changes in mean IPSS and BI score after prostate cryoablation regarding patients with preoperative mild urinary symptoms (IPSS 0-7) and moderate to severe urinary symptoms (IPSS ⱖ 8). (D) Changes in mean IPSS and BI score after prostate cryoablation regarding patients with smaller prostate volume (⬍30 mL) and larger prostate volume (ⱖ30 mL). * indicates P ⬍.05 between subcategories.
UROLOGY 76 (5), 2010
1261
.294 .037
.445 .112
.153 .217
.415
P
Table 3. Univariate and multivariate analysis of risk factors influencing urinary function after cryoblation
1262
⫹0.4 ⫺39.4 Pre-symptom scores were categorized by mild (IPSS 0-7) and moderate-severe (IPSS ⱖ 8) categories. PVR ⫽ postvoiding residual urine; Pre⫺ ⫽ preoperative; mod ⫽ moderate; PV ⫽ prostate volume.
49.8 ⫾ 74.1 79.7 ⫾ 91.2 ⫺3.8 ⫹2.4 16.4 ⫾ 10.2 16.6 ⫾ 11.1 20.2 ⫾ 10.9 14.2 ⫾ 9.1 50 (67.6) 24 (32.4)
.421 .717
50.2 ⫾ 39.6 40.3 ⫾ 42.5
⫺14.0 ⫺16.2 57.7 ⫾ 65.9 65.8 ⫾ 99.2 ⫺2.8 ⫹0.9 15.7 ⫾ 10.2 18.3 ⫾ 9.5 18.5 ⫾ 12.7 17.4 ⫾ 11.1 38 (51.4) 36 (48.6)
.100 .165
43.7 ⫾ 35.1 49.6 ⫾ 45.3
⫺25.9 ⫹7.2 73.5 ⫾ 92.1 38.2 ⫾ 51.2 ⫹1.7 ⫺7.6 18.3 ⫾ 10.7 13.7 ⫾ 9.4 16.6 ⫾ 9.9 21.3 ⫾ 12.2 50 (67.6) 24 (32.4)
.436 .028
47.6 ⫾ 42.2 45.4 ⫾ 38.1
⫺14.5 46.8 ⫾ 40.5 61.3 ⫾ 81.6 .154 ⫺1.6 16.4 ⫾ 10.4 18.0 ⫾ 10.6
All patients Case type Primary Salvage Pre-symptoms Mild Mod-severe PV (cm3) ⬍30 ⱖ30
74
P Category
Number (%)
Pre (Mean ⫾ SD) Peak Flow (mL/s) Post (Mean ⫾ SD) Differential Pre (Mean ⫾ SD)
Table 2. Changes in peak flow and PVR after cryoablation
PVR (mL) Post (Mean ⫾ SD)
Differential
Variables
OR
95% CI
P
Age Clinical stage (T1c vs T2) Case type (primary vs salvage) Hormonal therapy Prostate volume Catheterization period Preoperative PSA PSA Nadia Preoperative IPSS Preoperative BI Preoperative peak flow rate Preoperative PVR Preoperative IIEF5 Incontinence HTN DM BMI ⬍25 25-30 ⱖ30
0.97 1.44 5.23
Univariate 0.90-1.05 0.38-5.54 1.61-17.00
.416 .592 .006
1.58 0.93 1.15 0.89 0.17 0.93 0.82 1.02
0.49-5.04 0.86-0.99 1.01-1.30 0.76-1.07 0.01-3.12 0.82-1.02 0.52-1.28 0.97-1.09
.445 .034 .030 .224 .230 .126 .372 .419
1.00 0.95 2.39 1.67 0.66
0.99-1.01 0.86-1.04 0.75-7.60 0.51-5.41 0.16-2.64
.960 .253 .140 .395 .559
Ref 1.29 1.53
— 0.27-6.28 0.32-7.30
— .749 .594
Age Case type (primary vs salvage) Prostate volume Preoperative IIEF5 DM
1.00 5.37
Multivariate 0.91-1.09 1.16-24.92
.979 .032
0.96 0.91 0.85
0.89-1.04 0.89-1.02 0.19-3.89
.372 .104 .839
OR ⫽ odds ratio; CI ⫽ confidence interval; PVR ⫽ postvoiding residual urine; LUTS ⫽ lower urinary tract symptoms; HTN ⫽ hypertension; DM ⫽ diabetes mellitus.
detailed in Figure 1B. The mean IPSS at 6, 12, and 18 months were statistically different (P ⬍.001, .007, and .032, respectively) between surgical groups, as were the mean BI at 6 and 12 months (P ⫽ .002 and ⬍.001, respectively). However, at 18 months the mean BI returned toward baseline and did not show a significant difference between surgical groups (P ⫽ .133). With regard to changes of peak flow rate and PVR, peak flow rate improved and PVR reduced postoperatively in primary patients. On the contrary, salvage patients had a worsening peak flow rate and increasing PVR postoperatively. However, both groups did not show any statistical difference between pre- and postoperative scores with respect to peak flow rate and PVR (Table 2). Changes in Urinary Function Regarding Preoperative Urinary Symptoms The changes in IPSS and BI based on preoperative urinary symptom level (mild: IPSS 0-7 vs moderate to severe: IPSS ⱖ 8) are detailed in Figure 1C. When comparing changes in urinary function between these groups, the patients with moderate to severe symptoms showed more improvement after cryoablation than the patients with mild symptoms. The mean IPSS at 6, 12, UROLOGY 76 (5), 2010
and 18 months were statistically different (P ⬍.001, .007, and .032, respectively); however, there was no difference at 24 and 36 months (P ⫽ .066 and .642, respectively) between each subcategories. The mean BI until 12 months was statistically different between each group; however, at 18, 24, and 36 months the mean BI of the moderate to severe patients had improved and come close to the score of those patients with mild symptoms, which did not show a significant difference between each group (P ⫽ .834, .100, and .714, respectively). With regard to changes of peak flow and PVR, the patients with moderate to severe urinary symptoms had an improved flow rate and reduced PVR after surgery; however, both groups did not show any statistically significant difference between preand postoperative score (Table 2).
Changes in Urinary Function Regarding Prostate Volume The IPSS score of patients with a larger prostate volume are detailed in Figure 1D. Patients with prostate volume ⱖ30 or ⬍30 mL were categorized into a larger prostate volume group and smaller prostate group, respectively. The IPSS score of patients with a larger prostate volume had a temporary deterioration at 6 months compared with patients with a smaller prostate volume (P ⫽ .005); however, it recovered to baseline at 18 months (P ⫽ .394) and continued to improve, finally showing better improvement than those who had a smaller prostate volume. In terms of the BI score, the larger prostate group had deteriorated from 6 to 12 months temporally compared with the smaller prostate group (P ⫽ .041 and .013, respectively); however, it recovered at 18 months (P ⫽ .876) and continued to improve. Regarding the comparison of mean peak flow and PVR based on prostate volume pre- and postoperatively, there seemed to be a trend among patients who had larger prostate volume (ⱖ30 mL) to have an improved peak flow rate and reduced PVR (Table 2). In particular, when comparing pre- and postoperative PVR, the volumes significantly decreased postoperatively in the larger prostate volume group (P ⫽ .037).
COMMENT Cryoablation is recognized as an established minimally invasive procedure for the treatment of localized PCa in both the primary and salvage setting.3,5,6 Although several reports detailing oncologic outcomes of cryoablation have been published; there are not many series reporting quality of life (QOL) (eg, urinary function and sexual function) after cryoablation using improved third-generation technology. To our knowledge, this is the first study evaluating urinary function after prostate cryoablation using both uroflowmetry and validated QOL instruments. Outcomes from the Cryo On-Line Data registry reported that among the 1198 consecutive patients who underwent primary cryoablation, 3.6% of patients develUROLOGY 76 (5), 2010
oped urinary retention, 2.1% underwent transurethral resection of the prostate to remove sloughed tissue, and 4.8% developed incontinence with a pad rate of 2.9%.15 Although this is the largest pooled cryoablation multicenter series to date, this study does not report detailed and longitudinal urinary function analyzed using objective and subjective pre- and postoperative data. Ismail et al16 also reported on 100 patients who underwent salvage cryoablation. In this study, 13% of patients developed incontinence, 2% had urinary retention, and 1% had a urethral fistula post-cryoablation. In our study of 74 patients, 6 patients (8.1%) developed temporary urinary retention and no patients required TURP or had persistent urinary retention. Additionally, 7 patients (9.5%) had temporary incontinence with 2 patients (2.7%) having prolonged mild stress incontinence after cryoablation. No patient presented with a recto-urethral fistula. Seemingly, our urinary function morbidity was comparable with other contemporary cryotherapy series, indicating a relatively safe and standardized procedure. Using the American Urological Association Symptom Score (AUASS) to analyze urinary function deterioration after cryoablation, DiBlasio et al17 demonstrated that a lower preoperative PSA and higher biopsy Gleason sum were associated with a higher postoperative AUASS (P ⫽ .008 and .002, respectively) among a cohort of 78 consecutive patients. In addition, a larger prostate volume showed a trend toward worsening LUTS and higher postoperative AUASS outcomes (P ⫽ .070). Interestingly, our data did not demonstrate a positive correlation between deterioration of urinary function and prostate volume (odds ratio,0.96; P ⫽ .372). Conversely, the postoperative urinary function of the patients with moderate to severe symptoms and a larger prostate volume kept improving during the observation period. Additionally, univariate and multivariate analysis of our results may imply that patients with poor preoperative urinary function, pre-existing comorbidities (diabetes, hypertension, and obesity), and a large prostate volumes are amenable to be treated with cryoablation while maintaining urinary function. Regarding differences in QOL between primary and salvage cryoablation, Anastasiadis et al7 reported on 131 consecutive patients who underwent primary and salvage cryoablation using QOL questionnaires. In this study, primary cryotherapy patients fared significantly better in terms of physical and social functioning as compared with salvage cryoablation patients. Moreover, urinary symptoms were significantly more severe in the salvage group. Our study can support these results considering only salvage cryoablation was a risk factor in multivariate analysis. Additionally, the peak flow analysis between pre- and postsalvage cryoablation identified a statistically significant decrease (P ⫽ .028), which could be due to fibrosis in the posterior urethra because of cryoablation of the radiated prostate. 1263
Few published articles report on the longitudinal analyses of changes in IPSS, BI, and uroflowmetry after cryoablation. In a brachytherapy setting, there are several series analyzing urinary QOL including IPSS and uroflowmetry longitudinally, which demonstrated the changes of urinary function after brachytherapy during the entire follow-up period.18-21 Our results of both subjective (IPSS, BI) and objective data (uroflowmetry) revealed an improvement in urinary function after cryoablation within the entire cohort. In particular, urinary function of patients with moderate to severe urinary symptoms or a larger prostate volume improved sufficiently after cryoablation so as to have almost equal, if not better, scores at the end of the follow-up period than the patients with mild symptoms and a smaller prostate volume at preoperative point (Fig. 1C,1D). In addition, our results demonstrated that patients who had stable or improved urinary function after cryoablation had a significantly higher preoperative IPSS and BI score (eg, those with preoperative LUTS compared with patients who had worsened urinary function after surgery. These results suggest that if patients have good voiding function or low urinary symptoms preoperatively, cryoablation will likely not lead to further improvement in urinary function. However, for those patients who had preoperative LUTS (higher IPSS and BI), cryoablation improved urinary function after surgery, thus potentially offering efficacy as therapy for both LUTS and PCa. We assume this phenomenon was derived from the treatment efficacy of cryoablation, based on destroying prostate tissue and shrinking the prostate gland postprocedure thereby improving LUTS. This study has several limitations. First, this is a retrospective report of a prospective database involving a single center; thus, physician-assessed morbidities may induce more subjective factors than in a randomized, blinded study. Second, a formal urodynamics evaluation, which is the gold standard to assess flow and obstruction, was not indicated nor performed. The limitation of uroflowmetry in distinguishing between poor detrusor function and bladder outlet obstruction are previously published.22 Third, our cohort is relatively small (n ⫽ 74), especially in the salvage patients (n ⫽ 24), with intermediate follow-up (mean 42.5 ⫾ 20.3 months). However, we believe that the follow-up in this report is sufficiently long enough to assess any changes in urinary function, because most patients recovered by 12 months and showed further improvement at 18 months. Despite these limitations, our data may suggest that cryoablation is an appropriate, minimally invasive surgery in terms of preserving and potentially improving urinary function after surgery. This could facilitate decision-making for patients who desire to maintain urinary QOL when considering definitive therapy for localized PCa. To better understand the urinary effect of this procedure, further study is needed with longer follow-up and a larger number of patients. 1264
CONCLUSIONS Third-generation cryo-technology is a minimally invasive modality for the treatment of localized PCa in a primary and salvage setting. This study is the first report suggesting that cryoablation can preserve and might improve urinary function during the observation period, even if patients had moderate to severe urinary symptoms or a larger prostate volume preoperatively. Additionally, our results revealed that only the salvage setting is a predictive factor for worsening urinary function after cryoablation; however, there was no correlation with preoperative urinary function, prostate volume, and preexisting comorbidities. Thus, cryoablation is an ideal approach for preserving and potentially improving urinary function in the primary setting for patients who desire minimal surgical morbidity. References 1. Gonder MJ, Soanes WA, Shulman S. Cryosurgical treatment of the prostate. Invest Urol. 1966;3:372-378. 2. Hubosky SG, Fabrizio MD, Schellhammer PF, et al. Single center experience with third-generation cryosurgery for management of organ-confined prostate cancer: critical evaluation of short-term outcomes, complications, and patient quality of life. J Endourol. 2007;21:1521-1531. 3. Ng CK, Moussa M, Downey DB, et al. Salvage cryoablation of the prostate: followup and analysis of predictive factors for outcome. J Urol. 2007;178:1253-57 [discussion: 1257]. 4. Polascik TJ, Mayes JM, Mouraviev V. From whole-gland to targeted cryoablation for the treatment of unilateral or focal prostate cancer. Oncol Williston Park. 2008;22:900-906 [discussion: 906-907: 914]. 5. Bahn DK, Lee F, Badalament R, et al. Targeted cryoablation of the prostate: 7-year outcomes in the primary treatment of prostate cancer. Urology. 2002;60:3-11. 6. Polascik TJ, Nosnik I, Mayes JM, et al. Short-term cancer control after primary cryosurgical ablation for clinically localized prostate cancer using third-generation cryotechnology. Urology. 2007;70: 117-121. 7. Anastasiadis AG, Sachdev R, Salomon L, et al. Comparison of health-related quality of life and prostate-associated symptoms after primary and salvage cryotherapy for prostate cancer. J Cancer Res Clin Oncol. 2003;129:676-682. 8. Schroeck FR, Krupski TL, Sun L, et al. Satisfaction and regret after open retropubic or robot-assisted laparoscopic radical prostatectomy. Eur Urol. 2008;54:785-793. 9. Chin JL, Ng CK, Touma NJ, et al. Randomized trial comparing cryoablation and external beam radiotherapy for T2C-T3B prostate cancer. Prostate Cancer Prostatic Dis. 2008;11:40-45. 10. Chin JL, Pautler SE, Mouraviev V, et al. Results of salvage cryoablation of the prostate after radiation: identifying predictors of treatment failure and complications. J Urol. 2001;165:1937-1941 [discussion: 1941-1942]. 11. Han KR, Cohen JK, Miller RJ, et al. Treatment of organ confined prostate cancer with third generation cryosurgery: preliminary multicenter experience. J Urol. 2003;170:1126-1130. 12. Onik GM, Cohen JK, Reyes GD, et al. Transrectal ultrasoundguided percutaneous radical cryosurgical ablation of the prostate. Cancer. 1993;72:1291-1299. 13. Cohen JK, Miller RJ. Thermal protection of urethra during cryosurgery of prostate. Cryobiology. 1994;31:313-316. 14. Barry MJ, Fowler FJ Jr, O’Leary MP, et al. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol. 1549-57;148 [discussion: 1564, 1992].
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15. Jones JS, Rewcastle JC, Donnelly BJ, et al. Whole gland primary prostate cryoablation: initial results from the cryo on-line data registry. J Urol. 2008;180:554-558. 16. Ismail M, Ahmed S, Kastner C, et al. Salvage cryotherapy for recurrent prostate cancer after radiation failure: a prospective case series of the first 100 patients. BJU Int. 2007;100:760-764. 17. DiBlasio CJ, Derweesh IH, Malcolm JB, et al. Contemporary analysis of erectile, voiding, and oncologic outcomes following primary targeted cryoablation of the prostate for clinically localized prostate cancer. Int Braz J Urol. 2008;34:443-450. 18. Meyer JP, Bell CR, Elwell C, et al. Brachytherapy for prostate cancer: is the pretreatment prostate volume important? BJU Int. 2008;102:1585-1588.
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19. Aaltomaa SH, Kataja VV, Lahtinen T, et al. Eight years experience of local prostate cancer treatment with permanent I 125 seed brachytherapy—morbidity and outcome results. Radiother Oncol. 2009;91:213-216. 20. Bottomley D, Ash D, Al-Qaisieh B, et al. Side effects of permanent I 125 prostate seed implants in 667 patients treated in Leeds. Radiother Oncol. 2007;82:46-49. 21. Gutman S, Merrick GS, Butler WM, et al. Severity categories of the International prostate symptom score before, and urinary morbidity after, permanent prostate brachytherapy. BJU Int. 2006;97: 62-68. 22. Ather MH, Memon A. Uroflowmetry and evaluation of voiding disorders. Tech Urol. 1998;4:111-117.
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