- Email: [email protected]
Prostate Capsule Sparing versus Nerve Sparing Radical Cystectomy for Bladder Cancer: Results of a Randomized, Controlled Trial
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Prostate Capsule Sparing versus Nerve Sparing Radical Cystectomy for Bladder Cancer: Results of a Randomized, Controlled Trial Bruce L. Jacobs, Stephanie Daignault, Cheryl T. Lee, Khaled S. Hafez, Jeffrey S. Montgomery, James E. Montie, Jean E. Humrich, Brent K. Hollenbeck,* David P. Wood, Jr. and Alon Z. Weizer† From the Department of Urology, University of Pittsburgh School of Medicine (BLJ), Pittsburgh, Pennsylvania, and Divisions of Oncology (SD, CTL, KSH, JSM, JEH, AZW) and Health Services Research, Department of Urology (JEM, BKH), University of Michigan, Ann Arbor and Department of Urology, William Beaumont School of Medicine (DPW), Royal Oak, Michigan
Purpose: Prostate capsule sparing and nerve sparing cystectomies are alternative procedures for bladder cancer that may decrease morbidity while achieving cancer control. However, to our knowledge the comparative effectiveness of these approaches has not been established. We evaluated functional and oncologic outcomes in patients undergoing these procedures. Materials and Methods: We performed a single institution trial in patients with bladder cancer in whom transurethral prostatic urethral biopsy and transrectal prostate biopsy were negative. Men were randomized to prostate capsule sparing or nerve sparing cystectomy with neobladder creation and stratified by SHIM score (greater than 21 vs 21 or less). Our primary end point was 12-month overall urinary function as measured by BCI. Secondary end points included sexual function, cancer control and complications. Results: A total of 40 patients were enrolled in the study with 20 patients in each arm. Urinary function at 12 months decreased by 13 and 28 points in the prostate capsule and nerve sparing groups, respectively (p ¼ 0.10). Sexual function followed a similar pattern (p ¼ 0.06). There was no difference in recurrence-free, metastasis-free or overall survival (each p >0.05). The rate of incidentally detected prostate cancer was similar (p ¼ 0.15). Conclusions: Our study provides a randomized comparison of prostate capsule sparing and nerve sparing cystectomy techniques. We found no difference in functional or oncologic outcomes between the 2 approaches, although our study was underpowered due to a lack of patient accrual.
Abbreviations and Acronyms BCI ¼ Bladder Cancer Index PSA ¼ prostate specific antigen SHIM ¼ Sexual Health Inventory for Men Accepted for publication July 14, 2014. Study received institutional review board approval. Supported by National Institutes of Health Grant KL2 TR000146 (BLJ), American Cancer Society Research Scholar Grant RSGI-13-323-01CPHPS (BKH) and National Institutes of Health/ National Cancer Institute Grant R01 CA168691 (BKH). * Financial interest and/or other relationship with Urology. † Correspondence: Cancer Center Ambulatory Care Unit, Department of Urology, University of Michigan Comprehensive Cancer Center, 1111 Cancer Center, 1500 East Medical Center Dr., SPC5950, Ann Arbor, Michigan 48109 (telephone: 734-615-7228; FAX: 734-936-9102; e-mail: [email protected]).
Key Words: urinary bladder neoplasms, prostate, cystectomy, urinary diversion, mortality
RADICAL cystectomy is the standard treatment in patients with localized muscle invasive cancer or nonmuscle invasive urothelial cancer refractory to intravesical therapy1 and yet it is associated with
significant morbidity.2 To decrease morbidity prostate capsule sparing and nerve sparing cystectomies have been described in case series as potential ways to decrease side effects and improve quality of life outcomes
0022-5347/15/1931-0001/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Dochead: Adult Urology
http://dx.doi.org/10.1016/j.juro.2014.07.090 Vol. 193, 1-7, January 2015 Printed in U.S.A.
www.jurology.com
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without jeopardizing oncologic control. The 2 approaches attempt to preserve the neurovascular bundles lateral to the prostate. In addition, the prostate capsule sparing technique avoids extensive dissection of the pelvic floor musculature and the external urethral sphincter. These approaches may result in improved erectile and urinary function.3e9 However, compared to the more traditional radical cystectomy technique the benefits of these 2 approaches are largely demonstrated in retrospective studies. Limited evidence from randomized trials is available on the relative effectiveness of the prostate capsule sparing and nerve sparing approaches in terms of functional outcomes. To our knowledge the further and perhaps more importantly the relative cancer control of these 2 approaches is unknown. Despite the appeal of prostate capsule sparing radical cystectomy there is concern that leaving behind part of the prostate may lead to a higher rate of positive surgical margins and residual or future prostate cancer.10 Even if voiding and sexual function are improved in these patients, the prostate capsule sparing approach would ultimately be detrimental. For these reasons we performed a phase II, randomized clinical trial to evaluate functional and oncologic outcomes in patients treated with prostate capsule sparing or nerve sparing radical cystectomy with neobladder creation. We sought to understand potential differences in voiding function, sexual function and cancer control between these 2 patient populations to determine the potential of the approaches as alternative extirpative techniques for bladder cancer.
METHODS
All men underwent transurethral biopsy of the prostatic urethra and 12-core transrectal ultrasound guided prostate biopsy.12 Transurethral biopsy was performed with a resectoscope and tissue was sampled from the 5 and 7 o’clock positions. Transrectal prostate biopsy targeted all areas of the prostate as much as was feasible via the transrectal approach, including the anterior apex. Additional study exclusion criteria were creatinine greater than 2.2 mg/dl, prior pelvic radiation to the bladder or prostate, or a history of a radical prostatectomy. Of men who consented to randomization 5 were excluded from analysis due to prostate cancer on biopsy, 2 withdrew consent and 1 was excluded due to surgeon judgment.
Intervention Patients were randomly assigned to prostate capsule sparing or nerve sparing radical cystectomy with neobladder urinary diversion. Randomization was done the morning of surgery and patients were informed of the assignment as part of informed consent. These procedures share many common steps and the main difference is how the prostate is managed.13 With the prostate capsule sparing approach supra-ampullar dissection was performed to develop a plane anterior to the seminal vesicles. The endopelvic fascia was preserved on each side of the prostate. The prostate capsule was incised with a transverse incision on the distal anterior surface of the prostate and the adenoma was dissected from the capsule. For the nerve sparing approach the entire prostate and seminal vesicles were removed along with the bladder. The neurovascular bundles were spared by performing intrafascial dissection in retrograde fashion. These different cystectomy techniques necessitated different approaches to the urethral anastomosis. With the prostate capsule sparing approach the neobladder was anastomosed to the prostate capsule while with the nerve sparing approach the neobladder was anastomosed to the urethral stump.13 Extended pelvic lymph node dissection was performed with each approach, including dissection around the common iliac arteries.
Study Design
Measures
We performed a single institution clinical trial in which patients with urothelial cancer were randomized to prostate capsule sparing or nerve sparing cystectomy (ClinicalTrials.gov NCT01824329). The study protocol was approved by our institutional review board and patients provided written informed consent. Five surgeons participated in this study. Enrollment began in August 2007 and was completed in October 2011. Followup was completed in January 2013.
Men were stratified based on SHIM, a 5-question validated questionnaire used to evaluate sexual function. SHIM provides a score of 5 to 25 with 98% sensitivity and 88% specificity.14 Because a score of 21 or less indicates erectile dysfunction, stratification was based on a SHIM score of greater than 21 vs 21 or less. Baseline assessments included patient demographics and tumor characteristics. Urinary and sexual function was measured by BCI, a validated bladder cancer specific, health related quality of life instrument that measures urinary, sexual and bowel function, and bother domains.15 The index consists of 34 items in a total of 3 primary domains (urinary, bowel and sexual) and 2 subdomains (function and bother). Item responses are based on Likert scales with scores standardized to a scale of 0 to 100 points on which higher scores correspond to better health states. Each domain has been independently validated. The perioperative characteristics examined included estimated blood loss and operative time. Measured clinical outcomes included hospital length of stay, and 30-day
Patient Population Patients eligible for study included men 18 years old or older with clinical stage T2 or less urothelial cancer diagnosed within 3 months of enrollment.11 Cases down staged after neoadjuvant chemotherapy, eg from stage cT3 to cT2 or less, were eligible. Concern for nodal or metastatic disease on preoperative imaging was a finding that excluded patients from participation. The Appendix (http://jurology.com/) shows the specific imaging, laboratory and followup requirements. Dochead: Adult Urology
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readmission and 90-day major complication rates. A 229 major complication was defined as CTCAE (Common 230 Terminology Criteria for Adverse Events) grade 3 (ie se231 vere or medically significant but not immediately life 232 threatening, hospitalization or prolongation of hospitali233 zation indicated, disabling or limiting self-care daily 234 living activity) or higher.16 235 236 Outcomes 237 The primary end point was 12-month overall urinary function compared to baseline. Secondary end points were 238 12-month overall sexual function compared to baseline, 239 oncologic outcomes as measured by margin status, time to 240 disease recurrence, overall survival at 24 months, peri241 operative outcomes and complications. An independent 242 data and safety monitoring committee met every 3 months 243 to review study performance, adverse events, and data 244 validity and integrity. 245 Statistical Analysis 246 A randomized selection design17 was used to assess uri247 nary function in prostate capsule sparing and nerve 248 sparing cystectomy cases. Patients were randomized to 249 the surgical treatment arms using a balanced, stratified 250 (SHIM score greater than 21 vs 21 or less), randomized 251 block design. With 41 subjects per surgical group there 252 was 90% probability of selecting the superior treatment, 253 assuming that the superior treatment showed a 7-point 254 improvement in the 12-month urinary function change 255 from baseline compared with the inferior treatment. 256 Analysis was based on an intent to treat approach. Characteristics between groups were compared using 257 the Student t-test for continuous variables and the chi258 square test for categorical variables. Urinary function 259 and sexual function were evaluated using the Wilcoxon 260 rank test. Parameters related to clinical and pathological 261 stage were assessed by the Jonckheere-Terpstra test. 262 Recurrence-free, metastasis-free and overall survival was 263 analyzed by Kaplan-Meier methods and tested using the 264 log rank test. All analysis was done with SASÒ, version 265 9.2. The probability of a type I error was considered at 266 0.05 and all tests were 2-sided. 267 268 269 RESULTS 270 A total of 40 patients were enrolled in study with 20 271 randomized to each cohort. Baseline patient char272 ½T1 acteristics were similar in the 2 groups (see table). 273 In each group the operation was most commonly 274 performed via an open approach. For robotic pro275 cedures the neobladder was created extracorpore276 ally. A Hautmann reservoir was constructed in 277 more than 90% of patients. 278 The 12-month BCI was completed by 36 of the 279 40 enrolled patients (90%) and the primary end 280 point (urinary function) was evaluated in 34 (85%). 281 In 2 patients urinary function was not evaluated 282 and in 4 sexual function was not evaluated due 283 to missing data on BCI sections. For urinary func284 tion there was no statistical difference between 285 the 2 approaches (p ¼ 0.10). Average SD urinary Dochead: Adult Urology
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function at 12 months compared with baseline decreased by 13 30 and 28 33 points for prostate capsule sparing and nerve sparing, respectively (see table). Figure 1 shows a waterfall plot of the change in urinary function in the study population. Average sexual function at 12 months compared with baseline decreased by 1 11 and 23 30 points for prostate capsule sparing and nerve sparing, respectively (p ¼ 0.06). Figure 2 shows a waterfall plot of changes in sexual function stratified by SHIM score. Examination of responses to specific urinary and sexual function questions revealed that each group experienced the slowest improvement in nighttime frequency and leakage. The nerve sparing group also had slower improvement in daytime frequency. Of patients with prostate capsule sparing and nerve sparing 22% and 17% performed intermittent catheterization, and 55% and 65%, respectively, used aids or medication for erectile function. Pathological outcomes were similar in the 2 groups (see table). Most patients had tumor stage T2 or less and node negative disease. Three of the 7 patients with node positive disease had received neoadjuvant chemotherapy. Prostate cancer was detected in 3 patients in the prostate capsule sparing cohort and in 8 in the nerve sparing cohort. There was no difference between the groups in recurrence-free, metastasis-free and overall survival (figs. 3 to 5). Of the 40 patients with negative biopsies who underwent surgery prostate cancer was detected on final pathology in 11 (28%) (see table). Seven of the 8 patients (88%) with nerve sparing who had prostate cancer had undetectable PSA. In the 3 prostate capsule sparing cases of prostate cancer PSA was less than 0.1, 0.1 and 0.2 ng/ml, respectively. None of these patients received additional treatment. Gleason score and pathological prostate cancer stage were similar in the 2 groups (each p >0.05). One patient had a positive prostate cancer margin but undetectable PSA at followup. Perioperative characteristics and clinical outcomes were similar in the cohorts (see table). Operative time was 395 and 411 minutes for the prostate capsule sparing and nerve sparing approaches, respectively (p ¼ 0.65). No difference was observed in the 30-day readmission or 90-day major complication rates (each p >0.05).
DISCUSSION Our study provides a randomized comparison of prostate capsule sparing and nerve sparing cystectomy techniques. We found no difference in functional or oncologic outcomes between the 2 approaches, although our study was underpowered
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Study population demographics, clinical characteristics, pathological outcomes, prostate characteristics, and perioperative and clinical outcomes Prostate Capsule Sparing No. pts Mean SD age No. Eastern Cooperative Oncology Group performance status (%): 0 1 Mean SD body mass index (kg/m2) No. neoadjuvant chemotherapy (%) No. clinical stage (%): Ta/Tis T1 T2/T3 No. approach (%): Open Robot-assisted Median followup (mos) No. pathological tumor stage (%) T0 Ta/Tis T1 T2 T3 No. pathological nodal stage (%): N0 N1 N2 No. pos surgical margin (%): Soft tissue Ureter Urethra No. Ca (%): Urethra Prostate Mean SD No. lymph nodes removed
Demographic þ clinical characteristics 20 58 10 20 0 30 8 3 7 10
(100)
Nerve Sparing 20 59
e 0.70 0.49
6
(40)
18 2 31 10
(15) (35) (50)
2 4 14
(10) (20) (70)
(75) (25)
13 7
(65) (35)
5
p Value*
(90) (10) 4 (50)
0.76 0.75 0.23
0.73 15 5 Pathological outcomes 41
37
0.75 0.45
8 6 3 1 2
(40) (30) (15) (5) (10)
8 2 4 2 4
(40) (10) (20) (10) (20)
18 1 1
(90) (5) (5)
15 1 4
(75) (5) (20)
0 1 0
(5)
0 1 0
(5)
0.19
2 (10) 3 (15) 16 10 Preop þ biopsy characteristics 1.9 (0.2e5.5) 33 (14)
Median ng/ml PSA (range) Mean SD ultrasound prostate vol (ml) No. prostate biopsy results (%): Neg HGPIN
18 (90) 2 (10) Postop þ pathological characteristics 3 (15)
No. prostate Ca (%) No. Gleason score (%): 6 7 No. pathological tumor stage (%):† T2a T2b No. prostate Ca pos margin (%) Median mos PSA surveillance (95% CI)
4 8 16
(20) (40)
0.66 0.15 0.91
1.0 (0.3e5.1) 26 (8)
0.07 0.96 0.99
8
17 3
(85) (15)
8
(40)
(67) (33)
8 0
(100)
2 (67) 1 (33) 1 (33) 23 (6e34) Periop þ clinical outcomes 400 (200e1,500) 395 106
7 1 0 22
(88) (12)
2 1
0.99 0.99 0.99
0.15 0.10 0.45
Median ml estimated blood loss (range) Mean SD operative time (mins) No. diversion type (%): Neobladder Ileal conduit Median days hospitalization (range) Median days indwelling catheter time (range) No. 30-day readmission (%) No. 90-day major complication (%)‡
20 0 7 21 0 7
(100) (5e21) (13e47) (35)
(6e26)
575 (150e2,000) 411 109 18 2 8 21 3 12
(90) (10) (5e21) (12e34) (15) (60)
0.27 0.59 0.19 0.65 0.49 0.79 0.96 0.23 0.20
* Clinical stage, pathological tumor stages, pathological nodal stage and Gleason score Jonckheere-Terpstra test, Student t-test for continuous variables and Fisher exact or Mantel-Haenszel chi-square test for categorical variables. † No patient had lymph nodes positive for prostate cancer. ‡ CTCAE grade 3 or higher.
due to lack of patient accrual. The 2 approaches had similar perioperative outcomes and complication rates. Dochead: Adult Urology
Interest in prostate capsule sparing cystectomy stems from its potential to decrease morbidity. The approach preserves the neurovascular bundles,
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Figure 1. Average urinary function at 12 months vs baseline decreased by 13 30 and 28 33 points in patients with prostate capsule sparing and nerve sparing cystectomy, respectively. Urinary function did not differ for 2 approaches (Wilcoxon rank test p ¼ 0.10).
spares the seminal vesicles and limits dissection of the pelvic floor musculature around the external sphincter, which are techniques thought to improve voiding and erectile function compared with the nerve sparing approach or traditional cystectomy.13 Indeed, more than three-fourths of patients have reported preserved erectile function with the prostate capsule sparing approach.3,18,19 Most patients have also reported daytime and nighttime urinary continence.3,6,18,20,21
Figure 2. In nerve sparing cystectomy cohort SHIM score was 21 or less and greater than 21 in 10 patients each. In prostate capsule sparing cystectomy cohort SHIM score was 21 or less and greater than 21 in 11 and 9 patients, respectively. Average sexual function at 12 months vs baseline decreased by 1 11 points for prostate capsule sparing and by 23 30 points for nerve sparing. Sexual function did not differ for 2 approaches (Wilcoxon rank test p ¼ 0.06).
Dochead: Adult Urology
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Figure 3. Recurrence-free probability did not differ in patients randomized to prostate capsule sparing and nerve sparing cystectomy (log rank test p >0.05).
Our findings show that the prostate capsule approach had functional outcomes similar to those of the nerve sparing approach. Although the size of the observed effect was greater than what we defined as clinically important for urinary and sexual function, the variability of the effect required the sample size to be larger than what we could accrue during the study period. Patients treated with the prostate capsule sparing approach reported urinary and sexual function that was substantially closer to baseline than those treated with the nerve sparing approach at 12 months (see table, and figs. 1 and 2). It is unclear whether statistically significant differences in urinary and sexual function between the 2 approaches may have emerged had we attained our targeted recruitment of
Figure 4. Metastasis-free probability did not differ in patients randomized to prostate capsule sparing and nerve sparing cystectomy (log rank test p >0.05).
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Figure 5. Survival probability did not differ in patients randomized to prostate capsule sparing and nerve sparing cystectomy (log rank test p >0.05).
82 patients, which would have essentially doubled our sample size. Nevertheless, our study findings improve our understanding of urinary and erectile function outcomes after the prostate capsule sparing and nerve sparing approaches as well as the oncologic implications of the approaches. There is appropriate concern that the prostate capsule sparing approach may jeopardize bladder and prostate cancer control.10 Prostate cancer is incidentally detected in about 40% of radical cystectomy specimens, of which approximately 20% are clinically significant.10,22 About 25% of incidentally detected prostate cancers involve the prostatic apex,22 which may hinder complete resection using the prostate capsule sparing approach. In addition, the prostate harbors urothelial cancer in as many as half of cystectomy specimens, which further raises concerns about cancer control in the prostate capsule sparing setting.22e24 Our oncologic findings reinforce these concerns. Despite strict eligibility criteria, eg negative transurethral and prostate biopsies, 15% and 40% of prostate capsule sparing and nerve sparing cystectomies, respectively, still showed prostate cancer on final pathology evaluation. Although there was no differences in recurrence-free, metastasis-free or overall survival at this early surveillance point, the high incidence of prostate cancer gives cause for concern. Fortunately most of these patients had low
risk disease. While biopsy did not detect prostate cancer in these cases, newer technologies such as prostate magnetic resonance imaging and the prostate cancer antigen 3 test may help better identify them in the future. When interpreting our results, it is important to consider several limitations. 1) We could not achieve our targeted accrual. Historically it has been challenging to compare competing procedures in a randomized trial in the United States.25 Patients tend to be skeptical of surgical clinical trials due to the invasiveness and irreversibility of surgery.26 Further, patients generally have low willingness to participate in surgical trials due to an aversion to randomization and a desire to select the intervention.27 Recruitment rates in surgical randomized clinical trials are typically less than half of all eligible patients.28 In urology SPIRIT (Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial, ClinicalTrials.gov NCT00023686) is an example of a randomized trial of competing procedures that closed prematurely after having accrued only 56 of the intended 1,980 patients.25,29 Nonetheless, valuable information can still be obtained from a trial that does not meet accrual. 2) This was a single institution study. Designing a multi-institutional study and, thus, drawing from a larger pool of patients may have helped patient recruitment. 3) Prostate capsule sparing cystectomy is likely associated with a surgeon learning curve. It is challenging to develop a plane between the seminal vesicles and bladder base. Nonetheless, the surgeons who participated in this study were fellowship trained in oncology and had significant experience with performing cystectomy. These limitations notwithstanding, 2 important findings in this study merit consideration. 1) Although the study did not meet accrual, it provides initial estimates suggesting that the prostate capsule sparing approach has functional outcomes similar to those of the nerve sparing approach. 2) In highly select individuals, eg those with negative prostatic urethral and transrectal prostate biopsies, the prostate capsule sparing and nerve sparing approaches had similar but high cancer detection rates. In conclusion, in elucidating the functional and oncologic issues a future multi-institutional study may help overcome the accrual barrier and further inform the debate surrounding the usefulness of the prostate capsule sparing approach.
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Dochead: Adult Urology
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Prostate Capsule Sparing versus Nerve Sparing Radical Cystectomy for Bladder Cancer: Results of a Randomized, Controlled Trial Bruce L. Jacobs, Stephanie Daignault, Cheryl T. Lee, Khaled S. Hafez, Jeffrey S. Montgomery, James E. Montie, Jean E. Humrich, Brent K. Hollenbeck,* David P. Wood, Jr. and Alon Z. Weizer† From the Department of Urology, University of Pittsburgh School of Medicine (BLJ), Pittsburgh, Pennsylvania, and Divisions of Oncology (SD, CTL, KSH, JSM, JEH, AZW) and Health Services Research, Department of Urology (JEM, BKH), University of Michigan, Ann Arbor and Department of Urology, William Beaumont School of Medicine (DPW), Royal Oak, Michigan
Purpose: Prostate capsule sparing and nerve sparing cystectomies are alternative procedures for bladder cancer that may decrease morbidity while achieving cancer control. However, to our knowledge the comparative effectiveness of these approaches has not been established. We evaluated functional and oncologic outcomes in patients undergoing these procedures. Materials and Methods: We performed a single institution trial in patients with bladder cancer in whom transurethral prostatic urethral biopsy and transrectal prostate biopsy were negative. Men were randomized to prostate capsule sparing or nerve sparing cystectomy with neobladder creation and stratified by SHIM score (greater than 21 vs 21 or less). Our primary end point was 12-month overall urinary function as measured by BCI. Secondary end points included sexual function, cancer control and complications. Results: A total of 40 patients were enrolled in the study with 20 patients in each arm. Urinary function at 12 months decreased by 13 and 28 points in the prostate capsule and nerve sparing groups, respectively (p ¼ 0.10). Sexual function followed a similar pattern (p ¼ 0.06). There was no difference in recurrence-free, metastasis-free or overall survival (each p >0.05). The rate of incidentally detected prostate cancer was similar (p ¼ 0.15). Conclusions: Our study provides a randomized comparison of prostate capsule sparing and nerve sparing cystectomy techniques. We found no difference in functional or oncologic outcomes between the 2 approaches, although our study was underpowered due to a lack of patient accrual.
Abbreviations and Acronyms BCI ¼ Bladder Cancer Index PSA ¼ prostate specific antigen SHIM ¼ Sexual Health Inventory for Men Accepted for publication July 14, 2014. Study received institutional review board approval. Supported by National Institutes of Health Grant KL2 TR000146 (BLJ), American Cancer Society Research Scholar Grant RSGI-13-323-01CPHPS (BKH) and National Institutes of Health/ National Cancer Institute Grant R01 CA168691 (BKH). * Financial interest and/or other relationship with Urology. † Correspondence: Cancer Center Ambulatory Care Unit, Department of Urology, University of Michigan Comprehensive Cancer Center, 1111 Cancer Center, 1500 East Medical Center Dr., SPC5950, Ann Arbor, Michigan 48109 (telephone: 734-615-7228; FAX: 734-936-9102; e-mail: [email protected]).
Key Words: urinary bladder neoplasms, prostate, cystectomy, urinary diversion, mortality
RADICAL cystectomy is the standard treatment in patients with localized muscle invasive cancer or nonmuscle invasive urothelial cancer refractory to intravesical therapy1 and yet it is associated with
significant morbidity.2 To decrease morbidity prostate capsule sparing and nerve sparing cystectomies have been described in case series as potential ways to decrease side effects and improve quality of life outcomes
0022-5347/15/1931-0001/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Dochead: Adult Urology
http://dx.doi.org/10.1016/j.juro.2014.07.090 Vol. 193, 1-7, January 2015 Printed in U.S.A.
www.jurology.com
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without jeopardizing oncologic control. The 2 approaches attempt to preserve the neurovascular bundles lateral to the prostate. In addition, the prostate capsule sparing technique avoids extensive dissection of the pelvic floor musculature and the external urethral sphincter. These approaches may result in improved erectile and urinary function.3e9 However, compared to the more traditional radical cystectomy technique the benefits of these 2 approaches are largely demonstrated in retrospective studies. Limited evidence from randomized trials is available on the relative effectiveness of the prostate capsule sparing and nerve sparing approaches in terms of functional outcomes. To our knowledge the further and perhaps more importantly the relative cancer control of these 2 approaches is unknown. Despite the appeal of prostate capsule sparing radical cystectomy there is concern that leaving behind part of the prostate may lead to a higher rate of positive surgical margins and residual or future prostate cancer.10 Even if voiding and sexual function are improved in these patients, the prostate capsule sparing approach would ultimately be detrimental. For these reasons we performed a phase II, randomized clinical trial to evaluate functional and oncologic outcomes in patients treated with prostate capsule sparing or nerve sparing radical cystectomy with neobladder creation. We sought to understand potential differences in voiding function, sexual function and cancer control between these 2 patient populations to determine the potential of the approaches as alternative extirpative techniques for bladder cancer.
METHODS
All men underwent transurethral biopsy of the prostatic urethra and 12-core transrectal ultrasound guided prostate biopsy.12 Transurethral biopsy was performed with a resectoscope and tissue was sampled from the 5 and 7 o’clock positions. Transrectal prostate biopsy targeted all areas of the prostate as much as was feasible via the transrectal approach, including the anterior apex. Additional study exclusion criteria were creatinine greater than 2.2 mg/dl, prior pelvic radiation to the bladder or prostate, or a history of a radical prostatectomy. Of men who consented to randomization 5 were excluded from analysis due to prostate cancer on biopsy, 2 withdrew consent and 1 was excluded due to surgeon judgment.
Intervention Patients were randomly assigned to prostate capsule sparing or nerve sparing radical cystectomy with neobladder urinary diversion. Randomization was done the morning of surgery and patients were informed of the assignment as part of informed consent. These procedures share many common steps and the main difference is how the prostate is managed.13 With the prostate capsule sparing approach supra-ampullar dissection was performed to develop a plane anterior to the seminal vesicles. The endopelvic fascia was preserved on each side of the prostate. The prostate capsule was incised with a transverse incision on the distal anterior surface of the prostate and the adenoma was dissected from the capsule. For the nerve sparing approach the entire prostate and seminal vesicles were removed along with the bladder. The neurovascular bundles were spared by performing intrafascial dissection in retrograde fashion. These different cystectomy techniques necessitated different approaches to the urethral anastomosis. With the prostate capsule sparing approach the neobladder was anastomosed to the prostate capsule while with the nerve sparing approach the neobladder was anastomosed to the urethral stump.13 Extended pelvic lymph node dissection was performed with each approach, including dissection around the common iliac arteries.
Study Design
Measures
We performed a single institution clinical trial in which patients with urothelial cancer were randomized to prostate capsule sparing or nerve sparing cystectomy (ClinicalTrials.gov NCT01824329). The study protocol was approved by our institutional review board and patients provided written informed consent. Five surgeons participated in this study. Enrollment began in August 2007 and was completed in October 2011. Followup was completed in January 2013.
Men were stratified based on SHIM, a 5-question validated questionnaire used to evaluate sexual function. SHIM provides a score of 5 to 25 with 98% sensitivity and 88% specificity.14 Because a score of 21 or less indicates erectile dysfunction, stratification was based on a SHIM score of greater than 21 vs 21 or less. Baseline assessments included patient demographics and tumor characteristics. Urinary and sexual function was measured by BCI, a validated bladder cancer specific, health related quality of life instrument that measures urinary, sexual and bowel function, and bother domains.15 The index consists of 34 items in a total of 3 primary domains (urinary, bowel and sexual) and 2 subdomains (function and bother). Item responses are based on Likert scales with scores standardized to a scale of 0 to 100 points on which higher scores correspond to better health states. Each domain has been independently validated. The perioperative characteristics examined included estimated blood loss and operative time. Measured clinical outcomes included hospital length of stay, and 30-day
Patient Population Patients eligible for study included men 18 years old or older with clinical stage T2 or less urothelial cancer diagnosed within 3 months of enrollment.11 Cases down staged after neoadjuvant chemotherapy, eg from stage cT3 to cT2 or less, were eligible. Concern for nodal or metastatic disease on preoperative imaging was a finding that excluded patients from participation. The Appendix (http://jurology.com/) shows the specific imaging, laboratory and followup requirements. Dochead: Adult Urology
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readmission and 90-day major complication rates. A 229 major complication was defined as CTCAE (Common 230 Terminology Criteria for Adverse Events) grade 3 (ie se231 vere or medically significant but not immediately life 232 threatening, hospitalization or prolongation of hospitali233 zation indicated, disabling or limiting self-care daily 234 living activity) or higher.16 235 236 Outcomes 237 The primary end point was 12-month overall urinary function compared to baseline. Secondary end points were 238 12-month overall sexual function compared to baseline, 239 oncologic outcomes as measured by margin status, time to 240 disease recurrence, overall survival at 24 months, peri241 operative outcomes and complications. An independent 242 data and safety monitoring committee met every 3 months 243 to review study performance, adverse events, and data 244 validity and integrity. 245 Statistical Analysis 246 A randomized selection design17 was used to assess uri247 nary function in prostate capsule sparing and nerve 248 sparing cystectomy cases. Patients were randomized to 249 the surgical treatment arms using a balanced, stratified 250 (SHIM score greater than 21 vs 21 or less), randomized 251 block design. With 41 subjects per surgical group there 252 was 90% probability of selecting the superior treatment, 253 assuming that the superior treatment showed a 7-point 254 improvement in the 12-month urinary function change 255 from baseline compared with the inferior treatment. 256 Analysis was based on an intent to treat approach. Characteristics between groups were compared using 257 the Student t-test for continuous variables and the chi258 square test for categorical variables. Urinary function 259 and sexual function were evaluated using the Wilcoxon 260 rank test. Parameters related to clinical and pathological 261 stage were assessed by the Jonckheere-Terpstra test. 262 Recurrence-free, metastasis-free and overall survival was 263 analyzed by Kaplan-Meier methods and tested using the 264 log rank test. All analysis was done with SASÒ, version 265 9.2. The probability of a type I error was considered at 266 0.05 and all tests were 2-sided. 267 268 269 RESULTS 270 A total of 40 patients were enrolled in study with 20 271 randomized to each cohort. Baseline patient char272 ½T1 acteristics were similar in the 2 groups (see table). 273 In each group the operation was most commonly 274 performed via an open approach. For robotic pro275 cedures the neobladder was created extracorpore276 ally. A Hautmann reservoir was constructed in 277 more than 90% of patients. 278 The 12-month BCI was completed by 36 of the 279 40 enrolled patients (90%) and the primary end 280 point (urinary function) was evaluated in 34 (85%). 281 In 2 patients urinary function was not evaluated 282 and in 4 sexual function was not evaluated due 283 to missing data on BCI sections. For urinary func284 tion there was no statistical difference between 285 the 2 approaches (p ¼ 0.10). Average SD urinary Dochead: Adult Urology
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function at 12 months compared with baseline decreased by 13 30 and 28 33 points for prostate capsule sparing and nerve sparing, respectively (see table). Figure 1 shows a waterfall plot of the change in urinary function in the study population. Average sexual function at 12 months compared with baseline decreased by 1 11 and 23 30 points for prostate capsule sparing and nerve sparing, respectively (p ¼ 0.06). Figure 2 shows a waterfall plot of changes in sexual function stratified by SHIM score. Examination of responses to specific urinary and sexual function questions revealed that each group experienced the slowest improvement in nighttime frequency and leakage. The nerve sparing group also had slower improvement in daytime frequency. Of patients with prostate capsule sparing and nerve sparing 22% and 17% performed intermittent catheterization, and 55% and 65%, respectively, used aids or medication for erectile function. Pathological outcomes were similar in the 2 groups (see table). Most patients had tumor stage T2 or less and node negative disease. Three of the 7 patients with node positive disease had received neoadjuvant chemotherapy. Prostate cancer was detected in 3 patients in the prostate capsule sparing cohort and in 8 in the nerve sparing cohort. There was no difference between the groups in recurrence-free, metastasis-free and overall survival (figs. 3 to 5). Of the 40 patients with negative biopsies who underwent surgery prostate cancer was detected on final pathology in 11 (28%) (see table). Seven of the 8 patients (88%) with nerve sparing who had prostate cancer had undetectable PSA. In the 3 prostate capsule sparing cases of prostate cancer PSA was less than 0.1, 0.1 and 0.2 ng/ml, respectively. None of these patients received additional treatment. Gleason score and pathological prostate cancer stage were similar in the 2 groups (each p >0.05). One patient had a positive prostate cancer margin but undetectable PSA at followup. Perioperative characteristics and clinical outcomes were similar in the cohorts (see table). Operative time was 395 and 411 minutes for the prostate capsule sparing and nerve sparing approaches, respectively (p ¼ 0.65). No difference was observed in the 30-day readmission or 90-day major complication rates (each p >0.05).
DISCUSSION Our study provides a randomized comparison of prostate capsule sparing and nerve sparing cystectomy techniques. We found no difference in functional or oncologic outcomes between the 2 approaches, although our study was underpowered
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Study population demographics, clinical characteristics, pathological outcomes, prostate characteristics, and perioperative and clinical outcomes Prostate Capsule Sparing No. pts Mean SD age No. Eastern Cooperative Oncology Group performance status (%): 0 1 Mean SD body mass index (kg/m2) No. neoadjuvant chemotherapy (%) No. clinical stage (%): Ta/Tis T1 T2/T3 No. approach (%): Open Robot-assisted Median followup (mos) No. pathological tumor stage (%) T0 Ta/Tis T1 T2 T3 No. pathological nodal stage (%): N0 N1 N2 No. pos surgical margin (%): Soft tissue Ureter Urethra No. Ca (%): Urethra Prostate Mean SD No. lymph nodes removed
Demographic þ clinical characteristics 20 58 10 20 0 30 8 3 7 10
(100)
Nerve Sparing 20 59
e 0.70 0.49
6
(40)
18 2 31 10
(15) (35) (50)
2 4 14
(10) (20) (70)
(75) (25)
13 7
(65) (35)
5
p Value*
(90) (10) 4 (50)
0.76 0.75 0.23
0.73 15 5 Pathological outcomes 41
37
0.75 0.45
8 6 3 1 2
(40) (30) (15) (5) (10)
8 2 4 2 4
(40) (10) (20) (10) (20)
18 1 1
(90) (5) (5)
15 1 4
(75) (5) (20)
0 1 0
(5)
0 1 0
(5)
0.19
2 (10) 3 (15) 16 10 Preop þ biopsy characteristics 1.9 (0.2e5.5) 33 (14)
Median ng/ml PSA (range) Mean SD ultrasound prostate vol (ml) No. prostate biopsy results (%): Neg HGPIN
18 (90) 2 (10) Postop þ pathological characteristics 3 (15)
No. prostate Ca (%) No. Gleason score (%): 6 7 No. pathological tumor stage (%):† T2a T2b No. prostate Ca pos margin (%) Median mos PSA surveillance (95% CI)
4 8 16
(20) (40)
0.66 0.15 0.91
1.0 (0.3e5.1) 26 (8)
0.07 0.96 0.99
8
17 3
(85) (15)
8
(40)
(67) (33)
8 0
(100)
2 (67) 1 (33) 1 (33) 23 (6e34) Periop þ clinical outcomes 400 (200e1,500) 395 106
7 1 0 22
(88) (12)
2 1
0.99 0.99 0.99
0.15 0.10 0.45
Median ml estimated blood loss (range) Mean SD operative time (mins) No. diversion type (%): Neobladder Ileal conduit Median days hospitalization (range) Median days indwelling catheter time (range) No. 30-day readmission (%) No. 90-day major complication (%)‡
20 0 7 21 0 7
(100) (5e21) (13e47) (35)
(6e26)
575 (150e2,000) 411 109 18 2 8 21 3 12
(90) (10) (5e21) (12e34) (15) (60)
0.27 0.59 0.19 0.65 0.49 0.79 0.96 0.23 0.20
* Clinical stage, pathological tumor stages, pathological nodal stage and Gleason score Jonckheere-Terpstra test, Student t-test for continuous variables and Fisher exact or Mantel-Haenszel chi-square test for categorical variables. † No patient had lymph nodes positive for prostate cancer. ‡ CTCAE grade 3 or higher.
due to lack of patient accrual. The 2 approaches had similar perioperative outcomes and complication rates. Dochead: Adult Urology
Interest in prostate capsule sparing cystectomy stems from its potential to decrease morbidity. The approach preserves the neurovascular bundles,
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Figure 1. Average urinary function at 12 months vs baseline decreased by 13 30 and 28 33 points in patients with prostate capsule sparing and nerve sparing cystectomy, respectively. Urinary function did not differ for 2 approaches (Wilcoxon rank test p ¼ 0.10).
spares the seminal vesicles and limits dissection of the pelvic floor musculature around the external sphincter, which are techniques thought to improve voiding and erectile function compared with the nerve sparing approach or traditional cystectomy.13 Indeed, more than three-fourths of patients have reported preserved erectile function with the prostate capsule sparing approach.3,18,19 Most patients have also reported daytime and nighttime urinary continence.3,6,18,20,21
Figure 2. In nerve sparing cystectomy cohort SHIM score was 21 or less and greater than 21 in 10 patients each. In prostate capsule sparing cystectomy cohort SHIM score was 21 or less and greater than 21 in 11 and 9 patients, respectively. Average sexual function at 12 months vs baseline decreased by 1 11 points for prostate capsule sparing and by 23 30 points for nerve sparing. Sexual function did not differ for 2 approaches (Wilcoxon rank test p ¼ 0.06).
Dochead: Adult Urology
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Figure 3. Recurrence-free probability did not differ in patients randomized to prostate capsule sparing and nerve sparing cystectomy (log rank test p >0.05).
Our findings show that the prostate capsule approach had functional outcomes similar to those of the nerve sparing approach. Although the size of the observed effect was greater than what we defined as clinically important for urinary and sexual function, the variability of the effect required the sample size to be larger than what we could accrue during the study period. Patients treated with the prostate capsule sparing approach reported urinary and sexual function that was substantially closer to baseline than those treated with the nerve sparing approach at 12 months (see table, and figs. 1 and 2). It is unclear whether statistically significant differences in urinary and sexual function between the 2 approaches may have emerged had we attained our targeted recruitment of
Figure 4. Metastasis-free probability did not differ in patients randomized to prostate capsule sparing and nerve sparing cystectomy (log rank test p >0.05).
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Figure 5. Survival probability did not differ in patients randomized to prostate capsule sparing and nerve sparing cystectomy (log rank test p >0.05).
82 patients, which would have essentially doubled our sample size. Nevertheless, our study findings improve our understanding of urinary and erectile function outcomes after the prostate capsule sparing and nerve sparing approaches as well as the oncologic implications of the approaches. There is appropriate concern that the prostate capsule sparing approach may jeopardize bladder and prostate cancer control.10 Prostate cancer is incidentally detected in about 40% of radical cystectomy specimens, of which approximately 20% are clinically significant.10,22 About 25% of incidentally detected prostate cancers involve the prostatic apex,22 which may hinder complete resection using the prostate capsule sparing approach. In addition, the prostate harbors urothelial cancer in as many as half of cystectomy specimens, which further raises concerns about cancer control in the prostate capsule sparing setting.22e24 Our oncologic findings reinforce these concerns. Despite strict eligibility criteria, eg negative transurethral and prostate biopsies, 15% and 40% of prostate capsule sparing and nerve sparing cystectomies, respectively, still showed prostate cancer on final pathology evaluation. Although there was no differences in recurrence-free, metastasis-free or overall survival at this early surveillance point, the high incidence of prostate cancer gives cause for concern. Fortunately most of these patients had low
risk disease. While biopsy did not detect prostate cancer in these cases, newer technologies such as prostate magnetic resonance imaging and the prostate cancer antigen 3 test may help better identify them in the future. When interpreting our results, it is important to consider several limitations. 1) We could not achieve our targeted accrual. Historically it has been challenging to compare competing procedures in a randomized trial in the United States.25 Patients tend to be skeptical of surgical clinical trials due to the invasiveness and irreversibility of surgery.26 Further, patients generally have low willingness to participate in surgical trials due to an aversion to randomization and a desire to select the intervention.27 Recruitment rates in surgical randomized clinical trials are typically less than half of all eligible patients.28 In urology SPIRIT (Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial, ClinicalTrials.gov NCT00023686) is an example of a randomized trial of competing procedures that closed prematurely after having accrued only 56 of the intended 1,980 patients.25,29 Nonetheless, valuable information can still be obtained from a trial that does not meet accrual. 2) This was a single institution study. Designing a multi-institutional study and, thus, drawing from a larger pool of patients may have helped patient recruitment. 3) Prostate capsule sparing cystectomy is likely associated with a surgeon learning curve. It is challenging to develop a plane between the seminal vesicles and bladder base. Nonetheless, the surgeons who participated in this study were fellowship trained in oncology and had significant experience with performing cystectomy. These limitations notwithstanding, 2 important findings in this study merit consideration. 1) Although the study did not meet accrual, it provides initial estimates suggesting that the prostate capsule sparing approach has functional outcomes similar to those of the nerve sparing approach. 2) In highly select individuals, eg those with negative prostatic urethral and transrectal prostate biopsies, the prostate capsule sparing and nerve sparing approaches had similar but high cancer detection rates. In conclusion, in elucidating the functional and oncologic issues a future multi-institutional study may help overcome the accrual barrier and further inform the debate surrounding the usefulness of the prostate capsule sparing approach.
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Dochead: Adult Urology
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