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Prostate-sparing cystectomy: A review of the oncologic and functional outcomes. Contraindicated in patients with bladder cancer
Urologic Oncology: Seminars and Original Investigations 27 (2009) 466 – 472
Review article
Prostate-sparing cystectomy: A review of the oncologic and functional outcomes. Contraindicated in patients with bladder cancer John P. Stein, M.D., FACSa,1,*, Richard E. Hautmann, M.D.b, David Penson, M.D.a, Donald G. Skinner, M.D.a a
Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90089, USA b The University of Ulm, Ulm, Germany Received 17 October 2007; received in revised form 18 December 2007; accepted 31 December 2007
Abstract Purpose: The standard treatment of high-grade, invasive bladder cancer is radical cystectomy. Prostate-sparing techniques have recently become an alternative surgical approach for the treatment of the disease. We review the literature regarding the oncologic and functional outcomes for prostate-sparing approaches. Materials and methods: The literature pertaining to prostate-sparing cystectomy was reviewed. The oncologic issues of preserving the prostate in patients undergoing cystectomy for bladder cancer along with the functional outcomes were evaluated. Results: There is a significant incidence of bladder and prostate cancer involving the prostate, and prostate apex in men requiring cystectomy for transitional cell carcinoma of the bladder at the time of surgery. This involvement of the prostate with cancer maybe difficult to determine preoperatively. Importantly, although prostate-sparing procedures provide good potency results, the functional outcomes following cystectomy and orthotopic diversion to the urethra are not significantly different, particularly regarding daytime continence. Lastly, several studies suggest the oncologic outcomes following prostate-sparing cystectomy may be compromised with this surgical approach. Conclusions: The significant incidence of bladder and prostate cancer involving the prostate at the time of cystectomy, which is difficult to determine preoperatively, may preclude the general application of prostate-sparing techniques in most men requiring cystectomy. Concerns regarding the oncologic outcomes with prostate-sparing techniques, coupled with the excellent results seen with traditional radical cystectomy and orthotopic diversion, suggest that prostate-sparing procedure should be performed only in well-selected individuals. © 2009 Elsevier Inc. All rights reserved. Keywords: Bladder cancer; Cystectomy; Prostate-sparing surgery; Orthotopic diversion
1. Introduction Bladder cancer is the fourth most common cancer in men and the tenth most common cancer diagnosed in women, with transitional cell carcinoma (TCC) comprising nearly 90% of all primary bladder tumors. In 2008, it is estimated that 68,810 new patients will be diagnosed with bladder cancer, and there will be 14,100 deaths from the disease [1]. Although the majority of patients with bladder cancer present with superficial bladder tumors, 20% to 40% of patients will present with or develop muscle invasive dis-
* Corresponding author. Tel.: ⫹1-323-865-3709; fax: ⫹1-323-8650120. E-mail address: [email protected] (J.P. Stein). 1 Deceased. 1078-1439/09/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2007.12.014
ease. Invasive bladder cancer is a lethal malignancy; if untreated, over 85% of patients will die of the disease within 2 years of diagnosis [2]. Despite early and even aggressive treatment approaches for high-grade, invasive bladder cancer [3], nearly 25% of patients demonstrate pathologic evidence of lymph node metastases at the time of cystectomy [4,5]. These data underscore 2 important points regarding bladder cancer: (1) high-grade, invasive bladder tumors are potentially lethal, and (2) a significant number of patients have locally advanced disease at the time of definitive therapy. The rationale for an aggressive surgical approach employing radical cystectomy for high-grade, invasive bladder cancer is based on several important observations. First, the best long-term survival rates coupled with the lowest local recurrences are seen following radical cystectomy [4,5].
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Second, the morbidity and mortality of radical cystectomy have significantly improved over the past several decades. Third, TCC is generally a tumor resistant to radiation therapy even at high doses. Fourth, chemotherapy alone or in combination with bladder-sparing protocols have not demonstrated equivalent long-term survival rates comparable to cystectomy [6]. Fifth, radical cystectomy provides accurate pathologic staging of the primary bladder tumor (p-stage) and regional lymph nodes. This allows for selective application of adjuvant therapy based on precise pathologic evaluation. Lastly, improvements in lower urinary tract reconstruction (particularly orthotopic diversion) have made cystectomy more acceptable to patients and allowed them to maintain a reasonable functional status [7]. For the aforementioned reasons, radical cystectomy has become an ideal therapy for high-grade, invasive bladder cancer. Although the current oncologic standard for high-grade, invasive bladder cancer remains radical cystectomy, a recent trend in urologic oncology has been to minimize the surgical approach, that is, attempting organ preservation, without compromising the cancer outcomes. So-called prostate-preserving cystectomy has been recently advocated for patients with bladder cancer to improve clinical and functional outcomes, including continence, potency, and fertility. This modified surgical approach generally includes sparing the prostate, vasa deferentia, and seminal vesicles while resecting the prostatic adenoma (in some cases) and lower urinary tract reconstruction to the prostate. In appropriately selected men who require cystectomy, and for whom potency and fertility remain relevant issues, this may be an important technique, which may reduce the issue of erectile dysfunction and maintain the ability for reproduction. In fact, our group described and promoted a modified, prostate-sparing cystectomy in well-selected male patients, with nonurothelial malignancies or nonmalignant bladder diseases, that necessitated cystectomy but not necessarily prostatectomy [8]. It is clear that this modified surgical application can be performed in appropriately selected patients but must not compromise the oncologic control. Recently, various prostate-sparing techniques has been reported in patients with TCC of the bladder undergoing radical cystectomy [8 –22]. The fundamental rationale for
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this modified technique includes improvement in urinary continence (compared with orthotopic diversion to the proximal urethra), enhancement of erectile function, and to maintain the reproductive ability in younger patients. Oncologic issues including the risks of prostate adenocarcinoma and TCC involving the prostate in patients undergoing prostate-sparing cystectomy with bladder cancer is clearly a concern. In addition, the clinical results with orthotopic reconstruction are indeed good and, in the properly selected patient, nerve-sparing techniques may be performed to preserve erectile function. The intended application of prostate-sparing techniques was primarily focused upon quality of life issues and not necessarily with oncologic outcomes or to improve survival. While quality of life issues are important secondary concerns, survival remains paramount and should be the driving factor in treatment decisions, given the highly aggressive nature of invasive bladder cancer. In this review, the oncologic and functional issues will be addressed regarding men requiring cystectomy for bladder cancer. Surgeons must understand these oncologic implications and patients must be counseled regarding these issues when considering the surgical approach for bladder cancer.
2. Prostate cancer in men undergoing cystectomy for bladder cancer Prostate cancer (PCA) is the most common noncutaneous malignancy found in men and the second leading cause of cancer deaths in our country. It is recognized that the prevalence of PCA exceeds that of clinically detected tumors, with 30% of 50-year old men and as high as 70% of 80-year old men at autopsy study with the disease [23]. Although the majority of PCA found at the time of radical cystectomy has been regarded as clinically insignificant, it is unknown if these tumors would have become clinically or pathologically significant had they not been removed. The overall reported incidence of PCA involvement of the prostate in patients undergoing radical cystectomy ranges from 27% to 46% (Table 1) [4,23–30]. This variation depends upon the method in which the prostate was patho-
Table 1 Incidence of prostate cancer in radical cystectomy specimens for bladder cancer Reference
Year
Total no. patients
Median age
% PCA
Step-section
Winfield et al. [25] Kabalin et al. [26] Montie et al. [27] Abbas et al. [28] Plante et al. [29] Moutzouris et al. [30] Hautmann et al. [31] Stein et al. [4] Revelo et al. [24]
1987 1989 1989 1996 1998 1999 2000 2001 2004
80 66 84 40 260 59 133 845 121
63 y 64 y 64 y nm nm 66 60 67 67
27 38 46 45 18 27 43 29 41
No Yes Yes Yes No Yes Yes No Yes
nm: not mentioned.
(3 mm) (4.5 mm) (2–3 mm) (5 mm) (3mm) (2–3 mm)
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logically evaluated, with whole-mounted, step-sectioned prostates generally demonstrating greater than a 40% incidence of PCA. In a recent analysis of PCA in cystectomy specimens removed for bladder cancer, 41% of the patients demonstrated PCA [24]. Importantly, of these cancers 48% were clinically significant tumors: 16% with extracapsular extension and 20% with Gleason patterns 4 and 5 (scores 7 or greater). The finding that 60% of the PCA involved the prostate apex (78% of which were significant tumors) has clinical implications in patients undergoing prostate-sparing or even prostate apex-sparing cystectomy procedures [24]. These findings were confirmed by another report in which 27% of patients undergoing cystectomy for invasive TCC of the bladder were found to have PCA, with a propensity (one-third) involving the apex of the prostate [30]. The authors suggested that this tendency in the apex of the prostate with PCA demands a careful excision of the apical margins. Kabalin and associates previously reported a 38% incidence of PCA with a distinct apical predominance of these tumors in patients undergoing radical cystectomy for bladder malignancies [26]. Further pathologic evidence regarding prostate-sparing techniques and the oncologic safety comes from a retrospective histologic study that evaluated the frequency for urethral and prostatic lesions in cystectomy specimens removed for bladder cancer [29]. A total of 260 specimens were included and the prostate was analyzed in 3 planes (upper, middle, and lower) as well as the apex of the prostate. Urethral involvement with cancer (TCC) was observed in 31% of cases and was contiguous with the bladder tumor in more than one-half of these. Prostate cancer was observed in approximately 18% of cases. The authors conclude that the high frequency of urethral and prostatic involvement does not justify preservation of the prostate during cystectomy. The aforementioned pathologic findings regarding PCA in patients undergoing cystectomy for bladder cancer are indeed important. Not only is there a noteworthy incidence of PCA, but a substantial number of these are clinically significant with a predominance of the apical portion of the prostate. In a recent report, Ward et al, reviewed the prevalence of incidental PCA in men with a PSA of 0.1 to 2.0 ng/mL and normal digital rectal examination undergoing radical cystoprostatectomy for bladder cancer at the Mayo Clinic or Medical University of Innsbruck, Austria from
1988 to 2000 [43]. Of the 1,600 patients who underwent the procedure, 129 (8%) met the inclusion criteria. Of these, 23% were found to have incidental PCA. Of these, 7% had Gleason 7 disease or higher and 27% had tumors of 0.2 cc or greater. In summary, there remains a considerable prevalence of incidental PCA at the time of radical cystoprostatectomy, even in men at lowest risk for the disease. While many of these cancers may be clinically indolent, roughly one-fourth of these tumors have pathologic characteristics that indicate that they are clinically significant. The aforementioned pathologic findings regarding PCA in patients undergoing cystectomy for bladder cancer are indeed important. Not only is there a noteworthy incidence of PCA, a substantial number of these are clinical significant with a predominance of the apical portion of the prostate. In addition, preoperative risk factors, such as DRE or PSA, do not appear to be able to distinguish which patients will have prostate cancer or which incidentally detected cancers will be clinically significant. Collectively, these findings underscore the continued need to remove the entire prostate, with particular attention to the apex, in male patients undergoing cystectomy for invasive bladder cancer.
3. Prostate involvement with transitional cell carcinoma in men undergoing cystectomy for bladder cancer The incidence of prostate involvement with TCC in men undergoing cystectomy for the bladder cancer ranges from 12% to 48% (Table 2) [24,32–36]. This range may relate to patient selection and probably, more importantly, to the method in which the prostate is pathologically sectioned. Cystectomy series that employ whole mount section report an incidence of nearly 40% [24,32,33], while routine pathologic evaluation approaches 20% [34 –36]. In a large series of men undergoing cystectomy for bladder cancer with routine pathologic evaluation of the prostate, 17% of patients had some prostate involvement, including 7% with invasive stromal involvement [34]. Revelo and associates recently reported an overall incidence of 48%, with 10% of patients demonstrating invasive stromal involvement of the prostate with bladder cancer following cystectomy [24]. The fact there is a significant incidence of prostate involvement with TCC, and the inability to accurately determine
Table 2 Incidence of TCC in the prostate of radical cystectomy specimens Reference
Total no. patients
Prostate TCC
Ducts/urethra
Invasive (stroma)
Step-section
Reese et al. [32] Wood et al. [33] Revelo et al. [24] Stein et al. [34] Iselin et al. [35] Ngninken et al. [36]
115 84 121 768 70 283
33 (29%) 36 (43%) 58 (48%) 129 (17%) 14 (20%) 76 (27%)
17 (15%) 22 (26%) 45 (37%) 78 (10%) 11 (16%) 36 (12%)
16 (14%) 14 (17%) 13 (10%) 51 (7%) 3 (4%) 40 (15%)
Yes Yes Yes No No No
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this involvement preoperatively, raises concerns of routinely sparring the prostate in this group of patients. Prostate involvement with TCC may be subcategorized into superficial involvement (prostatic urethra and prostatic ducts) or invasive into the stroma. Patients with invasive stromal involvement of the prostate (P4a) demonstrate higher recurrence rates and worse survival [37]. The incidence of urethral recurrence is also higher in patients with any prostate involvement; invasive stromal involvement demonstrating the highest risk for urethral recurrence [34]. These clinical and oncologic implications of sparing the prostate in men with bladder cancer requiring cystectomy must be considered, particularly when a local recurrence following surgery is generally a fatal event. Preservation of any of the prostate in men with bladder cancer therefore has profound oncologic implications, particularly in young men with an extended life expectancy.
4. Apical involvement of the prostate with prostate cancer and transitional cell carcinoma in men undergoing cystectomy for bladder cancer The pathologic features of PCA and bladder cancer and the frequency of apical involvement were recently investigated from cystoprostatectomy specimens [24]. In this series of 121 consecutive cystoprostatectomy specimens, 41% had unsuspected PCA involvement and 48% had bladder cancer involving some portion of the prostate. Apical involvement of the prostate with PCA was observed in 60% of these patients (70% clinically significant), while 33% of patients with bladder cancer involving the prostate also demonstrating apical involvement. Overall, only 32 of 121 patients (26%) had no prostate or bladder cancer involvement of the prostate. Regarding apical involvement specifically, 39% of patients had PCA or TCC involvement of this region and would not have been appropriate for sparing this portion of the prostate during cystectomy.
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5. Voiding and continence in patients with orthotopic urinary diversion Orthotopic lower urinary tract reconstruction to the native intact proximal urethra can be performed in the majority of patients requiring cystectomy for bladder cancer with excellent functional outcomes [7]. In a comprehensive and detailed review of 2,238 patients undergoing an orthotopic neobladder, daytime continence was reported in 87% and nighttime continence observed in 72% [38]. It has been suggested that continence results following prostate-sparing cystectomy may be better. However, several issues should be understood when evaluating continence status in men following cystectomy. First, the definition of day and/or night-time continence is not standard and often not even defined. Second, most prostate-sparing cystectomy series report on much younger patients. This is important, as urinary continence (and potency) rates following cystectomy and orthotopic reconstruction are clearly associated with age, with younger patients reporting better continence [7,38 – 40]. It is emphasized the median age of patients undergoing prostate-sparing procedures are significantly younger compared with traditional cystectomy and orthotopic diversion to the urethra (Table 3). Regardless, there does not appear to be a significant difference in the daytime continence rates between the techniques, with a slight advantage of night-time continence in the prostate-sparing patients. It is assumed that preservation of the prostatic apex should optimize urinary continence in patients undergoing cystectomy and orthotopic reconstruction. This belief was based on the traditional concept that the apical prostate contains the inner smooth muscle component of the distal urethral sphincter mechanism, which augments the external striated muscle component in maintaining continence. In fact, it has been shown that preservation of the prostatic apex does not improve urinary continence in patients with intestinal neobladders compared with patients undergoing reconstruction to the membranous urethra [41]. When com-
Table 3 Prostate-sparing cystectomy: functional results Author
Spitz et al. [8] Muto et al. [9] Vallancien et al. [10] Colombo et al. [11] Terrone et al. [12] Meinhardt et al. [13] Ghanem [14] Nieuwenhuijzen et al. [15] Botto et al. [16] Martis et al. [17] Arroyo et al. [18] Saidi et al. [19]
No.
4 61 100 27 28 24 4 44 34 32 25 25
Median age
26 49 64 52 51 51 42 57 61 59 60 57
y y y y y y y y y y y y
Median follow-up
24 6 38 36 90 — 20 42 26 32 9 46
mo mo mo mo mo mo mo mo mo mo mo
Continence (%) Day
Night
100 95 97 100 59 96 100 95 90 98 100 100
100 31 95 100 — 91 100 74 85 80 100 86
Need for IC (%)
Potency (%)
25 1 0 15 93 17 75 28 3 — 0 —
100 95 82 100 53 83 — 77 89 80 84 86
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paring urodynamic studies between patients undergoing orthotopic diversion with the membranous urethral and the prostatic apex, there was no difference in the maximum urethral pressure, but significant lower flow rates were observed in those with preservation of the prostatic apex [41]. This may ultimately lead to difficulties in neobladder evacuation, hypercontinence, and potentially the increased need to perform catheterization to empty the neobladder in these patients. Overall, there does not appear to be a significant advantage from a continence perspective or voiding pattern with prostate-sparing techniques.
6. Erectile function in patients undergoing cystectomy for bladder cancer Potentially the greatest advantage of prostate-sparing techniques is preservation of sexual function. Sexual function domains may include erectile function, ejaculation, and involves fertility issues. Fertility and ejaculation are generally of little concern in elderly men requiring cystectomy whose median age approximates 67 years [4]. Erectile function however, represents the single most advantage of prostate-sparing cystectomy (Table 3). The reader is cautioned to remember that most of these studies did not use patientcentered methods or validated questionnaires to assess erectile function, which has been shown to lead to an overestimation of sexual function in previous studies of sexual function following radical prostatectomy. It should be noted that traditional nerve-sparing radical cystectomy can be successfully performed in well-selected men with excellent clinical outcomes, and without jeopardizing the oncologic results [39]. In addition, oral medication and injection therapy, along with advances in penile prostheses, have improved erectile function.
7. Oncologic outcomes in patients undergoing prostatesparing cystectomy Little data regarding the long-term oncologic outcomes with various prostate-sparing cystectomy are available today. However, several studies suggest that this approach may compromise the cancer outcomes compared with a standard radical cystectomy [19,22,42]. This not only includes the potential for local recurrences but also a higher pattern of distant failure as well [42].
8. Discussion The trend in urologic surgical oncology to minimize operative morbidity by anatomical and functional organ preservation (without compromising the oncologic principles) is not only laudable but appropriate. With this intent, a trend toward performing sexual-preserving radical cystec-
tomy in patients with high-grade, invasive bladder cancer has been seen. This surgical approach has advocated to improve the continence and potency rates following cystectomy and to preserve the ability to procreate. However, concerns related to the oncologic and functional outcomes for these patients with bladder cancer have been raised [42]. Several studies suggest the oncologic outcomes following prostate-sparing cystectomy may be compromised. Saidi and associates reported on 25 men (mean age 57 years) who underwent a prostate-sparing cystectomy with a median follow-up of 46 months [19]. All patients had a PSA less than 4 ng/ml or a negative prostatic needle biopsy and a transurethral resection of the prostate performed preoperatively to evaluate the prostatic urethra. Overall, 24% of patients developed a pelvic recurrence, 8% a urethral recurrence, and another 24% developed distant metastases. Although the functional outcomes were excellent (94% daytime continence, 75% nighttime continence, 75% with some erectile function), the authors concluded the oncologic results were substantially worse compared with those of a standard radical cystectomy [19]. These findings are supported by a review, which evaluated the oncologic results following three different prostatesparing techniques [22]. The authors concluded in this review that preservation of the prostate is not associated with increased morbidity and may improve functional results, however, it does not appear to ensure an equivalent level of cancer control with higher metastatic recurrence rates. The oncologic outcomes and patterns of recurrence following prostate-sparing cystectomy were recently evaluated in a review by Hautmann and Stein [42]. In this review, a total of 252 patients undergoing some form of prostatesparing procedure were evaluable (139 with pT1, N0, M0, and 113 with pT2, N0, M0 disease, median follow-up 40 months) and compared with 646 men undergoing a standard radical cystectomy, from the authors’ institution (median follow-up 36 months). The local and distant recurrences rates, based on similar pathologic staging, were then compared. The observed distant failure rate following prostatesparing cystectomy was twice as high as in the standard cystectomy group. It was suggested that the higher pattern of distant failure in those undergoing prostate-sparing cystectomy could be attributed to direct tumor spill to the liver and lungs, bypassing the regional lymph nodes, during the prostate resection. It is hypothesized that urothelial bladder cells have a route for tumor-cell dissemination and a starting point for hematogenous metastasis as the prostate vessels are opened during the surgical manipulation [42]. These speculative reasons and the fact that there is a significant incidence of PCA and TCC involving the prostate, coupled with no reliable method to determine preoperatively, suggest that prostate-sparing cystectomy should not be routinely performed in men with bladder cancer. We emphasize that one can perform a prostate-sparing cystectomy in younger men without TCC of the bladder, and we believe this may be an appropriate surgical approach in the carefully selected individual.
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Proponents for prostate-sparing techniques suggest that this modification may help overcome the technical difficulties of the urethral anastomosis, allowing for an easy and robust anastomosis with minimal leakage [14]. This simply is not the case. Orthotopic reconstruction can be performed to the urethra without technical difficulty in virtually all cases, and should avoid the problem of hypercontinence, more commonly associated with prostate-sparing techniques. Furthermore, daytime continence results following radical cystectomy and prostate-sparing cystectomy are not significantly different. Nighttime continence may be slightly better with prostatesparing procedures, however, the issue of urinary retention and need for intermittent catheterization appears to be more problematic in the prostate-sparing group. Should prostate-sparing procedures be applied to patients with high-grade, invasive bladder cancer requiring radical cystectomy, when approximately 50% of patients have locally advanced and/or node positive disease at the time of surgery? Although speculative, the potential for local tumor spill or distant tumor dissemination with a prostate-sparing procedure and manipulation are also serious concerns. The development of a local and/or distant recurrence following the surgical treatment of bladder cancer is generally a fatal event. The significant incidence of bladder and PCA involving the prostate at the time of cystectomy, which may be difficult to determine preoperatively, may also preclude the general application of prostate-sparing techniques in men undergoing cystectomy. Furthermore, most men at cystectomy are elderly (median age between 67 years) and not concerned with fertility at this stage of their life. Importantly, the functional outcomes following cystectomy and orthotopic diversion to the urethra are not significantly different regarding continence. Prostate-sparing procedures do provide better potency results; however, the application of nerve sparing approaches (in selected individuals), the use of oral and injectable therapies, and the improvements in penile prosthetic devices should reduce the apprehension of impotence following cystectomy. Radical cystoprostatectomy remains the treatment of choice for patients with bladder cancer, while the application of prostate-sparing techniques may be carefully applied, in selected individuals, with the future oncologic outcomes scrutinized.
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Review article
Prostate-sparing cystectomy: A review of the oncologic and functional outcomes. Contraindicated in patients with bladder cancer John P. Stein, M.D., FACSa,1,*, Richard E. Hautmann, M.D.b, David Penson, M.D.a, Donald G. Skinner, M.D.a a
Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90089, USA b The University of Ulm, Ulm, Germany Received 17 October 2007; received in revised form 18 December 2007; accepted 31 December 2007
Abstract Purpose: The standard treatment of high-grade, invasive bladder cancer is radical cystectomy. Prostate-sparing techniques have recently become an alternative surgical approach for the treatment of the disease. We review the literature regarding the oncologic and functional outcomes for prostate-sparing approaches. Materials and methods: The literature pertaining to prostate-sparing cystectomy was reviewed. The oncologic issues of preserving the prostate in patients undergoing cystectomy for bladder cancer along with the functional outcomes were evaluated. Results: There is a significant incidence of bladder and prostate cancer involving the prostate, and prostate apex in men requiring cystectomy for transitional cell carcinoma of the bladder at the time of surgery. This involvement of the prostate with cancer maybe difficult to determine preoperatively. Importantly, although prostate-sparing procedures provide good potency results, the functional outcomes following cystectomy and orthotopic diversion to the urethra are not significantly different, particularly regarding daytime continence. Lastly, several studies suggest the oncologic outcomes following prostate-sparing cystectomy may be compromised with this surgical approach. Conclusions: The significant incidence of bladder and prostate cancer involving the prostate at the time of cystectomy, which is difficult to determine preoperatively, may preclude the general application of prostate-sparing techniques in most men requiring cystectomy. Concerns regarding the oncologic outcomes with prostate-sparing techniques, coupled with the excellent results seen with traditional radical cystectomy and orthotopic diversion, suggest that prostate-sparing procedure should be performed only in well-selected individuals. © 2009 Elsevier Inc. All rights reserved. Keywords: Bladder cancer; Cystectomy; Prostate-sparing surgery; Orthotopic diversion
1. Introduction Bladder cancer is the fourth most common cancer in men and the tenth most common cancer diagnosed in women, with transitional cell carcinoma (TCC) comprising nearly 90% of all primary bladder tumors. In 2008, it is estimated that 68,810 new patients will be diagnosed with bladder cancer, and there will be 14,100 deaths from the disease [1]. Although the majority of patients with bladder cancer present with superficial bladder tumors, 20% to 40% of patients will present with or develop muscle invasive dis-
* Corresponding author. Tel.: ⫹1-323-865-3709; fax: ⫹1-323-8650120. E-mail address: [email protected] (J.P. Stein). 1 Deceased. 1078-1439/09/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2007.12.014
ease. Invasive bladder cancer is a lethal malignancy; if untreated, over 85% of patients will die of the disease within 2 years of diagnosis [2]. Despite early and even aggressive treatment approaches for high-grade, invasive bladder cancer [3], nearly 25% of patients demonstrate pathologic evidence of lymph node metastases at the time of cystectomy [4,5]. These data underscore 2 important points regarding bladder cancer: (1) high-grade, invasive bladder tumors are potentially lethal, and (2) a significant number of patients have locally advanced disease at the time of definitive therapy. The rationale for an aggressive surgical approach employing radical cystectomy for high-grade, invasive bladder cancer is based on several important observations. First, the best long-term survival rates coupled with the lowest local recurrences are seen following radical cystectomy [4,5].
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Second, the morbidity and mortality of radical cystectomy have significantly improved over the past several decades. Third, TCC is generally a tumor resistant to radiation therapy even at high doses. Fourth, chemotherapy alone or in combination with bladder-sparing protocols have not demonstrated equivalent long-term survival rates comparable to cystectomy [6]. Fifth, radical cystectomy provides accurate pathologic staging of the primary bladder tumor (p-stage) and regional lymph nodes. This allows for selective application of adjuvant therapy based on precise pathologic evaluation. Lastly, improvements in lower urinary tract reconstruction (particularly orthotopic diversion) have made cystectomy more acceptable to patients and allowed them to maintain a reasonable functional status [7]. For the aforementioned reasons, radical cystectomy has become an ideal therapy for high-grade, invasive bladder cancer. Although the current oncologic standard for high-grade, invasive bladder cancer remains radical cystectomy, a recent trend in urologic oncology has been to minimize the surgical approach, that is, attempting organ preservation, without compromising the cancer outcomes. So-called prostate-preserving cystectomy has been recently advocated for patients with bladder cancer to improve clinical and functional outcomes, including continence, potency, and fertility. This modified surgical approach generally includes sparing the prostate, vasa deferentia, and seminal vesicles while resecting the prostatic adenoma (in some cases) and lower urinary tract reconstruction to the prostate. In appropriately selected men who require cystectomy, and for whom potency and fertility remain relevant issues, this may be an important technique, which may reduce the issue of erectile dysfunction and maintain the ability for reproduction. In fact, our group described and promoted a modified, prostate-sparing cystectomy in well-selected male patients, with nonurothelial malignancies or nonmalignant bladder diseases, that necessitated cystectomy but not necessarily prostatectomy [8]. It is clear that this modified surgical application can be performed in appropriately selected patients but must not compromise the oncologic control. Recently, various prostate-sparing techniques has been reported in patients with TCC of the bladder undergoing radical cystectomy [8 –22]. The fundamental rationale for
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this modified technique includes improvement in urinary continence (compared with orthotopic diversion to the proximal urethra), enhancement of erectile function, and to maintain the reproductive ability in younger patients. Oncologic issues including the risks of prostate adenocarcinoma and TCC involving the prostate in patients undergoing prostate-sparing cystectomy with bladder cancer is clearly a concern. In addition, the clinical results with orthotopic reconstruction are indeed good and, in the properly selected patient, nerve-sparing techniques may be performed to preserve erectile function. The intended application of prostate-sparing techniques was primarily focused upon quality of life issues and not necessarily with oncologic outcomes or to improve survival. While quality of life issues are important secondary concerns, survival remains paramount and should be the driving factor in treatment decisions, given the highly aggressive nature of invasive bladder cancer. In this review, the oncologic and functional issues will be addressed regarding men requiring cystectomy for bladder cancer. Surgeons must understand these oncologic implications and patients must be counseled regarding these issues when considering the surgical approach for bladder cancer.
2. Prostate cancer in men undergoing cystectomy for bladder cancer Prostate cancer (PCA) is the most common noncutaneous malignancy found in men and the second leading cause of cancer deaths in our country. It is recognized that the prevalence of PCA exceeds that of clinically detected tumors, with 30% of 50-year old men and as high as 70% of 80-year old men at autopsy study with the disease [23]. Although the majority of PCA found at the time of radical cystectomy has been regarded as clinically insignificant, it is unknown if these tumors would have become clinically or pathologically significant had they not been removed. The overall reported incidence of PCA involvement of the prostate in patients undergoing radical cystectomy ranges from 27% to 46% (Table 1) [4,23–30]. This variation depends upon the method in which the prostate was patho-
Table 1 Incidence of prostate cancer in radical cystectomy specimens for bladder cancer Reference
Year
Total no. patients
Median age
% PCA
Step-section
Winfield et al. [25] Kabalin et al. [26] Montie et al. [27] Abbas et al. [28] Plante et al. [29] Moutzouris et al. [30] Hautmann et al. [31] Stein et al. [4] Revelo et al. [24]
1987 1989 1989 1996 1998 1999 2000 2001 2004
80 66 84 40 260 59 133 845 121
63 y 64 y 64 y nm nm 66 60 67 67
27 38 46 45 18 27 43 29 41
No Yes Yes Yes No Yes Yes No Yes
nm: not mentioned.
(3 mm) (4.5 mm) (2–3 mm) (5 mm) (3mm) (2–3 mm)
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logically evaluated, with whole-mounted, step-sectioned prostates generally demonstrating greater than a 40% incidence of PCA. In a recent analysis of PCA in cystectomy specimens removed for bladder cancer, 41% of the patients demonstrated PCA [24]. Importantly, of these cancers 48% were clinically significant tumors: 16% with extracapsular extension and 20% with Gleason patterns 4 and 5 (scores 7 or greater). The finding that 60% of the PCA involved the prostate apex (78% of which were significant tumors) has clinical implications in patients undergoing prostate-sparing or even prostate apex-sparing cystectomy procedures [24]. These findings were confirmed by another report in which 27% of patients undergoing cystectomy for invasive TCC of the bladder were found to have PCA, with a propensity (one-third) involving the apex of the prostate [30]. The authors suggested that this tendency in the apex of the prostate with PCA demands a careful excision of the apical margins. Kabalin and associates previously reported a 38% incidence of PCA with a distinct apical predominance of these tumors in patients undergoing radical cystectomy for bladder malignancies [26]. Further pathologic evidence regarding prostate-sparing techniques and the oncologic safety comes from a retrospective histologic study that evaluated the frequency for urethral and prostatic lesions in cystectomy specimens removed for bladder cancer [29]. A total of 260 specimens were included and the prostate was analyzed in 3 planes (upper, middle, and lower) as well as the apex of the prostate. Urethral involvement with cancer (TCC) was observed in 31% of cases and was contiguous with the bladder tumor in more than one-half of these. Prostate cancer was observed in approximately 18% of cases. The authors conclude that the high frequency of urethral and prostatic involvement does not justify preservation of the prostate during cystectomy. The aforementioned pathologic findings regarding PCA in patients undergoing cystectomy for bladder cancer are indeed important. Not only is there a noteworthy incidence of PCA, but a substantial number of these are clinically significant with a predominance of the apical portion of the prostate. In a recent report, Ward et al, reviewed the prevalence of incidental PCA in men with a PSA of 0.1 to 2.0 ng/mL and normal digital rectal examination undergoing radical cystoprostatectomy for bladder cancer at the Mayo Clinic or Medical University of Innsbruck, Austria from
1988 to 2000 [43]. Of the 1,600 patients who underwent the procedure, 129 (8%) met the inclusion criteria. Of these, 23% were found to have incidental PCA. Of these, 7% had Gleason 7 disease or higher and 27% had tumors of 0.2 cc or greater. In summary, there remains a considerable prevalence of incidental PCA at the time of radical cystoprostatectomy, even in men at lowest risk for the disease. While many of these cancers may be clinically indolent, roughly one-fourth of these tumors have pathologic characteristics that indicate that they are clinically significant. The aforementioned pathologic findings regarding PCA in patients undergoing cystectomy for bladder cancer are indeed important. Not only is there a noteworthy incidence of PCA, a substantial number of these are clinical significant with a predominance of the apical portion of the prostate. In addition, preoperative risk factors, such as DRE or PSA, do not appear to be able to distinguish which patients will have prostate cancer or which incidentally detected cancers will be clinically significant. Collectively, these findings underscore the continued need to remove the entire prostate, with particular attention to the apex, in male patients undergoing cystectomy for invasive bladder cancer.
3. Prostate involvement with transitional cell carcinoma in men undergoing cystectomy for bladder cancer The incidence of prostate involvement with TCC in men undergoing cystectomy for the bladder cancer ranges from 12% to 48% (Table 2) [24,32–36]. This range may relate to patient selection and probably, more importantly, to the method in which the prostate is pathologically sectioned. Cystectomy series that employ whole mount section report an incidence of nearly 40% [24,32,33], while routine pathologic evaluation approaches 20% [34 –36]. In a large series of men undergoing cystectomy for bladder cancer with routine pathologic evaluation of the prostate, 17% of patients had some prostate involvement, including 7% with invasive stromal involvement [34]. Revelo and associates recently reported an overall incidence of 48%, with 10% of patients demonstrating invasive stromal involvement of the prostate with bladder cancer following cystectomy [24]. The fact there is a significant incidence of prostate involvement with TCC, and the inability to accurately determine
Table 2 Incidence of TCC in the prostate of radical cystectomy specimens Reference
Total no. patients
Prostate TCC
Ducts/urethra
Invasive (stroma)
Step-section
Reese et al. [32] Wood et al. [33] Revelo et al. [24] Stein et al. [34] Iselin et al. [35] Ngninken et al. [36]
115 84 121 768 70 283
33 (29%) 36 (43%) 58 (48%) 129 (17%) 14 (20%) 76 (27%)
17 (15%) 22 (26%) 45 (37%) 78 (10%) 11 (16%) 36 (12%)
16 (14%) 14 (17%) 13 (10%) 51 (7%) 3 (4%) 40 (15%)
Yes Yes Yes No No No
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this involvement preoperatively, raises concerns of routinely sparring the prostate in this group of patients. Prostate involvement with TCC may be subcategorized into superficial involvement (prostatic urethra and prostatic ducts) or invasive into the stroma. Patients with invasive stromal involvement of the prostate (P4a) demonstrate higher recurrence rates and worse survival [37]. The incidence of urethral recurrence is also higher in patients with any prostate involvement; invasive stromal involvement demonstrating the highest risk for urethral recurrence [34]. These clinical and oncologic implications of sparing the prostate in men with bladder cancer requiring cystectomy must be considered, particularly when a local recurrence following surgery is generally a fatal event. Preservation of any of the prostate in men with bladder cancer therefore has profound oncologic implications, particularly in young men with an extended life expectancy.
4. Apical involvement of the prostate with prostate cancer and transitional cell carcinoma in men undergoing cystectomy for bladder cancer The pathologic features of PCA and bladder cancer and the frequency of apical involvement were recently investigated from cystoprostatectomy specimens [24]. In this series of 121 consecutive cystoprostatectomy specimens, 41% had unsuspected PCA involvement and 48% had bladder cancer involving some portion of the prostate. Apical involvement of the prostate with PCA was observed in 60% of these patients (70% clinically significant), while 33% of patients with bladder cancer involving the prostate also demonstrating apical involvement. Overall, only 32 of 121 patients (26%) had no prostate or bladder cancer involvement of the prostate. Regarding apical involvement specifically, 39% of patients had PCA or TCC involvement of this region and would not have been appropriate for sparing this portion of the prostate during cystectomy.
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5. Voiding and continence in patients with orthotopic urinary diversion Orthotopic lower urinary tract reconstruction to the native intact proximal urethra can be performed in the majority of patients requiring cystectomy for bladder cancer with excellent functional outcomes [7]. In a comprehensive and detailed review of 2,238 patients undergoing an orthotopic neobladder, daytime continence was reported in 87% and nighttime continence observed in 72% [38]. It has been suggested that continence results following prostate-sparing cystectomy may be better. However, several issues should be understood when evaluating continence status in men following cystectomy. First, the definition of day and/or night-time continence is not standard and often not even defined. Second, most prostate-sparing cystectomy series report on much younger patients. This is important, as urinary continence (and potency) rates following cystectomy and orthotopic reconstruction are clearly associated with age, with younger patients reporting better continence [7,38 – 40]. It is emphasized the median age of patients undergoing prostate-sparing procedures are significantly younger compared with traditional cystectomy and orthotopic diversion to the urethra (Table 3). Regardless, there does not appear to be a significant difference in the daytime continence rates between the techniques, with a slight advantage of night-time continence in the prostate-sparing patients. It is assumed that preservation of the prostatic apex should optimize urinary continence in patients undergoing cystectomy and orthotopic reconstruction. This belief was based on the traditional concept that the apical prostate contains the inner smooth muscle component of the distal urethral sphincter mechanism, which augments the external striated muscle component in maintaining continence. In fact, it has been shown that preservation of the prostatic apex does not improve urinary continence in patients with intestinal neobladders compared with patients undergoing reconstruction to the membranous urethra [41]. When com-
Table 3 Prostate-sparing cystectomy: functional results Author
Spitz et al. [8] Muto et al. [9] Vallancien et al. [10] Colombo et al. [11] Terrone et al. [12] Meinhardt et al. [13] Ghanem [14] Nieuwenhuijzen et al. [15] Botto et al. [16] Martis et al. [17] Arroyo et al. [18] Saidi et al. [19]
No.
4 61 100 27 28 24 4 44 34 32 25 25
Median age
26 49 64 52 51 51 42 57 61 59 60 57
y y y y y y y y y y y y
Median follow-up
24 6 38 36 90 — 20 42 26 32 9 46
mo mo mo mo mo mo mo mo mo mo mo
Continence (%) Day
Night
100 95 97 100 59 96 100 95 90 98 100 100
100 31 95 100 — 91 100 74 85 80 100 86
Need for IC (%)
Potency (%)
25 1 0 15 93 17 75 28 3 — 0 —
100 95 82 100 53 83 — 77 89 80 84 86
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paring urodynamic studies between patients undergoing orthotopic diversion with the membranous urethral and the prostatic apex, there was no difference in the maximum urethral pressure, but significant lower flow rates were observed in those with preservation of the prostatic apex [41]. This may ultimately lead to difficulties in neobladder evacuation, hypercontinence, and potentially the increased need to perform catheterization to empty the neobladder in these patients. Overall, there does not appear to be a significant advantage from a continence perspective or voiding pattern with prostate-sparing techniques.
6. Erectile function in patients undergoing cystectomy for bladder cancer Potentially the greatest advantage of prostate-sparing techniques is preservation of sexual function. Sexual function domains may include erectile function, ejaculation, and involves fertility issues. Fertility and ejaculation are generally of little concern in elderly men requiring cystectomy whose median age approximates 67 years [4]. Erectile function however, represents the single most advantage of prostate-sparing cystectomy (Table 3). The reader is cautioned to remember that most of these studies did not use patientcentered methods or validated questionnaires to assess erectile function, which has been shown to lead to an overestimation of sexual function in previous studies of sexual function following radical prostatectomy. It should be noted that traditional nerve-sparing radical cystectomy can be successfully performed in well-selected men with excellent clinical outcomes, and without jeopardizing the oncologic results [39]. In addition, oral medication and injection therapy, along with advances in penile prostheses, have improved erectile function.
7. Oncologic outcomes in patients undergoing prostatesparing cystectomy Little data regarding the long-term oncologic outcomes with various prostate-sparing cystectomy are available today. However, several studies suggest that this approach may compromise the cancer outcomes compared with a standard radical cystectomy [19,22,42]. This not only includes the potential for local recurrences but also a higher pattern of distant failure as well [42].
8. Discussion The trend in urologic surgical oncology to minimize operative morbidity by anatomical and functional organ preservation (without compromising the oncologic principles) is not only laudable but appropriate. With this intent, a trend toward performing sexual-preserving radical cystec-
tomy in patients with high-grade, invasive bladder cancer has been seen. This surgical approach has advocated to improve the continence and potency rates following cystectomy and to preserve the ability to procreate. However, concerns related to the oncologic and functional outcomes for these patients with bladder cancer have been raised [42]. Several studies suggest the oncologic outcomes following prostate-sparing cystectomy may be compromised. Saidi and associates reported on 25 men (mean age 57 years) who underwent a prostate-sparing cystectomy with a median follow-up of 46 months [19]. All patients had a PSA less than 4 ng/ml or a negative prostatic needle biopsy and a transurethral resection of the prostate performed preoperatively to evaluate the prostatic urethra. Overall, 24% of patients developed a pelvic recurrence, 8% a urethral recurrence, and another 24% developed distant metastases. Although the functional outcomes were excellent (94% daytime continence, 75% nighttime continence, 75% with some erectile function), the authors concluded the oncologic results were substantially worse compared with those of a standard radical cystectomy [19]. These findings are supported by a review, which evaluated the oncologic results following three different prostatesparing techniques [22]. The authors concluded in this review that preservation of the prostate is not associated with increased morbidity and may improve functional results, however, it does not appear to ensure an equivalent level of cancer control with higher metastatic recurrence rates. The oncologic outcomes and patterns of recurrence following prostate-sparing cystectomy were recently evaluated in a review by Hautmann and Stein [42]. In this review, a total of 252 patients undergoing some form of prostatesparing procedure were evaluable (139 with pT1, N0, M0, and 113 with pT2, N0, M0 disease, median follow-up 40 months) and compared with 646 men undergoing a standard radical cystectomy, from the authors’ institution (median follow-up 36 months). The local and distant recurrences rates, based on similar pathologic staging, were then compared. The observed distant failure rate following prostatesparing cystectomy was twice as high as in the standard cystectomy group. It was suggested that the higher pattern of distant failure in those undergoing prostate-sparing cystectomy could be attributed to direct tumor spill to the liver and lungs, bypassing the regional lymph nodes, during the prostate resection. It is hypothesized that urothelial bladder cells have a route for tumor-cell dissemination and a starting point for hematogenous metastasis as the prostate vessels are opened during the surgical manipulation [42]. These speculative reasons and the fact that there is a significant incidence of PCA and TCC involving the prostate, coupled with no reliable method to determine preoperatively, suggest that prostate-sparing cystectomy should not be routinely performed in men with bladder cancer. We emphasize that one can perform a prostate-sparing cystectomy in younger men without TCC of the bladder, and we believe this may be an appropriate surgical approach in the carefully selected individual.
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Proponents for prostate-sparing techniques suggest that this modification may help overcome the technical difficulties of the urethral anastomosis, allowing for an easy and robust anastomosis with minimal leakage [14]. This simply is not the case. Orthotopic reconstruction can be performed to the urethra without technical difficulty in virtually all cases, and should avoid the problem of hypercontinence, more commonly associated with prostate-sparing techniques. Furthermore, daytime continence results following radical cystectomy and prostate-sparing cystectomy are not significantly different. Nighttime continence may be slightly better with prostatesparing procedures, however, the issue of urinary retention and need for intermittent catheterization appears to be more problematic in the prostate-sparing group. Should prostate-sparing procedures be applied to patients with high-grade, invasive bladder cancer requiring radical cystectomy, when approximately 50% of patients have locally advanced and/or node positive disease at the time of surgery? Although speculative, the potential for local tumor spill or distant tumor dissemination with a prostate-sparing procedure and manipulation are also serious concerns. The development of a local and/or distant recurrence following the surgical treatment of bladder cancer is generally a fatal event. The significant incidence of bladder and PCA involving the prostate at the time of cystectomy, which may be difficult to determine preoperatively, may also preclude the general application of prostate-sparing techniques in men undergoing cystectomy. Furthermore, most men at cystectomy are elderly (median age between 67 years) and not concerned with fertility at this stage of their life. Importantly, the functional outcomes following cystectomy and orthotopic diversion to the urethra are not significantly different regarding continence. Prostate-sparing procedures do provide better potency results; however, the application of nerve sparing approaches (in selected individuals), the use of oral and injectable therapies, and the improvements in penile prosthetic devices should reduce the apprehension of impotence following cystectomy. Radical cystoprostatectomy remains the treatment of choice for patients with bladder cancer, while the application of prostate-sparing techniques may be carefully applied, in selected individuals, with the future oncologic outcomes scrutinized.
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