Radical Cystectomy and Lymphadenectomy for Invasive Bladder Cancer: Towards the Evolution of an Optimal Surgical Standard

Radical Cystectomy and Lymphadenectomy for Invasive Bladder Cancer: Towards the Evolution of an Optimal Surgical Standard Ganesh V. Raj and Bernard H. Bochner The surgical management of invasive bladder cancer has undergone a significant evolution in technique since its initial introduction. Changes in the extent of surgery have largely reflected a better understanding of the natural history of bladder cancer and the recognized pathways of progression. Incorporation of contemporary surgical techniques that target the perivesical soft tissues, regional lymph nodes, and adjacent organs appear to enhance oncologic outcomes. A growing body of evidence indicates that the quality of radical cystectomy (RC) directly affects patient outcome. Recently, quality of life and functional considerations have led to surgical modifications such as nerve-, prostate-, vaginal wall–, and urethra-sparing approaches. While some modifications in appropriate candidates appear not to decrease cancer control, further studies will be needed to establish their role and safety. This ongoing evolution in the technique of RC and pelvic lymph node dissection (PLND) may help define a new surgical standard that provides optimal benefit in patients with invasive bladder cancer. Semin Oncol 34:110-121 © 2007 Elsevier Inc. All rights reserved.

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adical cystectomy (RC) and pelvic lymphadenectomy (PLND) continue to be recognized as the “gold standard” therapeutic modalities for locoregional, muscle-invasive bladder cancer. In addition, RC and PLND provide definitive treatment for high-risk, non-muscle, invasive bladder tumors that recur or progress despite intravesical therapy. Although the paradigm for treatment of invasive bladder cancer continues to evolve with the emerging role of perioperative systemic chemotherapy, the primary intent of RC is to obtain maximum local and regional control. While the curative intent of surgery has remained constant, the technique of RC and PLND has undergone several modifications based largely on an improved understanding of the natural history of bladder cancer. This review will describe the development of the modern RC and PLND, highlight patient outcomes following surgery, and define the current controversies over the extent of surgery needed to provide optimal tumor control and maximize functional results.

Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY. Address correspondence to Bernard H. Bochner, MD, Memorial SloanKettering Cancer Center, Department of Urology, Kimmel Center for Prostate and Urologic Diseases, 353 E 68th St, New York, NY 10021. E-mail: [email protected]

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0093-7754/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2006.12.011

Historical Standards for RC The first cystectomy was performed in the late 1800s. The initial surgical approach to the removal of the bladder for cancer consisted of a staged procedure that included an initial urinary diversion (uretero-enterostomies) followed by removal of the bladder. Excision of the bladder included no formal attempt to remove perivesical tissues or to control the regional pelvic lymphatics. In modern terms, this would be considered a simple cystectomy. Despite being a more limited procedure compared with contemporary RC, simple cystectomy represented a formidable procedure for its time as evidenced by the significant associated perioperative morbidity and mortality. In 1939 Hinman reported a perioperative mortality rate of 34.5% in 250 patients undergoing a simple cystectomy.1 Largely due to improvements in anesthesia and perioperative management, as well as increased surgical experience, mortality rates decreased. In Leadbetter and Cooper’s overview of surgical series from 1939 to 1948 of 429 patients undergoing a cystectomy, 342 survived the procedure.2 However, of patients surviving the surgery, 33% (range, 22.8% to 53.3%) died of recurrent disease, typically within 1 to 2 years after surgery. Further, there was a high incidence (47%) of local recurrence, likely within regional nodes. Overall, the early reported outcomes of patients undergoing cystectomy from these historical cohorts were poor,

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with nearly 50% dying within 1 to 2 years following surgical intervention. In 1950 Marshall and Whitmore reported a 38% local failure rate in 100 consecutive patients undergoing cystectomy for bladder cancer, and concluded that “the implications seem unavoidable that a more radical procedure might be worthy of trial.”3 The development of this more radical surgical approach was influenced by autopsy studies and clinical observations of the natural pathways of tumor progression for invasive bladder cancer. A more aggressive RC thus evolved with wide local excision of the perivesical tissues and a formal lymph node dissection as an attempt to control the regional nodes. As a result of these changes in surgical technique, from a simple to radical cystectomy, clinicians noted a decrease in the pelvic recurrence rate and a concomitant increase in disease-specific and overall survival.

Modern RC Relevant Surgical Anatomy The bladder is an entirely retroperitoneal organ, covered by peritoneum that posteriorly continues to envelop the seminal vesicles, prostate, and distal ureters. Inferiorly and laterally, the bladder is cushioned from the pelvic sidewall by perivesical and perirectal fat and loose connective tissue. Posteriorly, the rectal wall is adjacent to the back of the lower bladder, trigone, and prostate. The bladder neck is in continuity with the prostate, which lies immediately inferiorly. Neurovascular bundles responsible for erectile function are located posterolateral to the prostate and extend cephalad towards the seminal vesicles. These autonomic fibers continue along the rectal side wall into the pelvic plexus. In women, the peritoneum superior to the bladder is reflected over the uterus to form the vesicouterine pouch, while the posterior peritoneum forms the rectouterine pouch of Douglas. The base of the bladder and urethra lies adjacent to the anterior vaginal wall. Invasive bladder tumors located at the base of the bladder may involve the perivaginal tissues or anterior vaginal wall by direct invasion. In patients with bulky tumors pretreated with chemotherapy or in those who have received prior pelvic radiation, a fibrotic reaction is typically encountered as a response to treatment or tumor destruction. Normal surgical planes separating the bladder from the rectum, pelvic side walls, or pubis may be obliterated, increasing the likelihood of a positive surgical margin and/or injury to adjacent structures (ie, rectum).4 Invasive bladder cancer progresses locally to involve the full thickness of the bladder wall with subsequent involvement of perivesical fat, adjacent viscera, and musculoskeletal structures. Limited tumor extension into perivesical tissues is not reliably identified preoperatively by either physical examination or radiographic studies, and thus routine excision of all adjacent tissues is required to provide optimal tumor control. Disease originating at the bladder neck or posterior wall may progress to involve the prostate in men and the urethra, vaginal wall, and uterus in women. Tumor also may extend as a cuff around the anterior and lateral rectal walls

Figure 1 Location of different lymph nodes examined during a pelvic lymph node dissection in patients undergoing a radical cystectomy for invasive bladder cancer. IMA, inferior mesenteric artery.

when extensive perivesical disease is present. Following identification of large numbers of pelvic recurrences in early cystectomy series, surgical principles that incorporated the wide local excision of all perivesical tissues were instituted to remove all structures that may be potentially involved, including the bladder, prostate, seminal vesicles, and vas deferens. Additionally, care is taken to excise widely all perivesical and perirectal fat. In women, the bladder, uterus, anterior vaginal wall, fallopian tubes, ovaries, perivesical, and perivaginal fat are removed. Recent attempts have been made to preserve adjacent organs in select patients, such as the anterior vaginal wall in woman and the prostate in men (see below).

Normal Lymphatic Drainage of the Bladder The lymphatic drainage of the bladder has been well described since the turn of the 19th century as a rich lymphatic plexus originating in the lamina propria and muscularis of the bladder. Channels drain through the detrusor musculature into perivesical lymph nodes along the anterior, posterior, and lateral aspects of the bladder. These efferent lymphatics then feed into the primary pelvic lymphatic drainage regions along the external iliac, obturator, and hypogastric vessels, and the sacral promontory. Thus, the primary landing zone for bladder metastases includes the external iliac, obturator, hypogastric, and presacral nodal regions (Fig 1). All primary landing sites subsequently drain into more proximal common iliac node chain and then the retroperitoneal nodes. While contemporary tumor mapping studies in bladder cancer patients have identified solitary nodal metastases to the secondary drainage regions (“skip metastases”), this appears to be a rare event.5

Contemporary Surgical Techniques Contemporary RC is approached through a lower abdominal incision. Identification of the urachus allows for mobilization

112 of the superior aspect of the bladder while preventing early entry into the bladder. Mobilization of small bowel and colon allows for exposure of the retroperitoneum and lateral pelvic sidewall structures. While some surgeons prefer to ligate the vascular pedicles early, we proceed with lymph node dissection first, as this approach facilitates a more complete PLND and provides optimal visualization of the vascular pedicles. Once the lymph node dissection has been completed, lateral vascular pedicles from the superior vesical artery to the pelvic floor are controlled and divided. Posterior vascular pedicles are developed by incision of the peritoneal reflection along the anterior rectal wall as it meets the posterior bladder. The anterior rectal wall is freed from the back of the bladder and prostate (or upper vaginal wall in females). The posterior pedicles are then divided near the rectum to maximize the excision of the perirectal fat, which may be involved in more extensive tumors. The apical dissection is then performed, including the division of the dorsal venous complex and preparation of the urethra, if orthotopic reconstruction is contemplated. The neurovascular bundles responsible for erectile function also may be spared at this time or prior to division of the posterior vascular pedicles.6 In women, the approach is similar, with a wide resection of perivaginal tissues included with the removal of the uterus, ovaries, and fallopian tubes. Although the goal of RC, to provide complete local and regional control of disease, is not disputed, the extent of the procedure necessary to obtain maximal tumor control remains controversial. The extent of the PLND required at RC to optimize outcome and the ability to selectively preserve adjacent organs exemplify areas of current controversy.

Contemporary Lymphadenectomy Extent of Lymphadenectomy Recognition that regional pelvic lymph nodes were a site of a significant proportion of the local recurrences reported in early cystectomy series led to the incorporation of a formal lymphadenectomy at the time of RC to control regionally metastatic disease.7 However, controversy over the importance of the PLND has led to great variation in the extent of the procedure as performed by different surgeons. As some investigators cite reports of improved survival associated with more extensive lymph node resections,8 the boundaries of PLND have ranged from a more limited dissection with the proximal limit set at the bifurcation of the common iliac vessels to an extended lymphadenectomy that uses the bifurcation of the aorta or inferior mesenteric artery as the proximal limit (Fig 2). Early descriptions of the limits for the lymph node dissection were based on anatomic studies preformed in the 1930s and included extending the dissection to excise the secondary nodal drainage regions (ie, common iliac nodes). In 1946, Leadbetter and Cooper detailed their technique of PLND and defined the boundaries of dissection (ie, proximal-distal aorta, lateral-genitofemoral nerve, distal-circumflex iliac

G.V. Raj and B.H. Bochner

Figure 2 Extent of standard and extended lymphadenectomy performed at the time of radical cystectomy for invasive bladder cancer.

vein, and lymph node of Cloquet), which are still applicable today and essentially represent an extended lymph node dissection. Contemporary RC series demonstrate that up to a third of patients with regionally advanced bladder cancer (positive lymph nodes) can be rendered disease-free following RC and extended lymph node dissection.9-11 Others have questioned the need for an extended dissection in all patients. In 1987, a tumor-mapping study by Wishnow et al of 130 bladder cancer patients undergoing RC and PLND demonstrated that in the absence of gross pelvic adenopathy, lymph nodes located above the common iliac bifurcation were not involved.12 This information, based on 18 node-positive patients, convinced many to establish the proximal limits of dissection at the bifurcation of the common iliac vessels (excluding the common iliac, presacral and para-aortic lymph node regions) when no clinical evidence of lymph node involvement was present. However, more recent studies have found that microscopically positive lymph nodes may be present in nodal regions above the common iliac bifurcation even in patients with no gross evidence of nodal enlargement.5,10,13,14 In a prospective, multi-institutional study of 290 patients who underwent an extended mapping and lymph node dissection up to the level of the inferior mesenteric artery at the time of RC, Leissner et al noted that 25% of the 81 node-positive patients had metastatic lymph nodes outside the boundaries of the “limited” dissection, including 6.8% of patients with nodal involvement exclusively outside these limits.5 Similarly, Vazina et al found that 16% of the patients undergoing RC for locally advanced bladder cancer (pT3 or pT4) had lymph node metastasis outside the boundaries of a limited lymph node dissection.14 In a recent prospective evaluation at Memorial Sloan-Kettering Cancer Center (MSKCC) of 144 patients, microscopically positive lymph nodes above the common iliac lymph nodes were identified in patients with grossly normal lymph nodes. Additionally, 35% of all positive nodes were found outside the standard template in nodes residing above

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Table 1 Average Lymph Node Counts for Various Lymph Node Dissection Templates Study (first author)

Dissection Template

No.

Nodal Regions

Abdel-Latif10 Herr17 Frank20 Bochner13 Mills22 Stein9 Herr17 Vazina14 Bochner13 Leissner5

Standard Standard Standard Standard Extended Extended Extended Extended Extended Extended

418 729 154 56 452 244 144 176 88 290

Distal CI, ExtI, IntI, Obt Distal CI, ExtI, IntI, Obt ExtI, IntI, Obt CI, ExtI, IntI, Obt Iliac bifurcation, ExtI, IntI, Obt Distal aortocaval, CI, ExtI, IntI, Obt Distal CI, ExtI, IntI, Obt, presacral CI, ExtI, IntI, Obt, presacral, aortic bifurcation CI, ExtI, IntI, Obt, presacral, paraortal, paracaval CI, ExtI, IntI, Obt, presacral, paraortal, paracaval, interaortocaval

Mean Node Count (ⴞSD) 17.1 (ⴞ6.7) 13 (ⴞ12) 13 (ⴞ3) 14* 20* 30* 26 (ⴞ25) 26 (ⴞ14) 23* 43 (ⴞ16)

Abbreviations: CI, common iliac; ExtI, external Iliac; IntI, internal iliac; Obt, obturator. *Median node counts.

the bifurcation of the common iliac vessels.13 These findings suggest that intraoperative identification of gross adenopathy cannot be used as a reliable indicator to exclude removal of secondary drainage regions. In fact, Leissner’s study demonstrated that if only a limited dissection (obturator, hypogastric regions) was performed in their patient population, an astonishing 74% of all involved lymph nodes would have been left behind.5

Lymphadenectomy: Implications for Staging Given the important prognostic information provided by node status, accurate staging of the regional lymph nodes is of significant clinical importance. Node positivity identifies a high-risk group of patients that may benefit from adjuvant chemotherapy. It is important to establish standards for adequate staging by defining the minimal extent of node dissection that will accurately categorize patients as node-negative or node-positive. Performing an optimal lymph node dissection will provide a greater degree of confidence in nodal staging; however, the question of when is a negative lymph node dissection really negative remains to be established. With increasing numbers of lymph nodes removed, a higher likelihood exists of identifying a positive node. A patient who undergoes a limited lymph node dissection may be understaged due to limited sampling, while a more extensive lymph node dissection will provide a greater degree of confidence that appropriate nodal staging has been achieved. Establishing the extent of dissection needed to optimize staging can be based on the above cited tumor-mapping studies. Published data would suggest that a thorough removal of the primary drainage regions that includes the external iliac, hypogastric, obturator, and pre-sacral lymph nodes would provide adequate surgical staging information of the regional lymph nodes. While “skip metastases” involving the secondary nodal drainage sites without involvement of the primary nodes have been reported, this is likely to be an infrequent event and careful examination of the primary drainage regions should provide accurate information for the vast majority of patients. The number of lymph nodes examined has been used as a

surrogate quantifier of the extent or adequacy of PLND. Logically, extension of the boundaries of PLND should increase the number of lymph nodes retrieved. A standard lymph node dissection yields an average of eight to 14 nodes. An extended lymph node dissection up to the aortic bifurcation often yields 25 to 45 nodes13,15,16 (Table 1). However, the use of lymph node counts has been hampered by significant inter-institution and intra-institution variability in lymph node yields,13,17 variations in the extent of lymphadenopathy with clinical variables like patient age, comorbidity, and preoperative chemotherapy, anatomic divergence, tumor characteristics especially pathologic stage (see Table 2), completeness, and manner of pathologic evaluation including the use of fat-clearing solutions, and the manner in which nodes are submitted may all affect reported lymph node yields.18 It is our recommendation, based on anatomic studies and tumormapping data, that a minimum of 12 to 15 lymph nodes be evaluated at RC to provide reasonable certainty that the lymph node status has been correctly established.

Lymphadenectomy: Implications for Therapeutic Benefit The therapeutic value of PLND at RC has gained considerable attention and remains controversial. Proponents for the therapeutic benefits of extended lymphadenectomy note that mapping studies indicate a frequent involvement of nodes outside the standard lymphadenectomy templates. Additionally, prognostic studies have found that up to 40% to 50% of patients with limited lymph node involvement can be rendered disease-free after nodes are removed with the bladder via RC and extended PLND.19 While no randomized, prospective studies have been performed to document the therapeutic benefits of extending the limits of the lymph node dissection, several retrospective, single-institution reports suggest an improved outcome following a more extensive dissection. In a retrospective comparison between two series of consecutive patients undergoing RC by a single surgeon, Poulsen et al reported a 90% 5-year, recurrence-free survival in or-

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114 Table 2 Lymph Node Involvement Stratified by Pathologic Stage

Study (First Author) Poulsen15 Vieweg83 Stein84 Frank20 Vazina14 Leissner5 Abdel-Latif10 Madersbacher29

% of Patients With Lymph Node Involvement Stratified by Pathologic Stage (total no. of patients in each stage) All (N)


pT3

pT4

26% (50/191) 28% (193/686) 24% (246/1,054) 15% (32/218) 24% (43/176) 28% (81/290) 26% (110/418) 24% (124/507)

11% (13/117) 13% (44/333) 11% (75/668) 10% (13/132) 11% (11/102) 12% (18/149) 13% (36/272) 11% (28/245)

51% (33/65) 43% (97/226) 45% (113/251) 20% (11/56) 40% (20/50) 44% (44/121) 48% (59/123) 35% (64/184)

44% (4/9) 41% (52/127) 43% (43/135) 27% (8/30) 50% (12/24) 50% (10/20) 65% (15/23) 41% (32/78)

gan-confined, node-negative patients, compared to only 71% for those who underwent a standard lymphadenectomy.15 Among the node-positive patients, extended lymphadenectomy was associated with a 24% 5-year recurrence-free survival compared with 7% with a standard lymph node dissection. Additionally, several retrospective analyses have indicated an association with improved outcome in N0 patients who have had a greater number of lymph nodes removed, using the number of lymph nodes as a surrogate for the extent of dissection.20 Leissner et al reported an 85% 5-year recurrence-free survival in pT1-pT2N0 patients with ⱖ16 nodes removed versus 65% when ⱕ15 nodes were removed (P ⬍.01). The benefits of a more extended lymph node dissection were noted for patients with pT3 disease as well.5 Herr et al reported a 20% 10-year actuarial survival following RC in N0 bladder cancer patients with zero to three lymph nodes examined compared to 60% for four to seven examined nodes versus 82% for eight or more examined nodes (P ⫽ .004). While these data may represent improved staging in the node-negative group, a similar association with improved survival was found in patients with node-positive disease.5,20-22 For patients with nodal metastases, Herr et al noted a 16% 10-year survival in patients with one to eight nodes examined, 39% for nine to 14 nodes examined, and 45% for more than 14 nodes examined (P ⫽ .02).17 Many published analyses correlating the number of lymph nodes harvested as a surrogate for the extent of PLND to survival have failed to account for potential biases that affect both survival and the extent of nodal dissection performed and thus the number of lymph nodes removed/reported. In a recent analysis of more than 1,121 RC patients at MSKCC, we demonstrated that older patients and those with greater comorbidities (those with a higher age-adjusted Charlson index), are more likely to have fewer nodes removed.20a Performing an analysis for an association of extent of dissection and outcome while controlling for age, stage, and comorbidity (American Society of Anesthesiologists risk score [ASA]), we continued to observe that a greater numbers of lymph nodes removed at RC remained a significant positive predictor of 3-year survival (P ⬍.0001). Thus, a 70-year-old patient who had six lymph nodes resected has a poorer survival outcome than a similar 70-year-old patient with 16 lymph

nodes evaluated, when controlling for comorbidities and pathologic stage. Based on mapping studies and the available studies correlating outcome to extent of dissection, the limited additional morbidity associated with the extended dissection and the inability to accurately stage the regional lymph nodes prior to cystectomy, we recommend the routine use of an extended lymph node dissection at RC for the twin purposes of accurate pathologic staging and maximizing potential therapeutic benefit. In our experience, the extended dissection does not significantly add to the morbidity of the procedure.23 Although an extended node dissection requires additional time to complete, the ensuing RC is facilitated and expedited following this anatomic dissection.

Outcomes With Modern RC Oncologic Outcomes The efficacy of RC is best measured by its ability to control both local and distant disease, as well as the ability to extend survival. As reported initially by Jewett and Strong, the risk of metastatic disease is directly related to the depth of invasion of the primary tumor.24 Outcome therefore is closely related to extent of primary tumor invasion, and thus serves as the basis for our current staging system.9,25-28 Table 3 lists the disease-free survival statistics based on pathologic stage of the primary tumor from several large contemporary surgical series. RC and PLND provide a cure for most patients with organ-confined tumors (⬎80% recurrence-free survival at 10 years), the majority of patients with extravesical disease that is completely resected (60% to 70% recurrence-free survival at 10 years), and a significant minority of those with regional lymph node metastases (30% to 35% recurrence-free survival at 10 years).26,27,29 The 5-year overall survival closely mirrors recurrence outcomes, as most patients who die within the first 5 years following surgery succumb as a result of their disease. Recurrences after RC typically occur within the first 3 years after surgery with involvement of bone, liver, and lung frequent distant sites of involvement. The risk of local tumor recurrence within the pelvis has decreased substantially from the nearly 40% reported in initial cystectomy series to 6% to 13% observed in contemporary reports.30,31

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Table 3 Recurrence-Free Survival Relative to Pathologic Stage and Nodal Status in Patients Undergoing Radical Cystectomy Study (first author)

Time Frame (yr)

pT2b, % (no.)

pT3, % (no.)

pT4, % (no.)

pN0, % (no.)

pNⴙ, % (no.)

Stein9,84 Cheng27 Ghoneim26* Madersbacher29

10 10 5 5

77 (669) 78 (132) 70 (190) 76 (228)

44 (385) 50 (26) 45 (766) 52 (184)

41 (137) 41 (30) 20 (70) 36 (78)

75 (808) 78 (186) 53 (838) 70 (383)

34 (246) 31 (32) 23 (188) 49 (124)

*Included 59% cases for squamous cell carcinoma.

This decrease may be attributed to patient selection, stage migration, and improved surgical technique. Patients with local recurrence typically have a higher pathologic stage of the primary tumor, nodal involvement, and have undergone a less extensive lymph node dissection. The majority of patients with locally recurrent disease present symptomatically 8 to 18 months after RC. Local recurrence portends a poor prognosis, with a median survival of 4 to 8 months following diagnosis, despite systemic and local interventions. Examination of risk factors for recurrence following RC and PLND has identified regional lymph node status as one of the most important prognostic predictors. Patients with lymph node involvement demonstrate approximately 30% 5-year survival compared to nearly 70% for those without evidence of nodal metastases (Table 3). Extent of involvement of the regional lymph nodes also correlates with risk of recurrence and death from disease, identifying a relatively good-risk subgroup of patients with limited disease. Patients with four or fewer positive lymph nodes exhibit a 41% 5-year recurrence-free survival compared with 10% for patients with more extensive (⬎4 positive) lymph nodal involvement. Alternative lymph node parameters consider the extent of the lymph node dissection at the same time as evaluating the number of involved lymph nodes. If one considered two patients, both with four positive lymph nodes, the first had a total of 40 lymph nodes evaluated and the second has only 10, would we expect that both patients would have a similar prognosis? Studies have evaluated the ratio of positive nodes to total number of nodes reported in the dissection specimen (so called “lymph node density”) to allow for consideration of the extent of dissection along with the nodal tumor burden.10,32-34 Data from MSKCC and the University of Southern California noted a 50% to 64% 5-year survival for lymph node density less than 20% compared to 8% to 20% 5-year survival if the lymph node density was greater than 20%.32,34 Several additional clinical and pathologic features in bladder cancer have been identified to contain important prog-

nostic information. These include histology of the primary tumor, lymphovascular invasion, delay from diagnosis of disease to RC, age, and patient comorbidity. Presently, prognostic models for bladder cancer are reflected in the current American Joint Committee on Cancer (AJCC) staging system, and are based on the pathologic characteristics of depth of invasion of the primary tumor and the status of the regional lymph nodes. More recently, alternative prognostic statistical models, such as nomograms, have been developed that allow for the simultaneous consideration of multiple variables. These statistical models have been noted to provide a more individualized outcome prediction over standard risk-group modeling. In 2003 we initiated an effort to construct an international database of bladder cancer patients treated with RC and PLND, with the goal of developing an outcomes nomogram predicting the recurrence risk following RC. Twelve centers of excellence contributed data on more than 9,000 bladder cancer patients, which, to our knowledge, constituted the largest database for invasive bladder cancer managed by RC. Transitional cell carcinoma represented the majority of cases entered into the database (Table 4). At 4, 6, and 10 years following RC, 4,840, 3,132, and 1,412 patients were available for evaluation, respectively. Kaplan-Meier curves depicting the risk of disease recurrence and overall survival for the international bladder consortium dataset are depicted in Figures 3 and 4. The nomogram, constructed to predict the 5-year progression-free survival (Fig 5), was found to be a more accurate predictive model than our

Table 4 Distribution of the Histologic Subtypes of Patients in the International Bladder Cancer Nomogram Consortium Histologic Subtype

No. of Patients

Transitional cell carcinoma Squamous cell carcinoma Adenocarcinoma Unclassified Total

6,748 1,306 320 690 9,064

Figure 3 Risk of tumor recurrence following radical cystectomy for more than 9,000 patients in the International Bladder Cancer Nomogram Consortium. From Bochner B, et al. J Clin Oncol 24:39673972, 2006. Reprinted with permission from the American Society of Clinical Oncology.

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risk-stratify patients and improve patient selection for additional therapy either prior to or following RC.

Urothelial Recurrence Following Radical Cystectomy

Figure 4 Probability of survival following radical cystectomy for more than 9,000 patients in the International Bladder Cancer Nomogram Consortium: Kaplan-Meier survival analysis. From Bochner B, et al. J Clin Oncol 24:3967-3972, 2006. Reprinted with permission from the American Society of Clinical Oncology.

present day AJCC staging system and superior to standard pathologic subgroupings (organ-confined, extravesical disease, lymph node–positive tumors) with area under the curve (AUC) values of 0.75, 0.68, and 0.62, respectively. Novel predictive models that input prognostic characteristics from a variety of sources will continue to enhance our ability to

The risk of upper tract recurrence following RC in the overall population with invasive bladder cancer is relatively low at 2% to 4%.35 Surveillance of the upper tracts after treatment for invasive bladder cancer is accomplished primarily with urine cytology and upper tract imaging. Urine cytology is heralded for its high specificity (⬎95%) in detecting transitional cell carcinoma of the urinary tract; however, the sensitivity of urinary cytology in this setting, particularly a voided cytology, is significantly lower. Patients found to have carcinoma in situ of the ureter in the cystectomy specimen are at higher risk for developing an upper tract recurrence.35,36 The incidence of urethral recurrences after RC is 8% to 17%, at a median of 1 to 3 years after surgery.30,37 The best method for early detection of urethral recurrence is with cytologic examination of urethral washings or voided cytologies.38 Early detection is associated with a good treatment outcome as noninvasive disease can be effectively managed with urethrectomy.38-40 Patients with prostatic stromal invasion are at highest risk for the development of

Figure 5 International bladder cancer postoperative nomogram predicting 5-year risk of recurrence following radical cystectomy. Instructions for physicians: Locate the patient’s gender on the gender axis. Draw a straight line up to the points axis to determine how many points towards recurrence the patient receives for gender. Repeat this process for each of the remaining axes, drawing a straight line each time to the points axis. Sum the points received for each predictive variable and locate this number on the total points axis. Draw a straight line down from the total points to the 60-month progression-free prediction axis for their specific risk of recurring at 5 years. RC.Stage97 indicates AJCC 1997 pathologic staging. From Bochner B, et al. J Clin Oncol 24:3967-3972, 2006. Reprinted with permission from the American Society of Clinical Oncology.

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Table 5 Reported Incidence of Perioperative Complications Following Radical Cystectomy Including Early (within 30 days of RC) and Late (after 30 days post RC) Complications Study (first author)

N

Perioperative Mortality (%)

Early Complications (%)

Late Complications (%)

Bracken85 Frazier41 Stein9 Chang46 Knap86 Hollenbeck45

241 675 1054 304 268 2538

2.5 2.5 3 0.3 2 —

32 31.9 28 30.9 57 30.5

34 29.3 — — 29 —

a urethral recurrence.37,39 Given the increasing rate of orthotopic urinary diversion after cystectomy, surveillance of the urethra remains an important aspect of long-term follow up.38,40

Complications Given that the average patient age at RC is approximately 64 years, and most patients have a long history of smokingrelated comorbidities, RC, PLND, and urinary diversion remains a formidable surgical procedure with a perioperative morbidity of 30% to 60% (Table 5).41 The mortality rates for RC have been reduced from 20% prior to 1970 to the contemporary 0.5% to 2%. The subset of older patients (ⱖ80 years) undergoing RC appears to tolerate the procedure equally as well as patients in their 60s to 70s.42-44 Surgeon experience and hospital volume of RC performed may contribute to decreased operative morbidity and mortality.45,46 Common complications include ileus, atelectasis, deep vein thrombosis, wound infection, rectal injury, blood loss, and bowel obstruction.46-48 Our review of the MSKCC radical cystectomy series reveals that the incidence of postoperative complications requiring intervention is low (15% to 17%). Meticulous attention to perioperative details and improvements in surgical technique and postoperative care may further reduce this rate of complications.45,48-52

Continuing Evolution in Surgical Technique The modern RC evolved from the observed outcomes associated with the simple RC for patients with invasive bladder cancer. Using surgical techniques that increase the extent of resection of the perivesicle tissues, adjacent organs, and regional lymph nodes, improved local and distant disease control can be obtained. The necessity of the radical exenterative approach has recently been challenged by some who have suggested that functional considerations may be appropriately served in select patients. Functional considerations have led to the modification of the modern RC, with fertility and sexual function–sparing techniques most recently reported.53-58

Alterations in RC in Men Interest in altering the traditional RC in men has been based on functional considerations that attempt to improve postoperative voiding and sexual function. The two main technical alterations include preservation of the neurovascular bun-

dles to maintain erectile function and preservation of the prostate to improve both potency and voiding function following orthotopic reconstruction. Anatomic nerve-sparing approaches such as those pioneered by Walsh and colleagues have enabled preservation of potency during RC.59 Younger men who are preoperatively potent may represent optimal candidates for nerve preservation during RC. Preservation of the neurovascular bundle during RC should be performed when there is no evidence of tumor in the regions of the posterior-lateral aspect of the prostate, seminal vesicles, or lateral perirectal fat in the area of the pelvic plexus. Preservation of sexual function has been noted in about 50% of selected patients undergoing nervesparing techniques.59-63 Tumor control does not appear to be compromised when nerve-sparing surgery is performed in appropriately selected patients, with local recurrence rates and overall survival statistics similar in nerve sparing and non–nerve-sparing series.59 More recently, investigators have suggested that voiding function is improved in men who have undergone orthotopic reconstruction and nerve-sparing surgery.61 Nonrandomized series note a quicker return of urinary control in nerve-sparing patients. Whether the sparing of nerve function or the meticulous technique used for dissection at the prostatic apex is responsible for the improved voiding function remains unclear. More recently, several groups have reported experiences with prostate-sparing cystectomy for bladder cancer patients. The rationale for prostate-sparing procedures is the presumption that erectile function will be better preserved compared to cystoprostatectomy, and that preservation of the prostate and prostatic apex will improve voiding function in those men who are reconstructed to the urethra. Vallencien et al reported the Montsouris experience with more than 100 prostate-sparing cystectomies on men who were selected based on normal preoperative digital rectal examinations, normal prostate serum antigen (PSA), percent free PSA more than 15%, no abnormalities on transrectal prostate ultrasonography, and negative intraoperative frozen sections of transurethrally obtained prostatic urethra.64 Functional results noted that 98% of patients obtained complete continence, and that baseline potency was maintained in 82%. However, oncologic outcomes associated with these approaches may not be favorable. In a review of 266 patients from seven studies examining outcomes of patients who had undergone prostate-sparing cystectomy, the observed distant

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118 failure rate was almost twice as high as would be expected for patients with similar pathologic stages at an average follow-up of 40 months. Additionally, any retained prostatic tissue had at least a 6% risk of significant prostate cancer and a potential risk of tumor involvement with transitional cell carcinoma. In fact, studies using step-sectioned techniques of the prostate of men who had undergone cystectomy for bladder cancer have reported an 18% to 48% rate of involvement by transitional cell carcinoma and a 41% rate of adenocarcinoma of the prostate, rates significantly higher than those reported from prostate-sparing approaches.65,66 Overall, despite careful patient selection, prostate-sparing approaches appear to be associated with an unacceptablly higher oncologic failure rate. The published literature presently does not support the use of this approach.67

Alterations in RC in Women In women, the traditional RC involves an anterior exenteration or an en bloc removal of the bladder, uterus, fallopian tubes, ovaries, anterior vaginal wall, and urethra. The rationale for this approach includes concerns about local control of invasive disease and the prevention of subsequent urothelial recurrences. However, with the advent of orthotopic bladder replacement, preservation of the female urethra has been shown to be safe in most women undergoing RC, allowing for the opportunity of reconstruction to the native urethral remnant. Investigators have found that intraoperative frozen-section analysis of the urethral margin in women provides an accurate assessment of proximal urethral involvement, and may appropriately determine candidacy for orthotopic diversion. In the University of Southern California series of 88 women who underwent orthotopic diversion based on a negative intraoperative frozen-section of the proximal urethra, none demonstrated a urethral recurrence at a median follow up of 30 months.54 Current indication for urethrectomy in female patients includes those patients with any preoperative evidence of carcinoma in situ or overt carcinoma involving the urethra or an involved intraoperative frozen-section analysis of the urethral margin.55 Bladder neck involvement and invasive posterior wall tumors that involve the vaginal wall are associated with a higher risk of urethral involvement.30 However, up to 50% of woman with bladder neck involvement will not have evidence of disease within the urethra. Reported urethral recurrence rates are low in women who have undergone orthotopic reconstruction using these selection criteria (1.4% to 2%).30,37 Proponents for preservation of the anterior vaginal wall cite improved function of the vagina, and potential benefits relating to orthotopic reconstruction including decrease in the neobladder–vaginal fistula rate and prevention of postoperative urinary retention. In carefully selected cases with appropriate preoperative and intraoperative evaluations, the anterior vaginal wall may be safely preserved.56 However, in any situation where there is a concern of an adequate posterior bladder wall surgical margin, the anterior vaginal wall should be removed en bloc with the RC specimen.

Removal of gynecologic organs in most women undergoing RC has been routine practice and justified by the average patient’s age and postmenopausal status. For the select few women who are considering future pregnancy, preservation of the reproductive organs may be considered. Detailed pathologic review of female RC specimens has noted that only 2.6% to 5% had involvement of the uterus, ovaries, or tubes by their bladder tumor, and only 2% of women in whom intact gynecologic organs were removed had an unsuspected primary uterine or gynecologic malignancy.57,58 These data suggest that the uterus, fallopian tubes, and ovaries may be preserved in some patients who have had a thorough preoperative evaluation of their gynecologic organs and who are at low-risk for local invasion into these organs. We routinely remove the uterus, ovaries, and tubes in all postmenopausal women, as well as in younger women who are disinterested in future fertility. However, preservation of the anterior vaginal wall is attempted in appropriately selected women to maintain sexual function and facilitate orthotopic reconstruction. Taken together, the extent of RC in women may range from the traditional anterior exenteration to removal of the bladder with urethral and vaginal wall preservation. Rare situations in which tumor factors allow, fertility concerns may be addressed by preservation of the uterus, fallopian tube, and ovaries.

Follow-up Post-RC Follow-up strategies after RC are based on: (1) potential for progression of invasive urothelial tumors, (2) panurothelial susceptibility for subsequent urothelial tumor recurrence, and (3) recognized complications of urinary diversion. A surveillance program following RC should consider a patient’s individual risk for the development of local and distant recurrences and should include a routine physical examination, urinary cytology, and laboratory and radiographic studies. Computed tomography urography and/or magnetic resonance imaging may be used to evaluate recurrences in the chest abdomen, pelvis, and collecting system. The retained urethra should be periodically monitored for recurrence.38,39,68 The routine use of comprehensive serum chemical analyses provides liver function tests and alkaline phosphatase levels that may be used for monitoring of liver and bony involvement and metabolic abnormalities.69 Metabolic consequences of urinary diversion including hypochloremic, hypokalemic, metabolic acidosis should be monitored and evaluated with a routine chemistry panel. Additionally, patients should be monitored for upper tract obstruction related to mechanical blockage, the presence of stones, or changes to the reservoirs detrimental to function.

Standardization of RC and Lymphadenectomy Although the data from several academic medical centers suggest that excellent outcomes following RC and extended

Optimization of the modern radical cystectomy lymphadenectomy are possible, there remains significant variation in the RC performed across the United States today. In an analysis of the Surveillance, Epidemiology and End Results (SEER) data, Konety et al reported that more than 40% of RCs performed in the SEER cohort from 1988 to 1996 did not have an associated PLND. Further, only 22% had more than 10 lymph nodes dissected.70,71 Although the ultimate number of nodes retrieved depends on multiple factors, the surgeon plays a major role in determining the completeness of lymphadenectomy.72 Thus, not all RCs are the same. Several poorly defined parameters may influence the quality of RCs performed. The experience of the surgeon may be vital. In an analysis of the randomized cooperative group trial (Southwest Oncology Group [SWOG] 8710, Intergroup [INT]-0080) comparing neoadjuvant chemotherapy plus RC with RC alone for locally advanced bladder cancer, surgeons specifically trained in urologic oncology were more likely to achieve negative margins, perform at least a standard lymph node dissection, and remove more nodes than general urologists. Generally, patients operated on by experienced urologic oncologists in high-volume centers enjoyed better survival and fewer local recurrences than those operated on by community urologists in low-volume institutions. As previously mentioned, the quality of surgery may be influenced by the age and health of the patient. Surgeons may perform a more limited operation in patients with significant comorbidities to minimize operating time and lessen the morbidity associated with longer and more extensive surgery. While these alterations in technique may be necessary in select patients to improve tolerance of the RC, this decision must be weighed against the possibility of compromising the potential staging and therapeutic benefits of a more extensive procedure.

119 increasing proportion of elderly patients, given the current aging trend of the US population.

Timing of RC Several centers have demonstrated a significant relationship between the time of initial diagnosis of bladder cancer until RC and adverse pathologic and survival outcomes. In a review of more than 300 patients with invasive bladder cancer, those with a delay greater than 90 days from diagnosis to RC were more likely to have extravesical extension of disease (81%) than those who underwent surgery within 90 days of diagnosis (52%) (P ⫽ .01).77 Estimated 3-year survival was demonstrated to be worse in another study of 189 patients from the M.D. Anderson Cancer Center for patients who waited 12 weeks or more from diagnosis to RC compared to those who were operated on sooner (35% v 62%, P ⬍.01).78 These data indicate that once a patient has been determined to be a candidate for RC, treatment should be initiated without delay.

Minimally Invasive Approaches Recently, several groups have reported the feasibility of performing a RC laparoscopically with or without robotic assistance.16,79-82 While the minimally invasive approach offers the potential to accelerate recovery from RC, no documented decrease in hospital stay or perioperative recovery time has been reported. Additionally, the surgical and oncologic efficacy of such approaches remains to be established. Questions remain regarding the ability to routinely perform a similar extent of the dissection and the ability to obtain similar recurrence and survival outcomes; they must be adequately examined prior to considering minimally invasive surgery for routine use.

Patient Selection Factors With advent of rigorous preoperative medical evaluation and postoperative clinical care pathways, RC may be safely performed with acceptable morbidity in the elderly high-risk patient.42-44,73 Patients with invasive bladder cancer are often elderly and have significant comorbidities.42,73-76 The median age of patients undergoing a RC in most series is 62 to 65 years. A recent analysis of the MSKCC radical cystectomy series of 1,121 RC patients indicated that between 1992 and 2005, there was an increasing trend toward operating on older patients with greater comorbidities. While this demonstrates the changing referral pattern to tertiary centers, a similar mortality rate over the same time period demonstrates that this population of patients can still be safely managed with standard therapy. This fact is important to consider, given that patients with higher age-adjusted Charlson-Romano indices are more likely to present with adverse pathologic features including extravesical spread and node positivity, possibly indicating a delay in referral for definitive management. Thus, maintaining adequate tumor control in the future will rely on providing timely, optimal therapy to the population of bladder cancer patients that will include an

Conclusions Standardization of the RC and PLND procedure should be established to provide maximal benefit in patients with invasive bladder cancer. Extended PLND provides vital staging information to be used to determine candidacy for adjuvant chemotherapy. Additionally, extended PLND may provide a therapeutic benefit in both node-negative and node-positive patients. The need to provide local and regional control of invasive bladder cancers, even extravesical tumors with positive nodes, will assume increasing importance as systemic therapy improves survival and reduces deaths from distant metastases. Accepted surgical standards for RC and PLND should be established and validated prospectively. A minimum number should be established based on prospective studies as a proxy measure of the quality of surgery. This is important not only for individual patient management but also for the design and evaluation of combined modality studies in bladder cancer. Quality of surgery should be evaluated as part of any study evaluating outcomes with multiple modalities.

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