Radical cystectomy with urinary diversion is one of the most complex urologic procedures and is associated with significant morbidity and mortality. Although it remains the gold standard for treatment of advanced localized disease, survival has not changed substantially over the preceding decades, and high complication rates and prolonged hospital stays remain common. However, recent years have seen the development of robotic-assisted radical cystectomy, trials on the benefit of extended lymph node dissection, and evidence supporting the role of Enhanced Recovery After Surgery protocols. This article reviews recent trends in surgical management of muscle-invasive bladder cancer.
Key points
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Use of robotic-assisted radical cystectomy has increased steadily during past decade, with comparable short-term surgical quality metrics and functional and complication outcomes compared with open radical cystectomy. Ongoing randomized trials are needed to demonstrate durable oncologic efficacy and equivalence to open surgery.
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Bilateral dissection of the primary pelvic lymph node drainage system is a critical part of the surgical approach; however, the proximal extent of the dissection is currently being evaluated in phase III trials.
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Enhanced recovery after surgery protocols show tremendous potential in the perioperative management of patients undergoing radical cystectomy, reducing complications and length of hospital stay through targeted interventions aimed at ensuring that patients’ medical status is optimized before surgery and that they return to baseline function as soon as possible postoperatively.
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Alvimopan has been shown in randomized controlled trials to provide quicker return of gastrointestinal function.
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Improved perioperative morbidity and mortality are seen with centralization of radical cystectomy in high-volume centers and with high-volume surgeons.
Introduction
Radical cystectomy with bilateral pelvic lymph node dissection (PLND) and urinary diversion is the gold standard for management of clinical stage T2 through 4a bladder cancer that is not metastatic and for non–muscle-invasive high-grade urothelial carcinoma that is refractory to intravesical therapy, and for palliation in patients with severe local symptoms. Open radical cystectomy (ORC) has been the mainstay of curative treatment for decades, with modifications including nerve-sparing continent urinary diversion and proximal extent of PLND. During the preceding 30 years, 5-year trends in relative survival of bladder cancer have only improved marginally, from 72% in 1975 through 1977 to 80% in 2003 through 2009. Although survival rates have not shifted dramatically, complication rates have improved but remain high, with rates up to 60% and prolonged hospital stays still common. Thus, novel technology, techniques, and management strategies have continually been sought to improve surgical outcomes after radical cystectomy.
This article discusses several modifications in surgical care. First, traditional ORC is performed via an open, infraumbilical midline incision. Surgeons continue to innovate and lengths of stay have steadily decreased. However, the introduction of robotic-assisted radical cystectomy (RARC) offers the hope of a less morbid surgical approach. Although uptake has not been as rapid as robotic-assisted laparoscopic prostatectomy (RALP), it is increasingly being used. Second, extended PLND was introduced. Although strong evidence exists for the benefit of bilateral PLND, the relative extent of lymphadenectomy, standard versus extended, is currently under investigation. Third, enhanced recovery after surgery (ERAS) protocols have emerged, with initial evidence from colorectal surgery showing tremendous potential in the perioperative management of patients undergoing radical cystectomy. Studies suggest that these protocols have reduced complications and length of hospital stay through targeted interventions aimed at ensuring that patients’ medical status is optimized before surgery and that they return to baseline function as soon as possible postoperatively. Fourth, level I evidence supports the use of alvimopan for earlier return of bowel function, and this agent is commonly incorporated within an ERAS protocol. Finally, the benefits of radical cystectomy centralization in high-volume surgical centers are reviewed.
Introduction
Radical cystectomy with bilateral pelvic lymph node dissection (PLND) and urinary diversion is the gold standard for management of clinical stage T2 through 4a bladder cancer that is not metastatic and for non–muscle-invasive high-grade urothelial carcinoma that is refractory to intravesical therapy, and for palliation in patients with severe local symptoms. Open radical cystectomy (ORC) has been the mainstay of curative treatment for decades, with modifications including nerve-sparing continent urinary diversion and proximal extent of PLND. During the preceding 30 years, 5-year trends in relative survival of bladder cancer have only improved marginally, from 72% in 1975 through 1977 to 80% in 2003 through 2009. Although survival rates have not shifted dramatically, complication rates have improved but remain high, with rates up to 60% and prolonged hospital stays still common. Thus, novel technology, techniques, and management strategies have continually been sought to improve surgical outcomes after radical cystectomy.
This article discusses several modifications in surgical care. First, traditional ORC is performed via an open, infraumbilical midline incision. Surgeons continue to innovate and lengths of stay have steadily decreased. However, the introduction of robotic-assisted radical cystectomy (RARC) offers the hope of a less morbid surgical approach. Although uptake has not been as rapid as robotic-assisted laparoscopic prostatectomy (RALP), it is increasingly being used. Second, extended PLND was introduced. Although strong evidence exists for the benefit of bilateral PLND, the relative extent of lymphadenectomy, standard versus extended, is currently under investigation. Third, enhanced recovery after surgery (ERAS) protocols have emerged, with initial evidence from colorectal surgery showing tremendous potential in the perioperative management of patients undergoing radical cystectomy. Studies suggest that these protocols have reduced complications and length of hospital stay through targeted interventions aimed at ensuring that patients’ medical status is optimized before surgery and that they return to baseline function as soon as possible postoperatively. Fourth, level I evidence supports the use of alvimopan for earlier return of bowel function, and this agent is commonly incorporated within an ERAS protocol. Finally, the benefits of radical cystectomy centralization in high-volume surgical centers are reviewed.
Robotic-assisted laparoscopic cystectomy
Although laparoscopic cystectomy was first reported in the literature in the early 90s, it was not widely embraced because of the high technical skill required. The robotic platform, however, provides the benefits of a magnified 3-dimensional image; the ability to use an EndoWrist, which allows superior motion over laparoscopic instruments; and a more ergonomic position that effectively makes minimally invasive radical cystectomy a viable alternative for surgeons with advanced laparoscopic and robotic experience. Potential benefits include reduced blood loss, fewer transfusions, lower narcotic requirements, quicker return of bowel function, shortened length of stay and improved cosmesis. These perceived advantages are offset by longer operative times and a lack of tactile feedback, which is typically a mainstay of ORC in determining resectability and the presence of extravesical disease. Furthermore, in a value-based purchasing environment, cost must be accounted for in the evaluation of the relative advantages and disadvantages associated with these 2 approaches. In addition, RARC may be limited in patients with multiple prior abdominal surgeries or in those who cannot tolerate the pneumoperitoneum or steep Trendelenburg position required because of body habitus or comorbidities.
The technique for RARC initially developed through replicating the steps and principles of the open procedure. In addition, the preexisting and widespread uptake of RALP certainly aided in the advancement and modification of RARC, specifically shortening operative times, reducing blood loss, and improving lymph node yield.
Complications
Radical cystectomy with PLND is a morbid operation, with complication rates up to 60% and mortality rates of 1% to 7%. A driving force behind adoption of RARC was the belief that the minimally invasive approach would lessen the burden of these complications through reduced blood loss, decreased need for transfusion, and absence of a large, midline incision. A small pilot randomized controlled trial (n = 40) found that the RARC group (400 mL; interquartile range [IQR], 300.0–762.5) had a decreased estimated blood loss compared with the ORC group (800 mL; IQR, 400–1100) but similar blood transfusion rates and no significant reduction in “excessive length of stay” (>5 days; 65% vs 90%; P = .11) compared with the ORC group. Blood transfusion rates in radical cystectomy series range from 42% to 60% because of intraoperative blood loss and preoperative anemia secondary to deconditioning, hematuria, and use of neoadjuvant chemotherapy. Retrospective studies also suggest that transfusions are associated with worse outcomes in patients with bladder cancer who are undergoing radical cystectomy.
It is important to note when comparing RARC with ORC that most studies are retrospective or prospective in nature and randomized trials are limited. Memorial Sloan Kettering Cancer Center (MSKCC) recently published results of a randomized trial of 118 patients assessing whether RARC would be associated with a lower rate of perioperative complications than open surgery, with extracorporeal urinary diversion (ECUD) being used in both arms. In the intention-to-treat analysis, the investigators reported that 37 patients (62%) who underwent RARC and 38 (66%) who underwent open surgery had a grade 2 to 5 complication ( P = .66), and that rates of high-grade complications were also similar ( P = .90). Intraoperative blood loss was less in the RARC group (mean difference, 159 cm 3 ), but length of surgery was significantly shorter in the open-surgery group (mean difference, 127 minutes; P <.001). The mean length of hospital stay was similar in the RARC and ORC arms (8 days; P = .53). This trial was stopped early because interim analysis showed that outcomes had met predefined criteria for futility in showing a difference in complications between ORC and RARC. Unfortunately, details on types and severity of complications were limited. Randomized data are still not available for investigating oncologic and pain control outcomes and whether intracorporeal urinary diversion (ICUD) affects any of the perioperative morbidity or functional outcomes.
A recent meta-analysis showed that patients undergoing RARC experienced fewer overall perioperative complications ( P = .04), had less estimated blood loss ( P <.001), required fewer perioperative transfusions ( P <.001), and had a shorter length of hospital stay ( P <.001). These findings provide at best level III evidence, which is not sufficient to support meaningful comparisons, as evidenced by the data from the randomized trials reported earlier. Long-term studies are needed to determine complication rates beyond the perioperative period, including complications associated with urinary diversion that may take months or years to present.
Oncologic Outcomes
Margin status at radical cystectomy is a short-term oncologic marker known to affect cancer-specific survival. Studies seem to show equivalent rates of positive surgical margins between ORC and RARC, ranging from 0% to 9% ( Table 1 ). One of the few randomized trials comparing ORC and RARC observed no significant differences between oncologic outcomes of positive margins (5% each; P = .50) or number of lymph nodes removed (n = 23 vs 11, respectively; IQR, 15.00–28.00 vs 8.75–21.50, respectively; P = .135). However, only 40 patients were randomized, thus limiting definitive conclusions. A second small randomized controlled trial (n = 41) found similar median nodal yields between ORC and RARC (18 ORC vs 18 RARC; P = .515). Oncology outcomes from the MSKCC randomized trial have not yet been published. Although most of the technical hurdles have been overcome for RARC with respect to many quality metrics by advanced laparoscopic/robotic surgeons, no level I evidence yet supports a claim that RARC is better than, worst than, equivalent to, or noninferior to ORC with respect to probability of progression, cancer-specific survival, or overall survival.
| Author | Institution | Level of Evidence | Number of Patients | Lymph Node Yield | Positive Surgical Margins | Median Estimated Blood Loss (mL) | Median Operative Time (min) | Length of Stay (d) | Overall Complications | Ileal Conduit | CSS (2-y) | OS (2-y) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Parekh et al, 2013 | University of Texas Southwestern | 2 | 20 | 11 (median) | 5% | 400 | 300 | 6.0 | 25% (>grade 2) | N/A | N/A | N/A |
| Nix et al, 2010 | University of North Carolina | 2 | 21 | 19 (mean) | 0% | 200 | 252 | 4.0 | 33% | 50% | N/A | N/A |
| Kader et al, 2013 | Wake Forest | 3 | 100 | 18 (mean) | 11% | 423 (mean) | 451 (mean) | 6.0 | 35% (90 d) | 97% | N/A | N/A |
| Knox et al, 2013 | University of Alabama | 3 | 58 | 21 (mean) | 7% | 276 (mean) | 468 (mean) | 6.3 (mean) | 43% (30 d) | 91% | N/A | N/A |
| Nepple et al, 2013 | Washington University | 3 | 36 | 17 (median) | 14% | 675 (mean) | 410 (mean) | 7.9 (mean) | 81% | 73% | 68% | |
| Ng et al, 2010 | Weill Cornell | 3 | 83 | 16 (median) | 7% | 460 (mean) | 365 (mean) | 5.5 | 48% (90 d) | 56% | N/A | N/A |
| Kauffman et al, 2011 | Weill Cornell | 4 | 85 | 17 (median) | 6% | 400 | 360 | N/A | 71% | 85% | 79% | |
| Pruthi et al, 2010 | University of North Carolina | 4 | 100 | 19 (mean) | 0% | 250 | 258 | 4.9 (mean) | 8% (>grade 3) | 61% | 94% (18 mo) | 91% (18 mo) |
| Guru et al, 2009 | Roswell Park | 4 | 100 | 17–26 (mean) | 3% | 598 (mean) | 343 (mean) | N/A | 38% | 93% | N/A | N/A |
| Bochner et al, 2014 | Memorial Sloan Kettering | 2 | 60 | N/A | N/A | N/A | 456 (mean) | 8 (mean) | 62% (≥grade 2) | N/A | N/A | N/A |
One retrospective series reported on long-term oncologic outcomes in 121 patients who underwent RARC, with a median follow-up of 5.5 years. They found that 24 patients (20.0%) had node-positive disease and 8 patients (6.6%) had positive soft tissue margins. The 5-year actuarial overall, cancer-specific, and recurrence-free survival rates were 48%, 71%, and 65%, respectively. However, 56% of patients in this cohort had pT2 through pT4 cancers, indicating that almost 50% had low-volume disease.
The challenge of accurately assessing the oncologic outcome of RARC in the absence of large well-designed randomized controlled trials is largely caused by selection bias present in nonrandomized studies. Although more of a factor in earlier series, older, more complex patients with higher-stage disease are still more likely to undergo open than robotic surgery. Statistical analysis can only partially compensate for this.
Although short-term outcomes and pathologic findings between ORC and RARC may be comparable, long-term outcomes and results of ongoing larger randomized controlled trials are required before equivalence can be properly assessed. Oncologic principles remain true regardless of surgical modality, and radical cystectomy with bilateral PLND, including external and internal iliac and obturator nodes, should be performed in a timely fashion in all patients with muscle-invasive bladder cancer, and radical cystectomy should be considered for primary therapy in higher-risk patients with pT1G3 bladder cancer.
Extracorporeal Versus Intracorporeal Urinary Diversion
On completion of the bladder removal and lymph node dissection, incontinent cutaneous (ileal conduit), continent cutaneous diversion, or orthotopic urinary diversion can be conducted either extracorporeally or intracorporeally. In early experience, ECUD was more commonly used because of the increased complexity and prolonged operative times of ICUD. However, intracorporeal diversion is gaining popularity because of increasing experience and potential benefits, including decreased bowel exposure and handling, reduced risk of fluid imbalance, reduced pain, and smaller incision. Novel devices, such as the robotic vessel-sealing instruments and staplers, have potential to improve operative times and ease of procedure but at a substantial additional expense.
A recent study from the International Robotic Cystectomy Consortium reported on 768 patients who had ECUD (570 conduits, 198 neobladders) and 167 who had ICUD (106 conduits, 61 neobladders). The investigators reported that operative time was similar (414 minutes; P >.05) and that patients receiving ICUD were less likely to experience a 90-day postoperative complication compared with those undergoing ECUD (41% vs 49%; P = .05). Limitations of this retrospective study include only reporting 90-day outcomes and that ICUD were more likely to be performed on healthier patients and by more experienced practitioners. Gore and colleagues previously reported in 2010 that perioperative complications were similar between patients receiving either an ileal conduit or a continent diversion, but did not comment on whether open or robotic surgery was used.
Ongoing randomized trials will help determine whether robotic approaches can improve oncologic and functional outcomes. The largest trial currently underway is randomized open versus robotic cystectomy (RAZOR) (ClinicalTrials.gov identifier: NCT01157676 ) ; this is a multi-institutional noninferior phase III trial that will randomize patients with T1–T4, N0–1, M0 bladder cancer to undergo either open or robotic surgery, with approximately 160 patients in each arm. The purpose of this trial is to compare open versus RARC, PLND, and urinary diversion in terms of oncologic outcomes, complications, and quality-of-life measures, with a primary end point of 2-year progression-free survival. Full data from the RAZOR trial are not expected until 2016 to 2017.
Extended lymph node dissection
A bilateral PLND is an important component of a radical cystectomy, because the lymph nodes may be the only site of metastases. Thus, pelvic lymphadenectomy can be both prognostic and therapeutic. Studies show that positive pelvic lymph nodes are found in 21% to 35% of patients. Stein and colleagues reported on 246 patients who had positive lymph nodes at the time of radical cystectomy and PLND, noting 5- and 10-year recurrence-free survival rates of 35% and 34%, respectively.
The minimum requirement for bilateral (standard) lymphadenectomy includes all lymphatic tissue distal to the common iliac bifurcation, and includes the external iliac, internal iliac, and obturator fossa extending to the Cooper ligament distally, the pelvis sidewall laterally, and the bladder medially. An extended pelvic lymphadenectomy includes the lymph nodes at least up to the aortic bifurcation, and includes the bilateral common iliac, presacral, and presciatic (or fossa of Marseilles) nodes and the nodal regions of standard dissection. Some surgeons extend the dissection above the aortic bifurcation up to the origin of the inferior mesenteric artery. Retrospective data suggest that the proximal extent of node dissection and individual surgeon’s experience may have a beneficial impact on the therapeutic outcome and overall survival. The limits of node dissection do not differ between open and RARC. Repeat studies have shown that RARC lymph node yields can equal those of ORC with adequate surgeon effort and case volume.
Studies of efficacy of extended lymph node dissection are complicated by the fact that lymph node yield depends on node viability, method of submission (en bloc or separate), and processing technique. Furthermore, in routine clinical practice, lymphadenectomy is less commonly performed and lymph node yields have been lower than those reported in published studies. Although thorough, extended node dissection adds time to an already lengthy procedure; however, current evidence supports a survival benefit, and therefore it should be performed when possible.
Most studies are retrospective or provide insufficient quality of evidence to make definitive conclusions regarding extent of node dissection. The Southwest Oncology Group has initiated a randomized trial to compare disease-free survival of patients with muscle-invasive urothelial carcinoma of the bladder undergoing radical cystectomy with extended PLND versus standard pelvic lymphadenectomy (ClinicalTrials.gov identifier: NCT01224665 ). The estimated enrollment is 620 patients; accrual began in 2011, with estimated completion in 2022.
Related posts:
Bladder Cancer
Nonurothelial Bladder Cancer and Rare Variant Histologies
Second-Line Therapies in Metastatic Urothelial Carcinoma
Management of Low-risk and Intermediate-risk Non–Muscle-invasive Bladder Carcinoma
First-Line Treatment and Prognostic Factors of Metastatic Bladder Cancer for Platinum-Eligible Patients
First-line Treatment of Metastatic Disease
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