Current Opinion in Oncology:
Genitourinary system: Edited by Arif Hussain
Morgan, Todd M; Clark, Peter E
Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Correspondence to Peter E. Clark, MD, Vanderbilt University Medical Center, A-1302 Medical Center North, Nashville, TN 37232-2765, USA E-mail: firstname.lastname@example.org
Purpose of review: To review the diagnosis and management of all stages of bladder cancer with an emphasis on studies and developments within the last year.
Recent findings: Cystoscopy remains the gold standard for diagnosis of bladder tumors, though fluorescent light and urinary biomarkers can both improve the sensitivity of cancer detection. Management of high-risk patients with nonmuscle invasive cancer continues to be controversial, with a number of risk assessment tools developed to help stratify patients to cystectomy or bladder-sparing regimens. Intravesical therapy is utilized both as a one-time perioperative regimen and as a weekly regimen, and research continues in the development of agents for bacillus Calmette-Guerin-refractory superficial bladder cancer. In patients undergoing cystectomy, evidence supports the need for an adequate lymphadenectomy. Although there are limited data on robotic assisted radical cystectomy, initial reports suggest that an appropriate lymph node dissection can be performed. The role of bladder-sparing modalities as well as the use of adjuvant and neoadjuvant therapies is still debated. Trials investigating these therapies continue to seek to improve both oncologic outcomes and quality of life for patients with invasive bladder cancer.
Summary: Progress continues in bladder cancer diagnosis and management, and we anticipate that future work will further advance the care of patients with this disease.
There were estimated to be approximately 70 980 new cases of bladder cancer and 14 330 deaths from bladder cancer in the United States in 2009 . Although population-adjusted incidence rates have remained stable the past 35 years, bladder cancer remains the fifth leading new cancer diagnosis in the United States and is fourth among men. This article will review the diagnosis and management of bladder cancer, emphasizing developments over the past year.
Direct cystoscopic visualization of the bladder continues to be the gold standard in patients with microscopic or gross hematuria. Although increasing evidence supports the greater sensitivity of fluorescence cystoscopy for detection of bladder tumors, it remains to be seen whether this will translate into decreased progression rates and improved overall survival [2,3]. Newer technologies under development may improve the precision of identifying bladder tumors while also providing real-time pathologic information. For example, optical coherence tomography (OCT) allows cross-sectional imaging of bladder tissue using a small probe and may both identify bladder tumors and determine their depth of invasion . When coupled to fluorescence cystoscopy, OCT demonstrated a sensitivity of 97.5% and a specificity of 97.9% for the identification of malignant bladder lesions [5•]. Confocal laser endomicroscopy is another interesting technology under investigation. Using a 2.6 mm probe, cellular architecture can be assessed with successful differentiation between normal urothelium, low-grade tumors, and high-grade tumors [6•].
Significant research continues to focus on the development and implementation of urinary biomarkers for both diagnosis and surveillance. Although six tests currently have the Food and Drug Administration (FDA) approval, many more are under investigation . The most effective current application is in the surveillance of patients with a history of bladder carcinoma. Nuclear matrix protein-22 (NMP22), for example, has consistently demonstrated significantly greater sensitivity than cytology in predicting recurrence in patients with a history of bladder cancer . Additionally, although NMP22 performs better than cytology in the diagnosis of bladder cancer , a recent trial of NMP22 in a cohort of asymptomatic patients demonstrated a low positive predictive value likely related to the very low cancer prevalence in this population . UroVysion (Abott Molecular Inc., Des Plaines, Illinois, USA) is a fluorescence in-situ hybridization assay that also consistently outperforms cytology with respect to sensitivity, though at significantly greater cost . Additionally, it may be used in patients who have undergone intravesical therapy [12,13]. Other recent studies have evaluated panels of genes [14,15], urinary microsatellite analysis , and chromosomal instability  as potential markers of bladder cancer recurrence and progression. Finally, urinary proteomics has recently shown promise, with urinary cystatin B being one example of an investigational protein identified through proteomic profiling that appears to be an independent predictor of both recurrence and progression [18,19].
Management of nonmuscle-invasive bladder cancer
Although up to 80% of bladder cancers are nonmuscle invasive (NMIBC) at the time of diagnosis, 15–25% will eventually progress to invasive disease. Complete transurethral resection of the tumor with close cystoscopic surveillance remains the standard of care . Although many different surveillance protocols are employed, Hollenbeck et al. [21•] demonstrated that increasing use of surveillance and treatment in patients with early-stage bladder cancer does not necessarily improve outcomes. In their SEER-Medicare cohort, expenditures for providers with greatest use of resources were over two-fold that of the lowest expenditure quartile, yet mortality was not improved. When recurrent tumors are detected by cystoscopic surveillance, options include endoscopic resection with possible intravesical chemotherapy vs. a more aggressive intervention such as radical cystectomy.
Level I evidence supports a single, prophylactic postoperative instillation of intravesical chemotherapy in patients with NMIBC . This is based on a 39% decrease in the odds of tumor recurrence and is reflected in the published guidelines [20,23•]. It is important to note that immediate intravesical therapy postresection should be held if there is concern for bladder perforation. Interestingly, a recent study brings the effectiveness of perioperative therapy into question. Gudjonsson et al. [24•] randomized 305 patients to receive either postoperative epirubicin or resection alone. Although a significant decrease in recurrence was seen in the epirubicin group as a whole (hazard ratio 0.56, P = 0.002), this effect was limited to patients with primary or solitary tumors. No benefit was observed for those with intermediate or high-risk NMIBC.
Despite improvements in intravesical therapy, patients with T1 disease opting to pursue bladder-sparing therapy rather than radical cystectomy present a substantial challenge. These patients carry a high risk of recurrence and progression, and there are not yet clear criteria delineating which patients should undergo aggressive surgical management. Current standard of care mandates complete transurethral resection of these tumors and inclusion of the muscularis propria in the tumor specimen. Understaging of T1 lesions without the presence of muscularis propria has been well documented and may be as high as 62% . Re-resection is required in the absence of muscle in the biopsy specimen, and some have advocated a second resection of all newly diagnosed T1 lesions to decrease the risk of understaging . Furthermore, though radical cystectomy overtreats a significant percentage of these patients, the survival benefit has been repeatedly documented. A recent study reported 10-year cancer-specific survival of 78.7% in a large nonrandomized cohort undergoing early cystectomy and 64.5% in those undergoing delayed cystectomy .
In order to stratify patients to cystectomy vs. bladder-sparing regimens, a number of predictors have been identified. The presence of carcinoma in situ (CIS) or muscularis mucosa invasion has been consistently associated with upstaging at cystectomy [28–31]. Other important predictors of understaging and disease progression include lymphovascular invasion, variant histology such as small-cell or micropapillary components, and urethral involvement [31–33]. Although assessment of these factors can help guide treatment direction, additional tools to help differentiate those at high risk of progression from those unlikely to progress are needed. An increasing number of risk assessment tools have been developed; however, none have been sufficiently validated to justify routine use [31–35].
There are a number of additional evidence-based principles of intravesical therapy for NMIBC that form the foundation for treating these patients. A recent individual patient data meta-analysis confirmed the superiority of bacillus Calmette-Guerin (BCG) to mitomycin C (MMC) in the treatment of NMIBC, but only with inclusion of a maintenance regimen [36••]. CIS, in particular, responds well to BCG treatment, with a complete response rate of up to 68% . Additionally, patients suffering a recurrence after one induction course of BCG may respond to another induction and/or maintenance course of BCG. Continued disease after this, however, signals unlikely benefit from additional BCG.
Significant research continues to be devoted to improving the efficacy of intravesical therapy. Administration of MMC via microwave hyperthermia  or electromotive drug administration  has shown benefit over MMC alone. A derivative of MMC, apaziquone, has also demonstrated potential as an intravesical agent and has recently been given FDA fast-track status for approval in NMIBC [40,41]. In patients with BCG-refractory CIS, valrubicin remains the only FDA-approved drug and is again available . Other promising agents include mycobacterial cell wall-DNA complex, with response rates up to 46% in a mostly pretreated population , and DTA-H19, a DNA plasmid carrying the diphtheria toxin A gene . Both of these therapies are now in clinical trials.
Management of muscle-invasive bladder cancer
The standard therapy for muscle-invasive bladder cancer is radical cystoprostatectomy in men and anterior pelvic exenteration in women. Overall survival after cystectomy is closely related to pathologic tumor stage. In patients without lymph node involvement, Stein et al.  reported 10-year recurrence-free survival rates of 87% in T2, 76% in T3, and 45% in T4 disease. Lymph node involvement varied with tumor stage, ranging from 18% of patients with T2a disease to 45% of patients with T3/T4 disease, and the 10-year recurrence-free survival rate in these patients was 34%. Urethral recurrence after cystectomy is rare, and urethrectomy is only necessary in the setting of a positive urethral margin on intraoperative frozen section or when there is cancer invading the prostatic stroma in men. A follow-up report from the University of Southern California demonstrated that orthotopic diversion following radical cystectomy does not compromise oncologic outcomes in women . Recurrence-free survival at 10 years was 55%, with a low rate of pelvic or urethral recurrence (2.5%).
Recent large single-institution studies have confirmed the significant risks associated with cystectomy. In a single-center series of over 1100 radical cystectomy patients, the 90-day complication rate was 64%, with 13% graded as significant [47•]. Gastrointestinal complications were most common, followed by infectious and wound complications. Another single-institution series of 538 patients reported a 45% 30-day complication rate, with 7.4% classified as major . Increasing data support the need to perform cystectomies at high-volume centers. An evaluation of the complication rates at over 100 centers demonstrated significant differences in perioperative mortality depending on the number of cystectomies performed each year . Rates ranged from nearly 4% at centers performing fewer than three cystectomies annually to 1% at centers performing over 50 each year.
Two key surgical factors that have a significant impact on oncologic outcome are surgical margin status and the extent of lymphadenectomy. Dotan et al.  reported a positive surgical margin rate of 4.2% in their series of 1589 radical cystectomies. Patients with positive margins had a local recurrence rate of 21% at 5 years, compared with 6% in patients with negative surgical margins. The hazard ratio for disease-specific death in this and other studies has ranged from 2 to 2.7 in patients with positive margins [50,51]. The relationship between lymph node counts and survival after cystectomy has been repeatedly demonstrated. Herr  showed significant differences in survival among 68 node-positive patients depending on the number of lymph nodes removed. Additionally, among 258 node-negative patients, the number of lymph nodes removed remained an important predictor of survival. Another recent population-based study demonstrated an independent association between increasing lymph node counts and improved overall survival after cystectomy .
Lymph node density (LND) – the percentage of positive lymph nodes relative to the total number of lymph nodes removed – remains an important predictor of oncologic outcome. Among 248 node-positive patients treated at two high-volume cancer centers, patients with LND more than 20% were found to have an independent 2.75-fold greater risk of disease-specific death vs. those with LND less than 20% . Bruins et al.  found that even in patients with only 1–2 positive lymph nodes, LND is a significant predictor of survival at a density cut-off of 4%. Although these studies and others confirm the importance of obtaining a sufficient lymph node yield at surgery, still unknown is whether the benefit is solely one of staging accuracy or whether there is a therapeutic benefit from removal of nodal metastases. Surprisingly, 16% of patients in the SEER registry who underwent radical cystectomy in 2004 did not undergo lymphadenectomy, though this figure has decreased by over half since 1988 .
The importance of performing a satisfactory pelvic lymphadenectomy has become particularly relevant in light of the increasing use of minimally invasive approaches to radical cystectomy. Although a number of studies have evaluated the safety of laparoscopic and robotic assisted radical cystectomy, there is little data to date on either the adequacy of lymphadenectomy or oncologic outcomes. As expected, minimally invasive approaches appear to result in a decreased blood loss and transfusion requirement as well as shorter hospital stays [57–60]. In addition, Ng et al. [61•] have reported a significantly lower overall (41 vs. 59%) and major (17 vs. 31%) complication rate in their nonrandomized cohort of patients undergoing robotic vs. open radical cystectomy. Average lymph node counts have been reported in the range of 16–19; however, not all series have performed dissections within at least the standard boundaries [58,62]. Positive surgical margin rates have been appropriately low – zero in some small series and 7% in a larger series, which also reported a 9% positive margin rate in their open cohort [58,59,61•]. One review of data from 48 papers on laparoscopic and robotic cystectomies suggested that minimally invasive approaches can achieve comparable results to open surgery both in terms of the extent of lymphadenectomy and intermediate-term oncological outcomes . Further follow-up will be needed to assess the true oncologic efficacy of robotic cystectomy.
Another trend has been the increased use of prostate-sparing techniques, performed with the idea of increasing continence and potency [64–66]. Rozet et al.  describe utilizing transurethral resection of the prostate with frozen sections sent to exclude any prostatic urothelial carcinoma prior to bladder removal. They report high potency and continence rates as well as a 5-year overall survival rate of 67%. Significant questions remain, however, as to whether this is an appropriate approach from an oncologic perspective . Prostate adenocarcinoma has been identified in up to 48% of radical cystoprostatectomy specimens, with clinically significant features present in 35–48% of these patients with prostate cancer [69,70]. Prostatic urothelial carcinoma has also been identified in up to 48% of cystoprostatectomy specimens . Given the success of nerve-sparing techniques for preservation of erectile function in appropriate patients , the role of prostate-sparing cystectomy is limited.
As an alternative to radical cystectomy, a number of bladder-sparing regimens have been investigated. These consist of some combination of endoscopic resection, chemotherapy, and radiation. No randomized trials have compared these regimens with radical cystectomy; however, some series have demonstrated survival rates within the range of what would be expected with surgery. Rodel et al.  reported a 10-year disease-specific survival of 42% with over 80% of survivors preserving their bladder. A more recent study evaluated 63 patients with muscle-invasive cancer who had a complete response to neoadjuvant chemotherapy and subsequently refused cystectomy . At a median follow-up of over 7 years, overall survival was 64% with 54% preserving their bladder. Solsona et al. [74•] allowed 146 patients with microscopic residual muscle-invasive cancer to choose between radical cystectomy and cisplatin-based chemotherapy. There was no difference in cancer-specific survival between the two groups; however, of 51 responders in the bladder preservation group, five (10%) died after initial local recurrence .
Chemoradiation is likely more effective than chemotherapy alone, and one recent study showed excellent results with gemcitabine and radiation, reporting a 5-year disease-specific survival of 82% . Additionally, late pelvic toxicity may be lower than previously thought. A review of four RTOG studies found that only 7% of patients had significant late pelvic toxicity and nearly all resolved [77•]. Candidates for bladder-preserving protocols generally are recommended to have a solitary tumor less than 5 cm in size, clinical stage T2, no hydronephrosis, and no evidence of lymphatic or distant metastases.
Neoadjuvant and adjuvant chemotherapy
The administration of chemotherapy before or after radical cystectomy continues to be an area of significant interest and investigation. Neoadjuvant chemotherapy offers a number of theoretical and real advantages, including early treatment of microscopic metastases, downstaging of the primary tumor, and improved patient tolerance relative to adjuvant chemotherapy. A potential disadvantage, however, is the delay in cystectomy, as recent population-based studies have confirmed prior institutional series demonstrating worse outcome for patients with longer waiting periods between transurethral resection and cystectomy [78–80].
Currently, there is greater evidence supporting the use of neoadjuvant chemotherapy than there is in favor of adjuvant chemotherapy . In what remains one of the pivotal neoadjuvant trials, SWOG 8710 randomized 307 patients with locally advanced bladder cancer to cystectomy with or without neoadjuvant chemotherapy . Patients randomized to the chemotherapy group received methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) and had significantly improved overall and disease-specific survival (hazard ratio 0.75 and 0.60, respectively). The greatest benefit was to patients with T3 or T4 disease, whereas there appeared to be little impact on patients with T2 cancer. Notably, the survival benefit was largely linked to tumor downstaging, with pT0 rates of 38% in the MVAC group and 15% in the cystectomy-only group. A meta-analysis of 3005 patients from 11 randomized trials found that neoadjuvant chemotherapy provided a 5% absolute overall survival benefit at 5 years (P = 0.003) . To date, however, neoadjuvant chemotherapy is infrequently utilized even among patients with stage 3 or 4 disease .
In contrast to neoadjuvant chemotherapy, the data supporting the use of adjuvant chemotherapy are much less robust. Potential benefits of adjuvant therapy include the selection of patients at highest risk for failure and the ability to perform surgery without delay. However, most adjuvant chemotherapy trials have shown no benefit . Although a large meta-analysis found a statistically significant 9% improvement in survival at 3 years, the included studies had a number of methodological flaws such as poor accrual over long periods of time . Whether or not the neoadjuvant data can be extrapolated to the adjuvant setting remains an area of great interest and debate, with at least one study showing equivalent results . In patients with persistent node-positive disease at cystectomy despite neoadjuvant treatment, Kassouf et al.  found a significant improvement in recurrence-free survival with the administration of adjuvant chemotherapy (13 vs. 5 months, P = 0.02).
The importance of a multidrug, cisplatin-based regimen in the treatment of advanced urothelial carcinoma has been well documented. MVAC has generally been the gold standard for metastatic bladder cancer since the report by Loehrer et al.  demonstrating a significant survival benefit compared to cisplatin monotherapy. However, this study also confirmed the substantial toxicity of MVAC that carries an approximately 4% toxic death rate. As a result of a better safety profile and apparent noninferior efficacy, gemcitabine with cisplatin has become an acceptable alternative and, in many ways, the community gold standard in both the metastatic and the neoadjuvant settings . In a phase III trial of 405 patients with advanced disease randomized to MVAC vs. gemcitabine with cisplatin, there was no difference in overall or progression-free survival between the two study arms . This was not a formal equivalence trial, however, and it is unlikely that one will be performed.
Outcomes for patients with advanced bladder cancer continue to be poor despite these advances in chemotherapy, and successful new drug combinations and novel agents are needed. In a phase III trial, Sternberg et al.  randomized patients with advanced tumors to standard MVAC vs. a high-dose intensity MVAC regimen. Although toxicities remained relatively similar, patients in the high-dose regimen had significantly improved overall survival (hazard ratio = 0.73). Another regimen recently evaluated was sequential administration of doxorubicin and gemcitabine followed by ifosfamide, paclitaxel, and cisplatin . The median overall survival of 16 months was comparable to studies of MVAC and gemcitabine with cisplatin; however, 68% of patients experienced grade 3–4 neutropenia. Whether these investigations translate into a broader standardization of regimens remains to be seen. Surprisingly, Porter et al.  found gemcitabine, carboplatin, and paclitaxel to be the most commonly utilized chemotherapies in a 2003 SEER-Medicare cohort.
Nonplatinum-containing regimens remain an area of ongoing investigation. Calabro et al.  evaluated the administration of gemcitabine and paclitaxel in patients with advanced bladder cancer, reporting a median survival of 13 months. The authors suggest that this may be a potential treatment option for patients unable to receive cisplatin due to poor performance status or renal impairment. Additionally, there continues to be significant interest in targeted, molecular pathway-based therapies. Phase II trials of the tyrosine kinase inhibitors sorafenib and lapatinib as second-line therapies were both recently published [94,95]. Neither drug showed significant activity in this population, with median time to disease progression of approximately 2 months in each trial. The alkylating agent vinflunine has recently been evaluated in patients previously treated with a platinum-based regimen, resulting in a median progression-free survival of 2.8 months and again demonstrating the difficulty in slowing the disease course in these individuals .
Significant progress continues to be made in bladder cancer. The past year has seen increasing evidence to support the use of urinary biomarkers as well as further development of technologies to assist with cystoscopic identification of tumors. There is continued debate over how best to manage patients with T1 cancer; hopefully, newer intravesical therapies in BCG-refractory disease will help decrease the need for cystectomy in these and other high-risk NMIBC patients. In those undergoing cystectomy, substantial evidence supports the need for an adequate lymphadenectomy, and initial data regarding the robotic approach suggest that comparable lymph node counts are feasible in experienced hands. Finally, the role of bladder-sparing modalities as well as the use of adjuvant and neoadjuvant therapies continues to evolve, and further trials investigating these therapies will hopefully improve both oncologic outcomes and quality of life for patients with invasive bladder cancer.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 298).
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