Some studies report that tumour progression in patients with non–muscle-invasive bladder cancer (NMIBC) is associated with a poor prognosis. However, no systematic evidence is available.
The aim of the study was to systematically review literature to determine the long-term cancer-specific survival in patients with high-risk NMIBC (T1G3, multifocal, highly recurrent, or carcinoma in situ) having tumour progression.
A systematic review was conducted by searching PubMed and the Cochrane library for studies published between 2006 and 2011. Additional studies were identified by scanning reference lists of relevant papers. We attempted to retrieve missing data by contacting the corresponding author. Keywords used included bladder cancer, high-risk, high grade, carcinoma in situ, non-muscle invasive bladder cancer, progression, and survival. Studies were included when they met the following criteria: inclusion of at least 75 patients having high-risk NMIBC, patients were initially treated conservatively with transurethral resection of the bladder tumour and intravesical instillations, a median follow-up of at least 48 mo, and reporting data on progression to muscle-invasive bladder cancer (MIBC) and death resulting from bladder cancer (BCa).
Literature was systematically reviewed, and 19 trials were included, producing a total of 3088 patients, of which 659 (21%) showed progression to MIBC and 428 (14%) died as a result of BCa after a median follow-up of 48–123 mo. Survival after progression from high-risk NMIBC to MIBC was 35%. Progression to MIBC and BCa-related death in high-risk NMIBC were found to be relatively early events, occurring mainly within 48 mo. Finally, even in cases of early cystectomy in patients with high-risk NMIBC, a relevant proportion of these patients appear not be cured of their disease.
This study provides systematically gathered evidence showing a poor prognosis for patients with high-risk NMIBC and tumour progression.
Keywords: Bladder cancer, High-risk, Long-term, Non–muscle-invasive bladder cancer, Progression, Urothelial carcinoma, Survival, Systematic review.
Bladder cancer (BCa) is the second most common malignancy of the urinary tract. In 2008, the estimated incidence of BCa in Europe was 110 500 cases, of which 86 300 were diagnosed in men and 24 200 were diagnosed in women ; in men, BCa was the fourth most commonly diagnosed type of cancer. BCa accounted for 4.1% of all cancer-related deaths in men and 1.8% in women . In newly diagnosed cases of urothelial carcinoma of the bladder, approximately 75% present as non–muscle-invasive BCa (NMIBC), and 25% present as muscle-invasive BCa (MIBC) .
Transurethral resection of the bladder tumour (TURBT) in combination with intravesical chemotherapy or immunotherapy is considered standard therapy for NMIBC. However, despite intravesical treatment, patients are still at risk for tumour recurrence and progression to MIBC. Important risk factors for progression or recurrence are tumour size, stage and grade, multiplicity, prior recurrences, and the presence of carcinoma in situ (CIS) . Depending on patient risk profile, rates of recurrence can be as high as 78% within 5 yr, and rates of progression can be as high as 45% . For individual patients, recurrence and progression rates can be estimated using the European Organisation for Research and Treatment of Cancer (EORTC) risk tables .
In high-risk patients, conservative treatment with TURBT and intravesical instillations with bacillus Calmette-Guérin (BCG) can prevent recurrence, but the results with regard to progression are conflicting , , and , and whether intravesical instillations have beneficial effects on cancer-specific survival (CSS) is still controversial  and . In contrast, high-risk patients treated conservatively for too long may have a decreased CSS by deferring radical treatment and allowing progression to muscle-invasive disease , , and .
In cases of MIBC without lymph node or distant metastasis, radical cystectomy (RC) is the treatment of choice. A subset of patients subjected to RC for MIBC will present with a history of NMIBC in which the tumour finally progressed to muscle-invasive disease despite conservative treatment . In normal daily practice, primary and progressive MIBC are treated equally, assuming similar CSS in both groups.
However, a retrospective study of Schrier et al, for example, showed that progression in patients with NMIBC is associated with a poor prognosis that significantly worse than in primary MIBC. The 3-yr CSS in the group with progression to MIBC was 37% versus 67% in the group with primary MIBC . These findings suggest that patients with high-risk NMIBC could benefit from early radical treatment, especially if survival is poor in cases of progression to MIBC. The objective of this study was to systematically review recent literature with an emphasis on CSS in patients with high-risk NMIBC and tumour progression.
2. Evidence acquisition
The first step was to specify and document inclusion criteria and methods of the analysis, using methodologic recommendations for systematic reviews . The primary end point of this study was to determine CSS in patients with tumour progression; therefore, the search was focused on retrieving data on progression to MIBC and death resulting from BCa. Progression was defined as the development of muscle-invasive disease (≥T2) or the presence of metastatic disease in patients with a history of NMIBC.
2.1. Eligibility criteria
Studies were included when they met the following criteria: inclusion of at least 75 patients having high-risk NMIBC (according to European Association of Urology [EAU] guidelines: T1G3, multifocal or highly recurrent, CIS), patients were initially treated conservatively (TURBT and intravesical instillations), a median follow-up of at least 48 mo, reporting data on progression to MIBC and death resulting from BCa, and availability of the full text in English. Studies with both prospective and retrospective designs were included in this review.
These criteria for inclusion were chosen because they offered sufficient information on progression to MIBC and death from BCa. The minimum follow-up of at least 48 mo was chosen based on the EORTC risk tables . This study showed that in high-risk NMIBC, approximately 80–85% of those patients who will progress to MIBC will do so within 48 mo.
2.2. Information sources and study selection
Studies were identified by searching the National Library of Medicine (PubMed) and the Cochrane library for the period 2006–2011. To perform the search, the keyword bladder cancer was used in combination with each of the following individual keywords: (high risk OR high grade); (grade 3 OR T1G3); (non-muscle invasive OR superficial); carcinoma in situ; progression; and survival. In addition, reference lists of relevant articles were scanned to identify other relevant studies. The last search was run on 30 January 2011.
Study selection was performed in a standardised manner. Abstracts of papers were read and, when they were considered relevant, the full papers were obtained and reviewed to assess the eligibility criteria. Included papers were assessed for duplicates by checking included studies in meta-analysis. Retrospective studies were checked for using the same patient series. In case of duplicity, the most recent publication was used.
2.3. Data collection and quality assessments
For eligible studies, relevant data were obtained using a data-extraction sheet. We attempted to retrieve missing or unclearly reported data by contacting the corresponding author of the study. All data obtained were verified for consistency and compared with the data in the publication.
2.4. Statistical analysis
When data on progression to MIBC and death from BCa were available, CSS was calculated for those patients having tumour progression. In this calculation, it was assumed that death resulting from BCa was only possible after progression to MIBC or because of the presence of metastatic disease. The following formula was used: CSS
Statistical analysis was carried out using SPSS v.17.0.0 statistical software for Windows (IBM Corp., Somers, NY, USA). Continuous variables not conforming to a normal distribution were compared using the Mann-Whitney U test. Tests for trends were performed only when there was a prior hypothesis of a trend; p≤ 0.05 was considered statistically significant.
3. Evidence synthesis
In total, 1367 results were identified, of which 1354 were identified by searching PubMed and an additional 13 results were identified by screening reference lists. All 1367 records were screened, and 1227 studies were discarded, because these papers clearly did not meet the inclusion criteria after reviewing their abstracts. The full-text papers of the remaining 140 studies were obtained and examined in more detail, after which another 118 studies were excluded. Reasons for exclusion were short follow-up (n
Four studies did not report data on progression to MIBC or death from BCa , , , and . The corresponding authors of these studies were contacted by e-mail and all responded, except one . Data on progression to MIBC or death from BCa were not available for three of these studies , , and , which were therefore excluded. Figure 1 shows the flow of information through this systematic review.
In total, 19 studies were identified for inclusion in this review. For each study, the methodologic design, duration of follow-up, numbers of patients, proportions of tumour stages (Ta, T1, CIS, and concomitant CIS), restaging, progression to MIBC, and death from BCa were extracted. Based on the methodologic design of the trials, the included studies were sorted into two groups: prospective and retrospective trials, listed in Table 1 and Table 2, respectively.
|Source||No. of patients||Median follow-up||Restaging TURBT||Proportion of Ta/T1/ CIS*/cCIS**, %||Progression to MIBC, no. (%)||Death from disease, no. (%)||CSS in case of progression, %|
|Di Stasi et al, 2006 ||212||88 (IQR: 63–110)||Yes||0/100/0/27||33 (16)||23 (11)||30|
|Dalbagni et al, 2007 ||89||52 (range: 16–90)||Yes||0/100/0/38||22 (25)||15 (17)||32|
|Gradmark et al, 2007 ||250||123 (range: 46–176)||NR||42/25/33†||58 (23)||45 (18)||22|
|Esuvaranathan et al, 2007 ||80||54 (range: 6–114)||NR||24/49/27†||6 (8)||5 (6)||17|
|Gofrit et al, 2009 ||104||75||NR||38/25/37/63||22 (21)||12 (12)||45|
|Zieger et al, 2009 ||125||80 (range: 6–142)||NR||39/61/0/31||67 (54)||58 (46)||13|
|Sylvester et al, 2010 ||323||110||No||NR||50 (15)||18 (6)||64|
|Totals||1183||52–123||–||–||258 (22)||176 (15)||32 (range: 13–64)|
* Isolated CIS without concomitant papillary tumour.
** Papillary tumour with concomitant CIS.
† The presence of concomitant and isolated CIS were reported together.
TURBT = transurethral resection of the bladder tumour; CIS = carcinoma in situ; cCIS = concomitant carcinoma in situ; MIBC = muscle-invasive bladder cancer; CSS = cancer-specific survival; IQR = interquartile range; NR = not reported.
|Source||No. of patients||Median follow-up, mo||Restaging TURBT||Proportion of Ta/T1/CIS*/cCIS**, %||Progression to MIBC, no. (%)||Death from disease, no. (%)||CSS in case of progression, %|
|Kamel et al, 2006 ||105||48 (range: 8–156)||Yes||0/100/0/14||25 (24)||19 (18)||24|
|Moonen et al, 2007 ||105||58 (range: 3–161)||NR||NR||25 (24)||13 (12)||48|
|Margel et al, 2007 ||78||107 (range: 16–238)||NR||0/100/0/22||14 (18)||12 (15)||14|
|Queipo-Zaragoza et al, 2007 ||83||Mean: 58
||NR||0/100/0/27||31 (37)||17 (20)||45|
|Denzinger et al, 2007 ||132||68 (range: 1–180)||Yes||0/100/0/65||54 (41)||50 (38)||7|
|Serretta et al, 2008 ||165||103||No||0/100/0/0||14 (8)||9 (5)||36|
|Palou et al, 2009 ||92||91 (range: 3–173)||No||0/100/0/60||17 (18)||14 (15)||18|
|Park et al, 2009 ||144||65||No||0/100/0/12||19 (13)||10 (7)||47|
|Chade et al, 2010 ||476||61 (IQR: 30–98)||Yes||54/0/46/54||57 (12)||33 (7)||42|
|van Rhijn et al, 2010 ||164||77 (range: 4–259)||No||15/81/0/34||48 (29)||26 (16)||46|
|Alkhateeb et al, 2010 ||191||48||Yes||0/100/0/29||61 (32)||25 (13)||59|
|Alvarez-Mugica et al, 2010 ||170||53 (range: 3–190)||NR||0/100/0/24||36 (21)||24 (14)||33|
|Totals||1905||48–107||–||–||401 (21)||252 (13)||37 (range: 7–59)|
* Isolated CIS without concomitant papillary tumour.
** Papillary tumour with concomitant CIS.
The prospective group included 7 trials with a total of 1183 patients, of which 258 (22%) progressed to MIBC and 176 (15%) died from BCa after a median follow-up of 52–123 mo. The long-term CSS after progression to MIBC was 32% (range: 13–64). The retrospective group included 12 trials with a total of 1905 patients, of which 401 (21%) progressed to MIBC and 252 (13%) died of BCa after a median follow-up of 48–107 mo. The long-term CSS after progression to MIBC was 37% (range: 7–59).
Median CSS was 30% (interquartile range [IQR]: 17–45) for prospective studies and 39% (IQR: 20–47) for retrospective studies (p
In the current study, CSS was determined in patients with high-risk NMIBC and tumour progression. The literature was systematically reviewed, and 19 trials were included, providing a total of 3088 patients, of which 659 (21%) showed progression to MIBC and 428 (14%) died of BCa after a median follow-up of 48–123 mo. This translates into a long-term CSS of 35% in patients with high-risk NMIBC and tumour progression.
Prospective and retrospective studies were initially analysed separately, because we expected to find a worse CSS in retrospective studies dealing with high-risk NMIBC. This outcome could be the result of selective inclusion of more patients with high-risk cancers in retrospective studies. However, we did not find such a difference.
Two assumptions were used for this study. First, it was assumed that death from BCa in cases of NMIBC was not possible without progression to MIBC or the presence of metastatic disease. Second, it was assumed that progression to MIBC and death from BCa are relative early events (within 48 mo) when they occur. This assumption was based on the EORTC risk tables, which show that in high-risk NMIBC, approximately 80–85% of those patients who will progress to MIBC will do so within 48 mo . Consequently, to include most events of progression to MIBC and death from BCa, only studies with a median follow-up of at least 48 mo were included. For the included studies, analysis showed no statistically significant difference in CSS between studies with a long (≥60-mo) and short (48–60-mo) follow up, supporting the second assumption that progression to MIBC followed by cancer-related death are relative early events when they occur. This assumption made it possible to combine all data on progression to MIBC and BCa-related death to calculate a long-term CSS for the whole group.
Literature reports are limited and contradictory with regard to the prognosis of patients with NMIBC and tumour progression. In a retrospective study by Schrier et al. , the difference in prognosis between progressive and primary MIBC in 163 patients was studied. A CSS rate of 37% was found in 74 patients with progressive disease, compared to 67% for 89 patients with de novo MIBC after a follow-up of 3 yr (p
In contrast, there is literature reporting an equal survival rate for both progressive and de novo MIBC. In a retrospective study by Lee et al. , 422 patients were included and divided into three groups based on the final clinical stage before RC. The first group included 183 patients with high-risk NMIBC; the second group included 70 patients with progressive disease to clinical stage T2 BCa; the third group included 169 patients with de novo clinical stage T2 BCa. After a follow-up of 3 yr, the CSS rates were 76%, 63%, and 64%, respectively. The group with progressive MIBC had no survival disadvantage in comparison to the group with de novo MIBC (p
If indeed survival decreases significantly after progression to MIBC, the question arises whether aggressive therapy such as RC in high-risk NMIBC is able to improve the outcome of these patients. Therefore, early versus deferred RC is an important related subject. There are few retrospective studies in which long-term CSS has been studied, comparing early (within 3 mo after initial diagnostic TURBT) and deferred cystectomy in high-risk NMIBC , , and . These studies show that primary treatment of high-risk NMIBC with early RC provides good long-term oncologic results, having a CSS of 80% at 5 yr  and 76–78% at 10 yr  and . For deferred cystectomy, the long-term oncologic results are worse, showing a CSS of 69% at 5 yr  and 51–61% at 10 yr  and . In another retrospective study, CSS was compared among 46 patients having cystectomy for NMIBC that was refractory to conservative treatment and 262 patients having MIBC at the time of cystectomy . After a median follow-up of 58 mo, CSS was 67% in both groups (p < 0.05), despite a similar rate of understaging compared to other studies .
These findings illustrate that despite early RC, a relevant proportion of patients with high-risk NMIBC appears not be cured of their disease. However, survival is worse in patients with deferred RC, suggesting that early cystectomy does improve oncologic outcome. Apparently, a worst outcome is seen when progression to MIBC has occurred, as is shown in the current study. These findings support the suggestion that the increased use of conservative treatment in high-risk NMIBC might be related to a decrease in survival .
In contrast, these early versus late cystectomy series show that understaging is an important problem in high-grade NMIBC. Approximately 10–30% of cases were initially understaged and were therefore muscle invasive , , , and . In addition, in a large study on the issue of understaging in high-risk NMIBC, approximately 50% of the patients treated with RC for clinical T1G3 BCa were upstaged to MIBC . Therefore, correct staging is crucial for the choice of treatment between NMIBC and MIBC. A restaging TURBT is standard of care after the initial diagnosis of high-grade or stage T1 NMIBC in the current EAU guidelines. In a retrospective study by Dalbagni et al. , a similar survival was found between early and deferred cystectomy in carefully staged patients using restaging TURBT.
The results from this study emphasise that the management of high-risk NMIBC is one of the most challenging issues in urologic oncology. To decide whether a patient with high-risk NMIBC should have radical surgery or can be treated conservatively remains a difficult question. Obviously, critical risk factors such as concomitant CIS and early BCG failure must be considered , , and . Unfortunately, no markers to date can differentiate between indolent and aggressive tumours in high-risk NMIBC on an individual level  and .
To the best of our knowledge, this is the first study to systematically examine the prognosis of patients with high-risk NMIBC and tumour progression. CSS was calculated using numbers on progression to MIBC and death from BCa in a large population, included from a total of 19 studies with a sufficient long-term follow-up to study progression to MIBC and BCa-related death.
This study has several limitations. Almost two-thirds of the study population was included from retrospective studies. Selective inclusion of patients with different high-risk profiles between the included study populations (for example, different proportions of concomitant CIS or large tumours) could explain the wide variation in the rates of progression (8–54%) and CSS (7–64%).
Moreover, if any standard treatment protocol was reported in the included studies, some of the studies had different treatment protocols that were not always standardised or evidence based. This could also have introduced bias into the results, because treatment intensity and variation could influence CSS . Treatment advise in cases of progression to MIBC was comparable between the studies (RC in the case of nonmetastasised tumours and chemotherapy in cases of metastasised tumours).
In addition, only a few studies included in this review reported that restaging was performed as a standard after the initial diagnosis of high-grade NMIBC , , , , , and . Inclusion of studies without restaging could have introduced bias into the results because of treatment delay of missed and thus untreated MIBC in cases of understaging. However, in the current study, no significant difference in CSS was found between included studies with or without standard restaging TURBT.
Finally, an important limitation of this study is the lack of time-dependent data. CSS was not based on individual patient data but calculated from reported numbers on progression to MIBC and death from BCa. Therefore, there are no specific results available on time to progression to MIBC, time to RC, time to death from BCa, or survival in specific strata. This was also the reason that it was not possible to determine the exact follow-up of the calculated CSS.
This study provides systematically gathered evidence showing a poor prognosis for patients with high-risk NMIBC and tumour progression. Progression to MIBC and BCa-related death in high-risk NMIBC are relatively early events and occur mainly within 48 mo. However, even in cases of early cystectomy, a relevant proportion of patients appears not be cured of their disease. Still, the worst outcome is seen when progression to MIBC has occurred. It remains unclear why the CSS in these patients is so much worse.
Deferring RC obviously has a continuing risk of progression to MIBC as well as a continuing risk of understaging because of the inadequacy of current staging tools. Therefore, a more aggressive approach, such as early RC, should be strongly considered in the treatment of high-risk NMIBC.
Study concept and design: Witjes.
Acquisition of data: van den Bosch.
Analysis and interpretation of data: van den Bosch.
Drafting of the manuscript: van den Bosch.
Critical revision of the manuscript for important intellectual content: van den Bosch, Witjes.
Statistical analysis: van den Bosch.
Obtaining funding: None.
Administrative, technical, or material support: None.
Other (specify): None.
Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
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© 2011 European Association of Urology, Published by Elsevier B.V.