Study Type – Therapy (case series)
Level of Evidence 4
Study Type – Therapy (case series)
Level of Evidence 4
To evaluate data obtained from a large, multi-institutional, contemporary series of patients who underwent radical cystectomy (RC) in a universal healthcare system aiming to assess outcome and identify novel prognostic variables.
Data were collected and pooled from 2287 patients treated with RC between 1998 and 2008 by urological oncologists from eight Canadian academic centres. Collected variables included various clinicopathological parameters, recurrence and death. Survival and prognostic variables were analyzed using the Kaplan-Meier method and Cox regression analysis.
The median age of patients was 68 years with a mean (median) follow-up time of 35 (29) months. The 30, 60 and 90-day postoperative mortality rates were 1.3%, 2.6% and 3.2%, respectively. The 5-year overall, recurrence-free and cancer-specific survival was 57%, 48% and 67%, respectively, with a local recurrence rate of 6%. Pathological stage distribution was <pT2N0, n= 498 (23%); pT2N0, n= 365 (17%); pT3N0, n= 463 (21%); pT4N0, n= 170 (8%); and pTxN+, n= 507 (23%). Only 3.1% of patients received neoadjuvant chemotherapy and 19.4% received adjuvant chemotherapy. On multivariate analysis, lower pathological stage, negative surgical margins, receipt of adjuvant chemotherapy, performance of pelvic lymphadenectomy and an absence of smoking were associated with prolonged disease-specific and overall survival.
RC performed at academic centres provides excellent local control of disease and an acceptable clinical outcome with low perioperative mortality in patients who are treated within a universal healthcare system. Smoking, pelvic lymphadenectomy and receipt of adjuvant chemotherapy are independent prognostic factors for survival. Neoadjuvant chemotherapy continues to be under-utilized in Canada.
transurethral resection of bladder tumours
Radical cystectomy (RC) with pelvic lymphadenectomy (PLND) remains part of the standard of care in the treatment of muscle-invasive (MIBC) and refractory non-muscle invasive (NMIBC) bladder cancer [1–5]. Recently, advances in radiotherapy and chemotherapy have challenged its role, at the same time as offering newer combined bladder preservation alternatives. These new strategies, although potentially attractive in terms of health-related quality of life and oncological outcome, continue to be efficacious solely in select patient populations [6,7]. Furthermore, with improvements in the surgical care and techniques, complication and perioperative mortality rates of RC have decreased significantly to as low as 17–32% and 2–3%, respectively [1–3], with daytime and nocturnal continence rates as high as 85–90% and 50–90%, respectively, in cases with orthotopic diversions . With unilateral and bilateral nerve-sparing cystectomy, potency rates of 33% and 60% have been achieved . Most of the reported outcome results on RC were derived from older series or single centre experiences. The present study aimed to evaluate a contemporary series of patients with bladder cancer who were treated in a universal healthcare system by urological oncologists from academic centres across Canada to assess outcomes and identify novel prognostic variables.
Retrospective data were collected on patients who underwent RC for bladder cancer from eight academic centres across Canada between 1998 and 2008 as part of the Canadian Bladder Cancer Network. After Institutional Review Board approval, clinical and pathological information was obtained from the following institutions: McGill University Health Center, Montreal, Quebec; Laval University, Quebec City, Quebec; University of Western Ontario, London, Ontario; University of Alberta, Edmonton, Alberta; University of Ottawa, Ottawa, Ontario; University of Montreal, Montreal, Quebec; Dalhousie University, Halifax, Nova Scotia; and University of Manitoba, Winnipeg, Manitoba.
A standardized template was agreed upon and distributed to centres and all data were entered and tabulated in one database. Multiple strict quality control procedures were performed both internally and when all the data were aggregated to ensure optimal accuracy and concordance of data. Similar indication guidelines for surgery were used at all institutions and included patients with clinical evidence of muscle-invasive disease or non-muscle invasive tumours that were either recurrent or refractory to transurethral resection of bladder tumours (TURBT) and intravesical therapy. Clinical staging was performed by endoscopic evaluation with biopsy, and/or bimanual examination under anaesthesia. Imaging of the abdomen and urinary tract was performed in all patients with computerized tomography, magnetic resonance imaging, ultrasonography and/or excretory urography depending on the surgeon and institutional guidelines. The extent of lymphadenectomy was physician and institution-dependant. Decisions to offer neoadjuvant (NC) and adjuvant chemotherapy (AC) were made at the discretion of the treating physician and/or patient request. Pathological specimens were evaluated by staff pathologists with genitourinary expertise in each institution. Collected variables included age, gender, smoking, pelvic lymph node dissection, perioperative chemotherapy, various clinical and pathological parameters, recurrence, and death. Staging was performed in accordance with the 1997 TNM classification and grading according to the 2004 WHO system. The follow-up strategy consisted of office visits, serum chemistries, abdominal imaging, and chest radiography every 3–6 months for the first 3 years, with increasing intervals thereafter. Bone scans were ordered when clinically indicated.
Outcomes were measured by overall survival (OS), recurrence-free survival (RFS) and disease-specific survival (DSS). Cause of death was determined by the treating physician, based on chart review and/or the death certificate. Time to recurrence was calculated as the time interval from surgical intervention to the first evidence of clinical recurrence or last follow-up in the absence of any recurrence. Bladder cancer recurrences were classified as local (pelvic) and/or distant (metastasis). Time to OS was assessed as the time from cystectomy to the date of death, regardless of cause of death. Patients who were still alive were censored at the date of last follow-up. Finally, the time to DSS was determined as the time interval from surgery to the date of death from bladder cancer or last follow-up if the patients had not died of bladder cancer. If the patients had died of other causes, they were censored at the time of death. Perioperative mortality, defined as any death within 30 days of surgery or before discharge home, was censored at time of death for DSS but included as an event for OS.
The association between clinical and pathological categorical variables was performed using Fischer and chi-squared tests. Kaplan-Meier curves were used to estimate the OS, RFS and DSS of all patients and for subgroups classified according to pathological stage, nodal status and smoking habits. Survival estimates were correlated with patient’s clinical and pathological characteristics on univariate analysis. Subsequently, multivariate survival models were constructed for OS, RFS and DSS and analyses were performed according to the Cox proportional hazard regression model. P < 0.05 was considered statistically significant. All analyses were performed using SAS, version 9.1.3 (SPS Inc., Chicago, IL, USA).
The present study cohort consisted of 2287 patients; 484 females (21.2%) and 1803 males (78.8%) with a median (range) age of 68 (26–90) years and median and mean follow-up of patients alive of 29.3 months (interquartile range 9–50 months; range 1–176 months) and 35.2 months. Distribution of clinical staging among patients was cTis in 4.8%, cTa in 2.9%, cT1 in 18.6%, cT2 in 65.2%, cT3 in 4.6% and cT4 in 3.9%. Most patients (96%) did not have any pelvic adenopathy and hydronephrosis was reported in 27.7%. NC was offered to only 3.1% of patients. Finally, 66.4% of the study cohort reported a history of tobacco smoking.
The median (range) time from TURBT to surgery was 49 (1–592) days. The majority underwent an ileal conduit urinary diversion (79.6%) and 9% did not have lymphadenectomy. When a lymphadenectomy was performed, it was labelled as standard in 67% of patients and extended in the remaining 33%. The median number of nodes resected was nine (interquartile range 1–51). On pathological specimen examination, there was no evidence of cancer (pT0N0) in 7.4% of patients, whereas 73.2% had muscle-invasive disease (≥pT2Nx). Furthermore, in 24.5% of cases, positive nodal involvement was reported. In 76% of patients, tumour grade was high and concomitant cis was noted in 34% of specimens. Surgical margins were positive on pathological evaluation in 8.6% of cases. Finally, AC was offered to 19.4% of patients. Patient, clinical and pathological characteristics of the study cohort are summarized in Table 1.
|Age (years), median (range)||68 (26–90)|
|ECOG performance status|
|Clinical tumour stage|
|Time from TURBT to surgery (days), median (range)||49 (1–592)|
|Ileal conduit||1693 (79.63)|
|Continent cutaneous||20 (0.94)|
|Pathological tumour stage|
|Pathological node status|
|Number of nodes resected, median (range)||9 (1–51)|
The 30, 60 and 90-day mortality rates were 1.3%, 2.6% and 3.2%, respectively. A total of 561 patients (33%) had recurrence with a median (range) time to recurrence of 10.1 (0.2–192.4) months. Local recurrence rates were 6% in the overall group and 4% in the organ-confined node-negative group. The 5-year OS, RFS and DSS for the entire population were 57%, 48% and 67%, respectively. OS and DSS were significantly associated with pathological T-stage and lymph node status. The 5-year OS and DSS was significantly decreased in patients with nodal metastasis (pTxN+: 32% and 40%) compared to patients with organ-confined node-negative (≤pT2N0: 75% and 85%) or non-organ confined node-negative disease (>pT2N0: 53% and 62%) (P < 0.001) (Fig. 1a). Furthermore, the primary pT stage was associated with outcome even among patients with nodal metastasis. With increasing pT stage, both 5-year OS and DSS decreased from 49% and 55% for ≤pT2N+ tumours down to 31% and 42% for pT3N+ tumours and 20% and 23% for pT4N+ tumours (P < 0.001) (Fig. 1b).
On multivariate Cox regression analysis, younger age, absence of smoking history, lower pathological stage, negative surgical margins and use of AC were all independent prognostic factors for OS. With respect to DSS, absence of smoking history (Fig. 1c) and performance of lymphadenectomy (Fig. 1d) were independent prognostic factors for prolonged DSS on multivariate analysis. The univariate and multivariate analyses for OS and DSS are summarized in Table 2. When patients were stratified by history of smoking, there was no significant difference between the two groups with respect to pathological stage, performance of lymphadenectomy, or whether AC was offered (Table 3). On average, smokers were younger and had better performance status than non-smokers.
|Univariate analysisOS||Multivariate analysisOS||Univariate analysis DSS||Mulativariate analysisDSS|
|P||HR||95% CI||P||P||HR||95% CI||P|
|Pathological nodal status|
|Variable||Smoker(n= 1007)||Nonsmoker(n= 509)||P|
|Age (years), mean ± SD||67.5 ± 10.7||69.0 ± 10.2||0.002|
|Gender, n (%)||0.001|
|Male||820 (81.5)||376 (74.0)|
|Female||186 (18.5)||132 (26.0)|
|ECOG, n (%)||0.002|
|0–1||341 (95.8)||197 (89.1)|
|2–3||15 (4.2)||24 (10.9)|
|Charlson score, mean ± SD||5.2 ± 1.6||4.7 ± 1.7||0.003|
|Neoadjuvant chemometherapy, n (%)||27 (2.7)||25 (4.9)||0.026|
|PLND, n (%)||882 (87.6)||444 (87.2)||0.560|
|pT stage, n (%)||0.840|
|≤pT2||493 (50.5)||251 (51.0)|
|>pT3||483 (49.5)||241 (49.0)|
|pN stage, n (%)||0.297|
|pN0||699 (75.0)||359 (77.5)|
|pN+||233 (25.0)||104 (22.5)|
|Grade, n (%)||0.001|
|Low||75 (8.1)||65 (14.3)|
|High||854 (91.9)||391 (85.6)|
|Adjuvant chemotherapy, n (%)||176 (17.7)||87 (17.2)||0.805|
|Recurrence, n (%)||357 (35.5)||168 (33.0)||0.006|
RC performed at academic centres provides excellent local control of disease (6% local recurrence rate) and acceptable clinical outcome (5-year DSS of 67%), with low perioperative mortality in patients treated within a universal healthcare system. Smoking, adjuvant chemotherapy and PLND were independent prognostic factors for survival. Neoadjuvant chemotherapy continues to be under-utilized in Canada.
It has been previously reported that pathological stage and nodal status are the most important prognostic factors for patients undergoing RC for bladder cancer. In the present study, as would be expected, survival was adversely affected by increased pathological stage. This significant difference justifies the clinical importance of distinguishing organ-confined from non-organ-confined tumours [1,3]. Importantly, even in patients with nodal metastasis, the pathological stage in the primary organ (pT) was significantly associated with survival. These results are in agreement with a study by Vieweg et al. reporting differences in survival between primary organ and non-organ confined tumours were statistically significant even in node-positive cases (P= 0.001). One possible rationalization for this phenomenon could be that the more invasive the primary tumour, the higher the likelihood of haematogenous spread to distant organs, leading to a worse biology of disease and an outcome independent of lymphatic spread. As such, it is important to stage the primary organ in patients with nodal metastasis when prognosticating bladder cancer and enrolling patients in adjuvant therapy trials.
In the present study, the rate of lymph node metastasis was 24%. Although worse outcomes were observed in this group with positive nodal disease, the 5-year OS was a remarkable 32% following RC, thus supporting a potential therapeutic role for lymphadenectomy in patients with invasive bladder cancer. This is further supported by the fact that performance of lymphadenectomy was an independent prognostic factor for prolonged DSS in the present study. Although 30% of our patients did receive an extended dissection, the boundaries of the dissection were not clarified or standardized and, as such, any conclusions as to the benefits of an extended lymphadenectomy (or lack of) in the present study population cannot be addressed. However, the role and survival benefit of the extent of nodal dissection, in both node-negative and node-positive disease, have been previously reported in the literature, primarily using the number of nodes resected as a surrogate marker [10–12]. Notably, Herr et al. reported a 17% difference in survival when a standard dissection was performed compared to minimal nodes identified in the pathology specimen. Furthermore, in a head-to-head comparison with a standard dissection, extended dissection has been reported to offer superior survival outcomes even in patients with advanced and node-positive disease without increasing morbidity [14–16]. Finally, although the rates of patients receiving an extended PLND have not changed significantly over the duration of the present study (27–35%), a recent spike in 2007 shows a significant increase (45%), suggesting that this technique may be gaining momentum in Canada. However, pending completion of two randomized prospective studies in the USA and Europe, the definitive survival benefit of an extended PLND remains to be shown.
The benefit of NC in patients with operable cT2-4a tumours has been shown in three separate randomized trials and confirmed in a large meta-analysis [17–20]. In the present study, it was only offered in 3% of cases. Although this reflects its continued minimal use in Canada, it is not dissimilar from the rates obtained from studies in the USA (5%) . A review of the National Cancer Data Base from the USA lends further evidence to its scarce use across the border, with only 0.7% of 11 328 patients with stage III bladder cancer receiving NC . Trends appear to be on the rise in the present study cohort because 68.7% of patients who received NC did so after 2002, with a noticeable peak in use occurring around 2002–2003 coinciding with the advent of level 1 evidence showing the benefit of NC. Despite this phenomenon, the rate continues to be low, with only 7% of patients who were treated with RC after 2005 receiving NC. Similarly, the benefit of AC for pT3 or pN+ disease has been shown in three randomized trials and a meta-analysis to significantly improve survival [22–25]. In the present study, even when adjusting for age, gender, performance status and pathological stage, it was an independent prognostic variable for improved survival on multivariate analysis. However, only 19% of our cohort and only 46% of those with pN+ disease received AC.
Of high interest, two-thirds of patients in the present study reported a history of tobacco smoking. It is well established that smoking is a general health hazard associated with numerous illnesses, such as strokes, ischaemic heart disease, emphysema, chronic obstructive pulmonary disease and cancer. It is also the most recognizable risk factor for developing bladder cancer, leading up to 50–65% and 20–30% of male and female cases, respectively . This carcinogenic effect is secondary to some of its pyrolytic products, such as polynuclear aromatic hydrocarbons, acrolein and nitrosamines that bind to DNA and cause genetic mutations. Overall life expectancy is also reduced in regular smokers, with estimates in the range 2.5–10 years less than non-smokers [27,28]. As such, it would be expected to be associated with worse overall survival as was observed in the present study. However, in the present series, it was also associated with worse cancer-specific survival following RC. This was most pronounced at longer follow-up when there was a 9% increase in the chance of dying from bladder cancer after surgery in smokers or ever smokers. This association was further reinforced on multivariate analysis because tobacco smoking was shown to be an independent significant prognostic factor for worse DSS. When patients were stratified by history of smoking, there was no significant difference between the two groups with respect to pathological stage, performance of lymphadenectomy, or whether AC was offered. On average, smokers were younger and had better performance status than non-smokers. This is the first report on the impact of smoking on DSS following RC for bladder cancer, thus further emphasizing the deleterious associations of smoking not only with increasing bladder cancer incidence, but also with cancer-specific outcomes following curative surgical intervention. A more detailed evaluation of this association is warranted subsequent to important information regarding pack-year history, type of tobacco or date of smoking cessation becoming available in the database.
Although one of the strengths of the present study is that it involved patients treated during a contemporary period by urological oncologists from most of the academic institutions in Canada, making the conclusions more applicable, there are certain limitations that are worthy of note. First, as in any retrospective analysis, even when accounting for the multiple strict quality control procedures performed, there is always an inherent risk of bias. Furthermore, we relied on a retrospective analysis of medical records to ascertain death and assign the underlying cause of death, which may have further contributed to bias. The present study encompasses a period during which recommendations on diversion, extent of lymphadenectomy, perioperative chemotherapy and follow-up strategies have evolved and, as such, they are more reflective of the trends of urological oncology and the management of bladder cancer during that time span rather than current practice recommendations. Additionally, although similar indications for surgery were used across the different centres, staging techniques were not always uniform and consistent. Finally, this is a strictly Canadian experience and, as such, represents the dynamics of a universal healthcare system where delays in performing surgery may be longer than expected and this has previously been shown to adversely affect outcome . However, in the present study, the median delay from TURBT to RC was 49 days and is comparable to other reports from international studies conducted in Sweden (49 days), USA (42 days) and Germany (54 days) [30–32].
In conclusion, RC performed at academic centres provides excellent local control of disease and acceptable clinical outcome with low perioperative mortality in patients treated within a universal healthcare system. Smoking, performance of lymphadenectomy and adjuvant chemotherapy are independent prognostic factors for survival. Neoadjuvant chemotherapy continues to be under-utilized in Canada.