Abstract
The aim of this study was to evaluate the local recurrence and distant metastasis rates for urothelial carcinoma of the bladder after radical cystectomy and to identify the predictive factors for local recurrence and distant metastasis. The study population was 347 consecutive patients treated with radical cystectomy for urothelial carcinoma of the bladder at our institution. Local recurrence, distant metastasis, and both local and distant recurrence rates were 49 (14.1%) months, 96 (27.7%) months, and 17 (4.9%) months, respectively. The mean follow‐up times to recurrence were 14.37 ± 13.25 months (range, 2–60 months) and 14.43 ± 15.72 months (range, 2–109 months) for local recurrence and distant metastasis, respectively (p = 0.808). The mean post‐recurrence disease‐specific survival (PRDSS) times for local, distant, and both local and distant recurrences were 17.82 ± 3.18 months, 4.16 ± 0.39 months, and 11.41 ± 2.73 months, respectively (p < 0.001). The predictive factors for local recurrence and distant metastasis were stage and nodal involvement (p < 0.001). Sex, grade, lymphovascular invasion (LVI), carcinoma in situ (CIS), and lymph node density (LND; 10% cut‐off value) were not predictors for recurrence in the results of the multivariate analysis. The current study demonstrated that stage and pathological nodal involvement were independent predictors of local recurrence and distant metastasis. The results of this study suggest that the early diagnosis and intervention of invasive bladder cancer cases may decrease the number of high stage and lymph node positive cases that have a high risk of local and distant recurrences. The adjuvant treatment options in the presence of risk factors for recurrence may improve survival outcomes.
Keywords: Distant metastasis, Local recurrence, Radical cystectomy, Survival, Urothelial carcinoma
Introduction
Bladder cancer is the second most common tumor in the urogenital system and one of the most important causes of mortality and morbidity [1]. Most patients diagnosed with urothelial carcinoma of the bladder have superficial tumors; yet 20–40% of the patients have muscle and perivesical tissue invasion, even at the beginning. Half of the patients with invasive tumors already have metastasis, or metastasis can emerge later on.
Radical cystectomy is the gold standard in the treatment of muscle‐invasive bladder cancer and patients with noninvasive tumors in whom intravesical therapy failed. Although radical cystectomy is the gold standard, about one‐third of patients relapse and die from the disease [2]. The main reason for cancer specific mortality in patients treated with radical cystectomy is related to distant metastasis. In addition, long‐term survival is very rare after local recurrence. For that reason, it is thought that local recurrences are as significant as distant metastasis for disease‐specific survival [3].
Recurrences following cystectomy are usually seen in the 2nd year or 3rd year and their frequencies are 4–29% for local recurrences and 22–38% for distant metastasis. The upper urinary system relapse rate is 3–8% and urethral recurrence rate is 6–10%, which generally develops 2–3 years after cystectomy. Although cisplatin‐based chemotherapy following recurrences shows relatively positive response rates, it still has a weak effect on subsequent survival [3].
The current study evaluated local and systemic recurrence patterns in patients treated with radical cystectomy for urothelial bladder cancer and attempted to define the predictive factors influencing local and systemic recurrences.
Methods
Data of 475 patients who underwent radical cystectomy for invasive bladder cancer in our clinic between 1991 and 2011 were retrospectively analyzed. Criteria for inclusion in the study were as follows: (1) urothelial carcinoma diagnosis in the pathological evaluation of the cystectomy specimen; and (2) the availability of follow‐up data in cases after recurrences. Exclusion criteria were: (1) local or systemic metastasis at diagnosis; (2) cases of newly developed urothelial carcinomas in the upper urinary system or urethra; and (3) patients in which primary definitive treatments failed and who underwent salvage cystectomy. A total of 347 patients met the above criteria and were included in the study. In the current study, 49 (14.1%) patients had local recurrences, 96 (27.7%) patients had systemic recurrences, and 17 (4.9%) cases had both local and systemic recurrences.
All pathological data were evaluated using a standard protocol. The American Joint Committee on Cancer 2009 staging system and World Health Organization 1973 grading system were used [[4], [5]]. Pathological staging is defined as organ‐confined (T0/Ta/TIS/T1/T2, N0), extravesical (T3/T4, N0), and lymph‐node involvement (node‐positive) (Any T, N1–3). Lymph node density (LND) is defined as the number of positive lymph nodes divided into the total number of removed lymph nodes [6]. Primary tumor properties such as lymphovascular invasion (LVI) and the presence of concomitant carcinoma in situ (CIS) were recorded.
All patients received a standard surgical procedure including radical cystectomy, pelvic lymphadenectomy, and various urinary diversions [1]. All patients who underwent cystectomy for invasive bladder cancer were followed at 3 month periods for the first 2 years, 6 month periods for 3 years, and annually for the following years. Physical examination, chest radiography, and blood biochemistry were routinely performed during follow‐up. Intravenous pyelography, ultrasonography, and computed tomography were used in the 3rd month, 6th month, and 12th month after surgery and annually later on or on the occasion that a relapse was suspected. Local recurrences were defined as those occurring within the soft tissue field of exenteration, which is inside the bony pelvis. Distant recurrences were those occurring outside the pelvis [[1], [3]]. Time to recurrence (TTR) was defined as the period from the date of cystectomy to the date when the first recurrence was diagnosed; post‐recurrence follow‐up was the time after the recurrence (TAR). Post‐recurrence disease‐specific survival (PRDSS) graphics are based on TAR.
Independent samples t test was used to determine relationships between continuous variables. Pearson's Chi‐square test was used to evaluate categorical variables. The logrank test and the Kaplan–Meier method were applied for the univariate analysis [[7], [8]]. Multivariate Cox proportional hazards model was used to calculate predictive values of independent relationships between categorical variables that were prognostic in the univariate analysis [7]. Analyses were calculated using SPSS version 17.0 (SPSS Inc., Chicago, IL, USA). All p values were two‐sided and p ≤ 0.05 was considered statistically significant.
Results
A total of 347 patients were included in the study. The mean patient age at surgery was 61.50 ± 8.87 years. There were 321 male and 26 female patients. Patient demographic and clinicopathological characteristics are summarized in Table 1. In the current study, 49 (14.1%) patients had local recurrence, 96 (27.7%) patients had systemic recurrence, and 17 (4.9%) cases had both local and systemic recurrences. The characteristics of patients with local and systemic recurrences are shown in Table 2.
Table 1.
Patient demographic and clinicopathological characteristics.
| n | % | ||
|---|---|---|---|
| Mean age | 61.50 ± 8.87 | ||
| Sex | Male | 321 | 92.5 |
| Female | 26 | 7.5 | |
| Stage | Organ‐confined | 171 | 49.3 |
| Extravesical | 91 | 26.2 | |
| Node‐positive | 82 | 23.6 | |
| Unknown | 3 | 0.9 | |
| Grade | 1 | 6 | 1.7 |
| 2 | 75 | 21.6 | |
| 3 | 252 | 72.6 | |
| Unknown | 14 | 4.1 | |
| CIS | Positive | 46 | 13.3 |
| Negative | 173 | 49.9 | |
| Unknown | 128 | 36.9 | |
| LVI | Positive | 62 | 17.9 |
| Negative | 157 | 45.2 | |
| Unknown | 128 | 36.9 | |
| LND | <10% | 107 | 30.8 |
| ≥10% | 33 | 9.5 | |
| Unknown | 207 | 59.7 |
CIS = carcinoma in situ; LND = lymph node density; LVI = lymphovascular invasion.
Table 2.
Characteristics of patients with local and systemic recurrences.
| Local recurrence | Systemic metastasis | p | ||
|---|---|---|---|---|
| Patient number | 49 | 96 | ||
| Mean age | 60.71 ± 9.39 (42–82) | 61.73 ± 8.14 (42–80) | 0.610 | |
| No. of retrieval LN | 12.89 ± 10.51 (0–34) | 11.24 ± 8.18 (1–30) | 0.389 | |
| No. of positive LN | 0.95 ± 1.73 (0–7) | 1.76 ± 2.94 (0–13) | 0.113 | |
| LND | <10% | 26 (53.1) | 19 (19.8) | 0.007 |
| ≥10% | 9(18.4) | 15 (15.6) | ||
| Time to recurrence (TTR) | 14.37 ± 13.25 (2–60) | 14.43 ± 15.72 (2–109) | 0.808 | |
| CIS positive | 8 (16.3) | 13 (13.5) | 0.661 | |
| LVI positive | 18 (36.7) | 25 (26) | 0.712 | |
| Stage | Organ‐confined | 14 (28.6) | 23 (24) | 0.244 |
| Extravesical | 16 (32.7) | 36 (37.5) | ||
| Node‐positive | 19 (38.8) | 37 (38.5) | ||
| Grade | 1 | 0 | 2 (2) | 0.411 |
| 2 | 2 (4.1) | 10 (10.4) | ||
| 3 | 46 (93.9) | 82 (85.4) | ||
Data are presented as n (%) or mean ± SD (range), unless otherwise indicated.
CIS = carcinoma in situ; LN = lymph node; LND = lymph node density; LVI = lymphovascular invasion; TTR = time to recurrence.
Local recurrence rates were 8.2% in organ‐confined disease, 17.6% in extravesical disease, and 23.2% in lymph node positive disease in this study. Systemic metastasis frequency was 13.5% in organ‐confined disease, 39.6% in extravesical disease, and 45.1% in cases with lymph node involvement.
Patients were grouped according to recurrence sites (local, systemic, and local and systemic). Actuarial estimated DSS at 5 years was 28.3% for the local recurrence group, 0.43% for the systemic metastasis group, and 11.8% for the both local and systemic recurrence group. Mean DSS times were 41.07 ± 6.79 months for the local recurrence group, 18.30 ± 2.03 months for the systemic metastasis group, and 25.23 ± 4.62 months for the both local and systemic recurrence group, respectively (p < 0.001, Fig. 1).
Figure 1.
Kaplan–Meier curve demonstrating disease‐specific survival in patients stratified by recurrence site.
Sex, pT stage, lymph node involvement, grade, and LVI were significantly associated with local recurrence in the univariate analysis, whereas CIS and LND (10% cut‐off value) had no statistically significant effect in the univariate analysis. In Cox multivariate regression analysis, pT stage and lymph node involvement were described as predictors of local recurrence (p < 0.001). Sex, grade, LVI, CIS, and LND (10% cut‐off value) had no predictive effects on local recurrence in the multivariate analysis. Univariable and multivariable analysis results of the parameters that affected local recurrence are shown in Table 3.
Table 3.
Univariate and multivariate analyses of parameters predicting local recurrence.
| Parameter | Univariate p | Multivariate p |
|---|---|---|
| Sex | 0.012 | 0.269 |
| pT stage | <0.001 | <0.001 |
| Lymph node involvement | <0.001 | <0.001 |
| Grade | <0.001 | 0.114 |
| Presence of CIS | 0.488 | 0.752 |
| Presence of LVI | <0.001 | 0.638 |
| LND (<10% vs. ≥10%) | 0.059 | 0.057 |
CIS = carcinoma in situ; LND = lymph node density LVI = lymphovascular invasion.
Systemic metastasis was found in 96 cases, including 29 in lungs, 25 in bones, and 23 in the liver. Other organ metastasis such as the brain, skin, penis, and peritoneal cavity were less frequent. The pT stage, lymph node involvement, grade, LVI, and LND (10% cut‐off value) were significantly associated with systemic metastasis in the univariate analysis, whereas sex and CIS had no statistically significant effect in the univariate analysis. In the Cox multivariate regression analysis, pT stage and lymph node involvement were described as predictors of systemic metastasis (p < 0.001). Sex, grade, LVI, CIS, and LND (10% cut‐off value) had no predictive effects on systemic metastasis in the multivariate analysis. Univariable and multivariable analysis results of the parameters that affected the systemic metastasis are shown in Table 4.
Table 4.
Univariate and multivariate analyses of parameters predicting systemic recurrence.
| Parameter | Univariate p | Multivariate p |
|---|---|---|
| Sex | 0.220 | 0.986 |
| Stage | <0.001 | <0.001 |
| Lymph node involvement | <0.001 | <0.001 |
| Grade | <0.001 | 0.069 |
| Presence of CIS | 0.423 | 0.495 |
| Presence of LVI | <0.001 | 0.403 |
| LND (<10% vs. ≥10%) | <0.001 | 0.839 |
CIS = carcinoma in situ; LND = lymph node density; LVI = lymphovascular invasion.
In this series, 32 patients in the local recurrence group and 79 patients in the systemic recurrence group received adjuvant chemotherapy after radical cystectomy. Univariate analysis demonstrated that chemotherapy does not decrease the rate of local (p = 0.113) and systemic (p = 0.793) recurrence rates.
TTR was defined as the period from the date of cystectomy to the date when the first recurrence was diagnosed; post‐recurrence follow‐up was the TAR. Post‐recurrence disease specific survival (PRDSS) graphics are based on TAR. Mean TAR were 14.37 ± 13.25 months (range, 2–60 months) in local recurrence and 14.43 ± 15.72 months (range, 2–109 months) for systemic metastasis. The post‐recurrence follow‐up was calculated in order to achieve PRDSS rates according to recurrence sites. Actuarial estimated PRDSS at 1 year was 74.9% for the local recurrence group, 0.39% for the systemic metastasis group, and 41.2% for the both local and systemic recurrence group. Mean PRDSS times were 17.82 ± 3.18 months for the local recurrence group, 4.16 ± 0.39 months for the systemic metastasis group, and 11.41 ± 2.73 months for the both local and systemic recurrence group (p < 0.001, Fig. 2). Median PRDSS times were 12 months for local recurrence, 3 months for systemic metastasis, and 7 months for both local and systemic recurrence.
Figure 2.
Kaplan–Meier curve demonstrating post‐recurrence disease‐specific survival (PRDSS) in patients stratified by recurrence site.
Discussion
Bladder cancer is the second most common urological cancer following prostate cancer [[9], [10], [11], [12], [13], [14], [15], [16], [17]]. A total of 20–40% patients have the invasive disease even at the time of diagnosis [[2], [4]]. Invasive bladder cancer is such a lethal disease requiring aggressive treatment that when left untreated, in 2 years, fewer than 15% of patients are able to survive [11]. Most of the patients who developed recurrences following radical cystectomy die within 15 months, and very few of them may survive for 4 years [3]. Local recurrence after radical cystectomy is generally located in the pelvic soft tissues or pelvic lymph nodes. The possible mechanisms for local recurrence development are: incomplete excision of tumor, positive surgical margins, insufficient pelvic lymph node dissection, and spillage of tumor cells during operation [[16], [18]]. Before the usage of advanced imaging techniques such as computed tomography, local recurrences following radical cystectomies were rarely diagnosed [12]. Cole et al. [17] showed that local relapses were more common than previously thought. As advanced imaging techniques become more accessible, there is an increase in the diagnosis of recurrences. Recurrences following cystectomy are usually seen in the 2nd year or 3rd year and their frequencies range between 4% and 29% in local recurrences and 22% and 38% for distant metastasis. [[2], [3], [12], [13], [14], [15], [16], [17]]. For all recurrences, 3–8% are upper urinary system relapses and 6–10% are urethral recurrences, which developed 2–3 years after cystectomy and are thought to originate from dysregulated extravesical urothelium [3].
In the current study, 49 (14.1%) patients had local recurrences, 96 (27.7%) patients had systemic recurrences, and 17 cases (4.9%) had both local and systemic recurrences. These results are similar to those in the literature [[12], [13], [14], [15], [16], [17]]. Local recurrences are usually seen 2–3 years after radical cystectomy. In the current study, mean TTR were 14.37 ± 1325 months (range, 2–60 months) for local recurrence and 14.43 ± 15.72 months (range, 2–109 months) for systemic metastasis. Although there are new developments for the treatment of invasive bladder cancer, prognosis after local recurrences is not good because of the aggressive nature of these tumors. Therefore, it is very important to diagnose recurrences as early as possible by using different contemporary imaging techniques and determining the possible risk factors.
This study demonstrated that pT stage and lymph node involvement were the most important predictive factors for both local and metastatic recurrences. These findings are similar in different series. Local recurrences rates and prognostic factors in patients after radical cystectomy in the variable series are shown in Table 5. In the current study, local recurrence rates were 8.2% in organ‐confined disease, 17.6% in extravesical disease, and 23.2% in lymph node positive disease. Systemic metastasis frequency was 13.5% in organ‐confined disease, 39.6% in extravesical disease, and 45.1% in cases with lymph node involvement. There are various studies to determine the prognostic factors on local recurrence. Factors related to local recurrence are stage, lymph node involvement, extent of lymphadenectomy, and perioperative chemotherapy in one study [16]. Extravesical disease and lymph node involvement increase the risk of both local and systemic recurrence rates in most series [[1], [6], [14], [15]]. Greven et al. [19] found that local recurrence rates were 6% for stage pT1, 18% for stage pT3a, and 51% for stage pT3b. The results of the current study for local and systemic recurrence according to the stages were similar to the series in the literature (Table 6).
Table 5.
Local recurrence rates and prognostic factors after radical cystectomy in variable series.
| Studies | Local recurrence rate (%) | Prognostic factor |
|---|---|---|
| Brendler [16] | 3/76 (3.9) | NA |
| Stein [16] | 77/1054 (7.3) | NA |
| Volkmer [16] | 182/1270 (14.3) | NA |
| Fraizer [16] | 50/531 (9.4) | NA |
| Cheng [16] | 63/218 (28.8) | NA |
| Greven [19] | 13/83 (15.7) | Stage |
| Pollack [20] | 30/228 (13.2) | Stage |
| Herr [15] | 51/322 (15.8) | No. of retrieved lymph nodes (<8) |
| Honma [12] | 27/145 (18.6) | Concomitant SCC component/pure SCC |
| Ide [2] | 26/146 (17.8) | Concomitant AC component |
| Lymph node involvement | ||
| No. of retrieved lymph nodes (<8) | ||
| Current study | 49/347 (14.1) | Stage, lymph node involvement |
AC = adenocarcinoma; NA = not available; SCC = squamous cell carcinoma.
Table 6.
Local and systemic recurrence rates after radical cystectomy stratified by pathologic stage.
| Local recurrence (%) | Stein [1] (%) | Hautmann [16] (%) | Mardersbacher [14] (%) | Our study (%) |
|---|---|---|---|---|
| Organ‐confined | 6 | 4 | NA | 8.2 |
| Extravesical | 13 | 15.9 | NA | 17.6 |
| LN positive | 13 | 20.4 | 13 | 23.2 |
| Systemic recurrence (%) | ||||
| Organ‐confined | 13 | 9.5 | 25 | 13.5 |
| Extravesical | 32 | 19.2 | 37 | 39.6 |
| LN positive | 52 | 45.1 | 49 | 45.1 |
LN = lymph node; NA = not available.
Ide et al. [2] showed that local recurrence is an independent predictor of systemic metastasis and DSS. Likewise, Pollack et al. [20] reported that local recurrence with pT stage and lymph node involvement were predictive factors for DSS. The current study revealed that the predictive factors on both local and systemic recurrences were stage and lymph node involvement. Furthermore, Greven et al. [19] and Pollack et al. [20] reported stage as a local recurrence predictor on their studies. Ide et al. [2] described local recurrence predictors as lymph node involvement, removed lymph node number (<8), and concomitant adenocarcinoma component. There are also various studies that reported lymph node involvement as a predictive for DSS [[6], [15], [21]]. Honma et al. [12] reported that the single prognostic factor that affects local recurrence is concomitant squamous cell carcinoma (SCC) or pure SCC histology. Herr et al. [15] and Ide et al. [2] reported that the removal of less than eight lymph nodes has a prognostic value on recurrence. The current study included only cases with urothelial carcinoma histology and did not aim for a prognostic value of the number of lymph nodes removed. Instead, the study set the threshold value for the LND variable as 10%. In the univariate analysis regarding systemic metastasis, LND (<10% vs. ≥10%) had a predictive effect on survival, but in the multivariable analysis, LND (<10% vs. ≥10%) was not a predictor on survival.
In the current study, 49 (14.1%) patients had local recurrence, 96 (27.7%) patients had systemic recurrence, and 17 (4.9%) cases had both local and systemic recurrences. Mean TTR were 14.37 ± 13.25 months in local recurrence and 14.43 ± 15.72 months for systemic metastasis in this study, which is similar to the results found in the literature (1,3,14). Median TTR in reported series are between 9 months and 18 months, but typically < 12 months, which is a relatively short period [[19], [22], [23]]. Westney et al. [23] reported that 82% of the cases (27/33) developed local recurrence within 2 years in a review of their clinic's experience with local recurrences over 35 years. Most recurrences developed within the first 2–3 years in patients who underwent radical surgery, but some recurrences can be observed later. Therefore, it is important that close monitoring with strict follow‐up protocols, especially in the first 2–3 years, is important for earlier diagnosis of possible recurrences, increasing the efficiency of other treatment options and better prognosis.
The current study used post‐recurrence follow‐up in order to achieve PRDSS rates according to recurrence sites. Actuarial estimated PRDSS at 1 year was 74.9% for the local recurrence group, 0.39% for the systemic metastasis group, and 41.2% for the both local and systemic recurrence group, respectively. Mean PRDSS times were 17.82 ± 3.18 months for the local recurrence group, 4.16 ± 0.39 months for the systemic metastasis group, and 11.41 ± 2.73 months for the both local and systemic recurrence group, respectively (p < 0.001). Only Mitra et al. [3] did an extensive study on PRDSS parameters and reported PRDSS median times according to site recurrences. PRDSS median times of both studies are summarized in Table 7.
Table 7.
Post‐recurrence disease‐specific survival (PRDSS) median times according to site of recurrence.
| Mitra et al. [3] (median) | Our study (median) | |
|---|---|---|
| Local | 7.95 (5.45; 10.46) | 12 (5.21; 18.78) |
| Systemic | 5.95 (4.95; 6.94) | 3 (2.46; 3.53) |
| Local and systemic | 3.98 (2.87; 5.09) | 7 (0.00; 16.41) |
The current study had some limitations. Although this is one of the longest series in Turkey, retrospective design, single center experience, and insufficient data about post‐recurrence treatment protocols makes it more difficult to evaluate the efficiency of post‐recurrence treatment protocols and their effects on survival. A prospective study without these limitations could show the results that can aid the decision making process more clearly. Researching the prognostic factors that influence recurrences are important for the early diagnosis of recurrences and controlling them in a group of patients, reducing the risk of possible distant metastasis and better survival. In order to achieve local control, aggressive excision of neighboring tissues around the bladder, extended lymph node dissection, and adjuvant treatment protocols should be kept in mind.
This study found that stage and lymph node involvement were prognostic factors for both local and systemic recurrences. On the basis of these results, adjuvant therapy options must be taken into account in the presence of extravesical disease and lymph node involvement.
In conclusion, early diagnosis, close monitoring, and extended lymph node dissection regarding the prognostic value of lymph node involvement and usage of adjuvant therapies in extravesical and lymph node involved diseases would be beneficial to improve both local and systemic control of the disease.
Conflicts of interest: All authors declare no conflicts of interest.
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