Prognostic risk stratification of pathological stage T2N0 bladder cancer after radical cystectomy

Study Type – Therapy (individual cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Patients with urothelial carcinoma of the bladder (UCB) and pathological (p) stage T2N0 disease exhibit a range of clinical outcomes with an overall estimated 10–25% experiencing recurrence and death after radical cystectomy (RC). Nomograms to prognosticate UCB post‐RC have been developed in heterogeneous datasets of patients across different stages and do not address factors unique to pT2N0 disease. A user‐friendly prognostic risk model was devised for patients with pT2N0 UCB undergoing RC based on residual pathological stage at RC (pT2a, pT2b, OBJECTIVE ? To stratify risk of pathological (p) T2N0 urothelial carcinoma of the bladder after radical cystectomy (RC) based on pathological factors to facilitate the development of adjuvant therapy trials for high‐risk patients.

PATIENTS AND METHODS

? The study comprised 707 patients from a database of patients with pT2N0 urothelial carcinoma of the bladder who had undergone RC and not received perioperative chemotherapy. ? The effect of residual pT‐stage at RC, age, grade, lymphovascular invasion and number of lymph nodes removed on recurrence‐free survival was evaluated using Cox regression analyses. A weighted prognostic model was devised with significant variables.

RESULTS

? The median follow up was 60.9 months. In multivariable analyses, residual disease at RC (pT2a: hazard ratio (HR) 1.740, P = 0.03; for pT2b: HR 3.075, P < 0.001; both compared with P = 0.09) and lymphovascular invasion (HR 2.234, P < 0.001) were associated with recurrence‐free survival (c = 0.70). ? Three risk groups were devised based on weighted variables with 5‐year recurrence‐free survival of 95% (95% CI 87–98), 86% (95% CI 81–90) and 62% (95% CI 54–69) in the good‐risk, intermediate‐risk and poor‐risk groups, respectively (c = 0.68). The primary limitation is the retrospective and multicenter feature.

CONCLUSIONS

? A prognostic risk model for patients with pT2N0 bladder cancer undergoing RC with generally adequate lymph node dissection was constructed based on residual pathological stage at RC, grade and lymphovascular invasion. ? These data warrant validation and may enable the selection of patients with high‐risk pT2N0 urothelial carcinoma of the bladder for adjuvant therapy trials.     

Comparison of the new American Joint Committee on Cancer substratification in node-negative pT2 urothelial carcinoma of the bladder: analysis of patient outcomes in a contemporary series

Study Type – Prognosis (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? The prognostic value of pathological substratification in lymph node‐negative pT2 urothelial carcinoma of the bladder based on tumour depth has been controversially discussed in recent studies. In 1997, the AJCC and UICC modified the TNM staging system in bladder cancer providing a new substratification in pT2 bladder cancer based on a previous study of Jewett in 1952 reporting a worse prognosis for patients with deep muscle invasion compared to those with superficial muscle invasion. Recently, this prognostic significance has been considered of minor importance compared to significance of lymph node tumor involvement. Thus, many of these studies concluded that future revisions of the TNM staging system should consolidate both substages. However, these studies were hampered by the inclusion of patients with non‐urothelial carcinoma components, unknown number of retrieved lymph nodes, unknown extent of pelvic lymphadenectomy, and inclusion of patients undergoing neoadjuvant chemotherapy. This study addresses specifically the prognostic significance of pT2 substaging in urothelial cancer in a contemporary, consecutive series of patients treated with radical cystectomy. All patients had pure urothelial cell carcinoma, and underwent an extended lymphadenectomy approach. The number of retrieved lymph nodes was recorded. There was a significant difference in survival in patients with lymph‐node negative pT2a vs. pT2b disease. Therefore, this study supports the prognostic value of the current substratification in pT2 urothelial carcinoma of the bladder.

OBJECTIVE

? To determine whether there is a difference in survival in patients with node‐negative pT2a vs pT2b urothelial carcinoma of the bladder (UBC), as recent studies suggest that the new American Joint Committee on Cancer substratification may not have prognostic significance.

PATIENTS AND METHODS

? Of 252 patients undergoing radical cystectomy (RC) and extended bilateral pelvic lymphadenectomy (ePLND) between 1999 and 2009, 72 (28.6%), with a mean (range) age of 66 (44–83) years (50 men, 22 women), had pathologically confirmed pT2 UCB. ? Fisher’s exact test and Cox regression analysis were used for uni‐ and multivariate analysis of risk factors of recurrence at a median (range) follow‐up of 28 (2.2–115.7) months. ? Kaplan–Meier plots were used to estimate the impact of pT2 substratification in lymph node (LN)‐negative disease on recurrence‐free (RFS) and cancer‐specific (CSS) survival using log‐rank test.

RESULTS

? Of the 72 patients, 39 had pT2a (54.2%) and 33 pT2b UCB (45.8%) on definitive histological examination. The median (range) number of LNs removed was 19 (6–38) in pT2a and 22 (4–36) in pT2b (P = 0.31) UCB. ? At RC, there was LN‐positive disease in one patient with pT2a UCB, whereas seven patients with pT2b UCB had LN‐positive disease (P = 0.02). ? The median (range) number of LNs removed in LN‐positive disease was 18 (11–30) and in LN‐negative disease was 20 (4–38) (P = 0.52). ? In LN‐negative disease, actuarial 5‐year RFS was 85.9% in patients with pT2a UCB vs 37.5% in those with pT2b UCB (P < 0.001). Actuarial 5‐year CSS was 84.8% in patients with LN‐negative pT2a UCB vs 59.6% in patients with LN‐negative pT2b UCB (P = 0.01). ? In Cox regression analysis, pT2 substratification was the only independent risk factor of recurrence and cancer‐specific death (P < 0.001 and P = 0.008).

CONCLUSIONS

? In this contemporary series of patients undergoing RC with ePLND, there was a significant difference in RFS and CSS between LN‐negative pT2a and pT2b UCB, and pT2 substratification was the only risk factor of recurrence and cancer‐specific death. ? These data are supportive of the current concept of substratification in LN‐negative pT2 UCB.     

Human epidermal growth factor receptor 2 expression status provides independent prognostic information in patients with urothelial carcinoma of the urinary bladder

OBJECTIVE

To test whether the expression of human epidermal growth factor receptor 2 (HER‐2) is of prognostic value in a contemporary cohort of patients with urothelial carcinoma of the urinary bladder (UCB).

PATIENTS AND METHODS

Tissue microarrays of 198 patients were constructed and immunohistochemical stainings were performed on the primary tumours and on lymphatic nodal metastases. All patients were treated with radical cystectomy (RC) and regional lymphadenectomy for UCB. HER‐2 expression was assessed using continuous HER‐2 expression scores (ranging from 0.1 to 3.9) generated using an automated cellular imaging system. Scores of ≥1.0 in at least 10% of tumour cells were regarded as HER‐2 positive. We correlated HER‐2 scores with pathological and clinical variables, including disease recurrence and cancer‐specific mortality.

RESULTS

Of 198 patients undergoing RC with lymphadenectomy, there was HER‐2 positivity in 55 primary tumours (27.8%) compared with 44.2% of the evaluable positive lymph nodes (P < 0.001). HER‐2 positivity was significantly associated with the presence of lymphovascular invasion (LVI; P= 0.026). With a median (range) follow‐up of 35.4 (1.3–176.1) months, 101 patients (51.0%) had UCB recurrence and 82 patients (41.4%) died from the disease. In multivariable analyses that adjusted for the effects of pathological tumour stage, grade, LVI, lymph node metastasis and adjuvant chemotherapy, HER‐2 positive patients were at increased risk for both UCB recurrence (hazard ratio [HR] 1.955, P= 0.003) and UCB‐specific mortality (HR 2.066, P= 0.004) compared with patients with negative HER‐2 expression.

CONCLUSION

A positive HER‐2 status is associated with aggressive UCB and provides independent prognostic information for UCB recurrence and mortality. Assessment of HER‐2 status can be used to identify patients at high risk of disease progression who may benefit from adjuvant HER‐2‐targeted mono‐ or combined therapy after RC.     

International validation of the prognostic value of lymphovascular invasion in patients treated with radical cystectomy

Study Type – Prognosis (retrospective cohort)
Level of Evidence 2b

OBJECTIVE

To externally validate the prognostic value of lymphovascular invasion (LVI) in a large international cohort of patients treated with radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB).

PATIENTS AND METHODS

We collected data from 4257 patients treated with RC and pelvic lymphadenectomy for UCB, without neoadjuvant chemotherapy, at 12 centres. LVI was defined as presence of nests of tumour cells within an endothelium‐lined space.

RESULTS

LVI was detected in 1407 patients (33.1%); the proportion of LVI increased with advancing stage, higher grade, soft‐tissue surgical margin involvement, and lymph node metastasis (P < 0.001 for all). In standard multivariate models, LVI was associated with both disease recurrence (hazard ratio 1.43, P < 0.001) and cancer‐specific mortality (1.45, P < 0.001). In the entire cohort, adding LVI to a base model that included standard features improved only minimally its predictive accuracy for both recurrence and cancer‐specific mortality (by 1.1% and 1.2%, respectively). In 3122 patients with negative lymph nodes, LVI remained independently associated with and improved the predictive accuracy of the standard predictors for recurrence (hazard ratio 1.68, P < 0.001; +2.3%) and cancer‐specific mortality (1.70, P < 0.001; +2.4%). By contrast, in 1071 node‐positive patients, LVI only marginally improved the prediction of cancer‐specific recurrence (hazard ratio 1.20, P < 0.001; +0.2%) and survival (1.23, P < 0.001; +0.5%).

CONCLUSIONS

LVI is strongly associated with clinical outcome in node‐negative patients treated with RC. The assessment of LVI might help to identify patients who could benefit from adjuvant therapy after RC. After confirmation in different populations, LVI should be included in the staging of UCB.     

Prognostic significance of microscopic bladder neck invasion in prostate cancer

OBJECTIVE

To assess the prognostic significance of microscopic bladder neck invasion (BNI+) after radical prostatectomy (RP).

PATIENTS AND METHODS

From January 1988 to December 2006, 1480 patients with clinically localized prostate cancer were surgically treated at one tertiary university hospital. The risk of biochemical progression, defined as a prostate‐specific antigen (PSA) level after RP of >0.2 ng/mL, was assessed with univariate and multivariate analyses for clinical and pathological variables. We compared the biochemical progression‐free survival (bPFS) of patients with BNI+ vs stages pT2, pT3a, pT3b and positive lymph nodes (N+). In a second analysis, we evaluated the bPFS of patients in different stages associated with BNI+ and compared them with those in the same stages with no BNI.

RESULTS

BNI+ was found in 132 (9%) patients; the 5‐year bPFS was 86%, 54%, 26% and 10% for stages pT2, pT3a, pT3b and N+, respectively, while it was 30% for BNI+ (P < 0.001). There was no difference in the 5‐year bPFS between stage pT2 and pT2 + BNI (P = 0.32). Stages pT3a and pT3b had a better 5‐year bPFS than stage pT3a + BNI (P = 0.003) and pT3b + BNI (P = 0.001), respectively. In the univariate analysis all variables were associated with BP. In the multivariate analysis, only BNI+ had no association with BP (odds ratio 1.14, 95% confidence interval 0.70–1.85; P = 0.59).

CONCLUSIONS

Microscopic BNI+ in prostate cancer is not an independent risk factor for biochemical progression and should be regarded as a factor that worsens the prognosis of the underlying tumour stage. A longer follow‐up is necessary to confirm these findings.     

Outcome after radical cystectomy in patients with clinical T2 bladder cancer in whom neoadjuvant chemotherapy has failed

OBJECTIVE

To analyse the outcome after radical cystectomy (RC) in patients with clinical T2 bladder cancer not responding to neoadjuvant chemotherapy (NAC).

PATIENTS AND METHODS

In a retrospective analysis, study patients received NAC for clinical T2 disease before RC and a control group had RC for clinical T2 disease with no NAC. Patients treated with NAC were further grouped based on the pathological response; failure to respond was defined as ‘no change in T stage or a higher T stage in the RC specimen (≥pT2)’, and the relevant clinical and pathological data were analysed.

RESULTS

In all, 53 patients satisfied the inclusion criteria for the study group and 200 for the control group. In the study group 18 (34%) responded to NAC (group 1) of whom 11 (61%) were pT0 and seven (39%) pT1, and among the non‐responders (group 2) 19 (54%) were pT3/pT4 and 16 (46%) were pT2; 16 (46%) patients in group 2 had lymph node metastasis. The mean follow‐up was 26 months. In group 2, local recurrence occurred in six (17%) vs none in group 1. Seven patients (20%) in group 2 developed metastases, vs one (5%) in group 1 (P = 0.01). The 5‐year disease‐free survival was significantly lower for group 2 (40%) than group 1 (91%, P = 0.007) and the control group (67%, P = 0.04). There were 14 deaths from bladder cancer in group 2, vs one in group I (P = 0.01). The 5‐year disease‐specific survival was significantly lower for group 2 (52%) than group 1 (83%, P = 0.008) and the control group (70%, P = 0.001).

CONCLUSION

A lack of response to NAC is associated with a significantly higher local and distant recurrence, and with lower survival.     

Long-term outcome in patients with a Gleason score ≤ 6 prostate cancer treated by radical prostatectomy

Study Type – Therapy (individual cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Gleason score is an important clinical characteristic for treatment decisions in patients with prostate cancer. Gleason score ≤6 are generally considered low‐risk tumours with favourable clinical outcome. In this study we report long‐term data on the actual recurrence risk and survival in patients with Gleason score ≤6 tumours. We were able to demonstrate that while recurrence rates are relatively low, 18% of patients experience PSA recurrence, and 6% experience overt clinical metastases at 15‐year follow‐up.

OBJECTIVE

? To determine the actual recurrence risk of patients with a Gleason score (GS) ≤6 treated with radical retropubic prostatectomy (RRP) and bilateral lymphadenectomy in a cohort with long‐term follow‐up.

PATIENTS AND METHODS

? The USC/Norris Comprehensive Cancer Center database included 3235 consecutive patients who underwent RRP for prostate cancer between January 1972 and December 2005. We identified 1383 patients with a GS ≤ 6 in prostatectomy specimens. Median follow‐up was 8.3 years. Data on pathological and clinical characteristics and outcome were prospectively recorded. ? Statistical analysis was performed using the stratified log‐rank test and stepwise Cox regression analysis.

RESULTS

? A GS of 6 was present in 66%, 5 in 27%, 4 in 5% and 3 or 2 in 3% of cases. Tumour classification was pT2N0 (83%), pT3N0 (14%), pT4N0 (0.1%) and any TN1 (2%). ? Positive margins were seen in 18%. Estimated PSA and clinical recurrence rate were 14% and 4% after 10 years and 18% and 6% after 15 years, respectively. In multivariate analysis, N‐stage (P < 0.001), T‐stage (P= 0.02) and margin status (P < 0.001) were associated with PSA recurrence. ? N‐stage (P < 0.001) and T‐stage (P= 0.01) were associated with clinical recurrence. ? Overall, patients with a GS ≤ 6 accounted for 26% of all PSA recurrences and for 20% of all patients with clinical recurrences in the database.

CONCLUSION

? A relatively small proportion of patients with a GS ≤ 6 cancer developed PSA recurrence and/or overt metastasis. However, these patients account for a substantial minority of those who experienced recurrence and metastasis.     

Surveillance guidelines based on recurrence patterns after radical cystectomy for bladder cancer: the Canadian Bladder Cancer Network experience

Study Type – Prognosis (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Radical cystectomy with pelvic lymph node dissection is recognized as the standard of care for carcinoma invading bladder muscle and for refractory non‐muscle‐invasive bladder cancer. Owing to high recurrence and progression rates, a two‐pronged strict surveillance regimen, consisting of both functional and oncological follow‐up, has been advocated. It is also well recognized that more aggressive tumours with extravesical disease and node‐positive disease recur more frequently and have worse outcomes. This study adds to the scant body of literature available regarding surveillance strategies after radical cystectomy for bladder cancer. In the absence of any solid evidence supporting the role of strict surveillance regimens, this extensive examination of recurrence patterns in a large multi‐institutional project lends further support to the continued use of risk‐stratified follow‐up and emphasizes the need for earlier strict surveillance in patients with extravesical and node‐positive disease.

OBJECTIVES

• ? To review our data on recurrence patterns after radical cystectomy (RC) for bladder cancer (BC).
• ? To establish appropriate surveillance protocols.

PATIENTS AND METHODS

• ? We collected and pooled data from a database of 2287 patients who had undergone RC for BC between 1998 and 2008 in eight different Canadian academic centres.
• ? Of the 2287 patients, 1890 had complete recurrence information and form the basis of the present study.

RESULTS

• ? A total of 825 patients (43.6%) developed recurrence.
• ? According to location, 48.6% of recurrent tumours were distant, 25.2% pelvic, 14.5% retroperitoneal and 11.8% to multiple regions such as pelvic and retroperitoneal or pelvic and distant.
• ? The median (range) time to recurrence for the entire population was 10.1 (1–192) months with 90 and 97% of all recurrences within 2 and 5 years of RC, respectively.
• ? According to stage, pTxN+ tumours were more likely to recur than ≥pT3N0 tumours and ≤pT2N0 tumours (5‐yr RFS 25% vs. 44% vs. 66% respectively, P < 0.001). Similarly, pTxN+ tumours had a shorter median time to recurrence (9 months, range 1–72 months) than ≥pT3N0 tumours (10 months, range 1–70 months) or ≤pT2N0 tumours (14 months, range 1–192 months, P < 0.001).

CONCLUSIONS

• ? Differences in recurrence patterns after RC suggest the need for varied follow‐up protocols for each group.
• ? We propose a stage‐based protocol for surveillance of patients with BC treated with RC that captures most recurrences while limiting over‐investigation.

     

Macroscopic, but not microscopic, perivesical fat invasion at radical cystectomy is an adverse predictor of recurrence and survival

OBJECTIVE

To examine whether the presence of microscopic (pT3a) or macroscopic (pT3b) disease worsens the prognosis relative to pT2 disease at radical cystectomy, as the prognostic significance of pT3a vs pT3b perivesical fat invasion (pT3) is controversial.

PATIENTS AND METHODS

In all, 242 patients with pT3 disease (pT3a in 88, pT3b in 121) had radical cystectomy and bilateral pelvic lymphadenectomy for transitional cell carcinoma of the urinary bladder; they were compared with 172 who had organ‐confined muscle‐invasive disease (pT2). For the analyses we used univariable and multivariable Cox regression models of recurrence and cancer‐specific survival, adjusted for age, tumour grade, lymphovascular invasion and the presence of lymph node metastases.

RESULTS

In multivariable analyses, microscopic perivesical fat extension (pT3a) was not associated with higher recurrence (P = 0.3) or the mortality rate (P = 0.06) vs pT2 disease. Conversely, the presence of deep perivesical fat extension (pT3b) was associated with 1.8 times the rate of recurrence (P = 0.002) and with twice the rate of death (P = 0.001) vs pT2 disease.

CONCLUSION

These findings imply that a detailed assessment of the cystectomy specimen for the presence of microscopic perivesical fat invasion might not be necessary, as the presence of pT3a disease has no strong effect on recurrence or mortality. Moreover, patients with pT3a disease might not require more aggressive therapy than their counterparts with pT2 disease. However, further validation of our data is required.     

Association of tumor-associated trypsin inhibitor (TATI) expression with molecular markers, pathologic features and clinical outcomes of urothelial carcinoma of the urinary bladder

Purposes

To describe the differential tissue expression of tumor-associated trypsin inhibitor (TATI) in normal bladder urothelium, primary urothelial carcinoma of the bladder (UCB) and metastatic UCB and to assess the association of TATI expression with molecular markers commonly altered in UCB and clinical outcomes after radical cystectomy.

Methods

Slides from eight cystectomy patients without cancer, 191 radical cystectomy patients, 20 lymph nodes without metastasis and 40 lymph nodes with UCB were stained. Tissue expression of TATI, cyclin E1, cyclin D1, p53, p21, p27, pRB, Ki-67, Bcl-2, Caspase-3, Survivin and Cyclooxigenase-2 was measured in a tissue microarray. Cancer-specific and recurrence-free survival after radical cystectomy was recorded.

Results

TATI was expressed in 100% of patients without cancer, while 71% of radical cystectomy specimens and 90% of lymph node metastases exhibited decreased or no TATI expression. In radical cystectomy specimens, TATI expression decreased with advancing pathologic stage (P?P?=?0.055). In univariate analyses, but not in multivariable Cox proportional hazard regression analyses, decreased TATI expression was associated with increased probability of tumor recurrence and cancer-specific mortality. Decreased TATI expression was correlated with altered expression of Cyclooxigenase-2 (P?=?0.005), p21 (P?=?0.035) and Ki-67 (P?=?0.004).

Conclusions

We found that normal urothelium expresses TATI and that TATI expression decreases with advancing tumor stage. While there was no prognostic benefit to TATI when adjusted for standard clinicopathologic features, it seems to play an important biologic role in UCB pathogenesis and invasion. Its association with markers involved in the cell cycle, proliferation and inflammation serves as hypothesis for molecular interactions.     

Prognostic significance of lymphovascular invasion in radical prostatectomy specimens

Study Type – Prognosis (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? The reported incidence of lymphovascular invasion (LVI) in radical prostatectomy specimens ranges from 5% to 53%. Although LVI has a strong and significant association with adverse clinicopathologic features, it has almost uniformly not been found to be a predictor of biochemical recurrence (BR) on multivariate analysis. This study confirms that LVI is associated with features of aggressive disease and is an independent predictor of BCR. Given that LVI may play a role in the metastatic process, it may be useful in clinical decision‐making regarding adjuvant therapy for patients treated with RP.

OBJECTIVES

To determine whether lymphovascular invasion (LVI) in radical prostatectomy (RP) specimens has prognostic significance. The study examined whether LVI is associated with clinicopathological characteristics and biochemical recurrence (BCR).

PATIENTS AND METHODS

LVI was evaluated based on routine pathology reports on 1298 patients treated with RP for clinically localized prostate cancer between 2004 and 2007. LVI was defined as the unequivocal presence of tumour cells within an endothelium‐lined space. The association between LVI and clinicopathological features was assessed with univariate logistic regression. Cox regression was used to test the association between LVI and BCR.

RESULTS

LVI was identified in 10% (129/1298) of patients. The presence of LVI increased with advancing pathological stage: 2% (20/820) in pT2N0 patients, 16% (58/363) in pT3N0 patients and 17% (2/12) in pT4N0 patients; and was highest in patients with pN1 disease (52%; 49/94). Univariate analysis showed an association between LVI and higher preoperative prostate‐specific antigen levels and Gleason scores, and a greater likelihood of extraprostatic extension, seminal vesicle invasion, lymph node metastasis and positive surgical margins (all P < 0.001). With a median follow‐up of 27 months, LVI was significantly associated with an increased risk of BCR after RP on univariate (P < 0.001) and multivariate analysis (hazard ratio, 1.77; 95% confidence interval, 1.11–2.82; P= 0.017). As a result of the relatively short follow‐up, the predictive accuracy of the standard clinicopathological features was high (concordance index, 0.880), and inclusion of LVI only marginally improved the predictive accuracy (0.884).

CONCLUSIONS

Although associated with features of aggressive disease and BCR, LVI added minimally to established predictors on short follow‐up. Further study of cohorts with longer follow‐up is warranted to help determine its prognostic significance.     

Oncological control after radical prostatectomy in men with clinical T3 prostate cancer: a single‐centre experience

OBJECTIVE

To determine the effectiveness of cancer control afforded by radical prostatectomy (RP) in patients with clinical stage T3 prostate cancer.

PATIENTS AND METHODS

We retrospectively reviewed data for patients treated by RP for clinical stage T3 prostate cancer between 1995 and 2005. The following case characteristics were analysed: patient age, clinical presentation, preoperative prostate‐specific antigen (PSA) level, Gleason score, tumour stage (2002 Tumour‐Node‐Metastasis), surgical procedure, pathological data, margin and lymph node status, and recurrence. Biochemical recurrence was defined as an increase in PSA level of >0.2 ng/mL after surgery. Kaplan‐Meier survival curves were generated, and prognostic factors were evaluated.

RESULTS

Overall, 100 patients were included; only 79% of them had pT3 disease based on the pathological specimen. The median follow‐up after RP was 69 months. The RP was open in 77 and laparoscopic in 23, with no significant difference between these approaches (P = 0.38). The 5‐year PSA‐free survival after surgery was 45%, and 5‐year cancer‐specific survival was 90%. On univariable analysis, Gleason score >7 (P = 0.01), pathological stage (pT2‐T3a vs T3b) (P < 0.001), positive lymph node (P < 0.001), and positive margin (P < 0.001) were associated with recurrence. On multivariable analysis, lymph node, margin status and Gleason score were also significant (P < 0.05).

CONCLUSIONS

RP can be recommended as an alternative primary treatment that results in acceptable cancer control for clinical stage T3 prostate cancer in selected cases. However, the patient should be warned that surgery alone might not be sufficient to control the cancer, and that adjuvant therapy might be needed during the course of the disease.     

Stage-specific impact of pelvic lymph node dissection on survival in patients with non-metastatic bladder cancer treated with radical cystectomy

Study Type – Therapy (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? In patients treated with radical cystectomy, pelvic lymph node dissection may have a beneficial effect on cancer control outcomes. We examined the effect of pelvic lymph node dissection on stage‐specific cancer control outcomes.

OBJECTIVE

• ? To examine the effect of stage‐specific pelvic lymph node dissection (PLND) on cancer‐specific (CSM) and overall mortality (OM) rates at radical cystectomy (RC) for bladder cancer.

METHODS

• ? Overall, 11 183 patients were treated with RC within the Surveillance, Epidemiology, and End Results database.
• ? Univariable and multivariable Cox regression analyses tested the effect of PLND on CSM and OM rates, after stratifying according to pathological tumour stage.

RESULTS

• ? Overall, PLND was omitted in 25% of patients, and in 50, 35, 27, 16 and 23% of patients with respectively pTa/is, pT1, pT2, pT3 and pT4 disease (P < 0.001).
• ? For the same stages, the 10‐year CSM‐free rates for patients undergoing PLND compared with those with no PLND were, respectively, 80 vs 71.9% (P = 0.02), 81.7 vs 70.0% (P < 0.001), 71.5 vs 56.1% (P = 0.001), 43.7 vs 38.8% (P = 0.006), and 35.1 vs 32.0% (P = 0.1).
• ? In multivariable analyses, PLND omission was associated with a higher CSM in patients with pTa/is, pT1 and pT2 disease (all P ≤ 0.01), but failed to achieve independent predictor status in patients with pT3 and pT4 disease (both P ≥ 0.05).
• ? Omitting PLND predisposed to a higher OM across all tumour stages (all P ≤ 0.03).

CONCLUSIONS

• ? Our results indicate that PLND was more frequently omitted in patients with organ‐confined disease.
• ? The beneficial effect of PLND on cancer control outcomes was more evident in these patients than in those with pT3 or pT4 disease.
• ? PLND at RC should always be considered, regardless of tumour stage.

     

Clinical significance of lymphovascular invasion in upper urinary tract urothelial cancer

OBJECTIVES

To clarify the significance of lymphovascular invasion (LVI) in patients with pT3N0M0 upper urinary tract (UUT) urothelial carcinoma (UC) relative to prognosis in terms of disease‐specific survival, as LVI, which implies both blood vessel and lymph vessel involvement, is reportedly a poor prognostic factor in patients with UUT‐UC.

PATIENTS AND METHODS

The clinical records of 90 patients who had surgery for UUT‐UC were reviewed retrospectively. The median patient age was 71 years and the median follow‐up was 42 months. The prognostic significances of LVI (with vs without), T stage (<1 vs 2–4), grade (1–2 vs 3), N stage (0 vs 1–2), age (≤70 vs >70 years), gender and tumour location (renal pelvis vs ureter) for survival time were evaluated.

RESULTS

LVI of UUT‐UC was found in 34 patients (37.8%). There were significantly higher frequencies of LVI with advancing stage and lymph node metastasis. Kaplan‐Meier analysis showed that LVI was strongly associated with disease‐specific survival in all patients (P < 0.001) and in patients with pT3N0M0 disease (P < 0.001). Univariate analyses showed that LVI, T stage, N stage and tumour grade were significantly related to disease‐specific survival in all patients (P < 0.001, <0.001, 0.003 and 0.007, respectively). Multivariate analysis using Cox proportional hazards model showed that LVI was the only prognostic factor with independent significance for disease‐specific survival (P < 0.001).

CONCLUSIONS

LVI appears to be an important and independent prognostic factor for UUT‐UC in patients treated by nephroureterectomy. Our data suggest that the LVI status might be a predictive marker for disease‐specific survival in patients with T3N0M0 UTT‐UC.     

Upper urinary tract urothelial carcinoma with loco-regional nodal metastases: insights from the Upper Tract Urothelial Carcinoma Collaboration

Study Type – Therapy (multi‐insititutional cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Neoadjuvant chemotherapy offers survival benefits for patients with urothelial carcinoma of the bladder. However, it is still underutilized in the ‘biologically similar’ upper tract urothelial carcinoma. Systemic chemotherapy in a neoadjuvant setting is a more attractive option, as loss of renal function after nephrectomy can complicate the administration of adjuvant chemotherapy. We found that preoperative systemic therapy followed by aggressive surgical debulking is a promising treatment strategy for upper tract urothelial carcinoma patients with known or at risk of loco‐regional nodal metastasis.

OBJECTIVE

? To describe a multicentre experience with preoperative platinum‐based chemotherapy before radical nephroureterectomy (RNU) in patients with upper tract urothelial carcinoma (UTUC) with loco‐regional nodal metastases.

PATIENTS AND METHODS

? We identified 313 patients from the UTUC Collaboration (over 1200 patients), who underwent RNU with concomitant retroperitoneal lymph node dissection between 1990 and 2007 and met the inclusion criteria for one of three groups. ? Group 1 comprised patients who received chemotherapy before RNU because of biopsy‐proven loco‐regional nodal metastases. ? Group 2 consisted of patients who underwent primary RNU and were found to have metastatic nodal disease on final pathological review (node‐positive). ? Group 3 comprised a comparative cohort of patients treated with primary RNU for invasive or locally advanced (pT2/pT4) node‐negative (N0) UTUC.

RESULTS

? Groups 1, 2 and 3 included 18, 120 and 175 patients, respectively. The 5‐year disease‐free survival rates were 49%, 30% and 64%, whereas the 5‐year cancer‐specific survival rates were 44%, 36% and 69% in groups 1, 2 and 3, respectively. ? In group 1, on final pathological evaluation, nine patients were pN0, six patients were pT0 and five patients had pT0N0 disease. Kaplan–Meier survival analyses showed similar recurrence and survival rates in group 1 compared with group 3 (P= 0.14 and P= 0.06, respectively). ? Meanwhile, group 2 had significantly lower disease‐free and cancer‐specific survival rates compared with group 3 (P < 0.001 and P < 0.001, respectively) and compared with group 1 (P= 0.04 and P= 0.06, respectively).

CONCLUSIONS

? Preoperative chemotherapy followed by aggressive surgical consolidation may yield favourable oncological outcomes in patients with UTUC with loco‐regional nodal metastases. ? These data support further evaluation of neoadjuvant systemic therapy in patients at risk for locally advanced UTUC.     

International validation of the prognostic value of subclassification for AJCC stage pT3 upper tract urothelial carcinoma of the renal pelvis

Study Type – Prognosis (inception cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Tumour stage is a powerful predictor of clinical outcomes and the most important factor driving clinical decision‐making after radical nephroureterectomy (RNU) in upper tract urothelial carcinoma (UTUC). It has been suggested that renal pelvic pT3 subclassification into microscopic infiltration of the renal parenchyma (pT3a) versus macroscopic infiltration or invasion of peripelvic adipose tissue (pT3b) has strong prognostic value. This is an external validation study of the prognostic value of pT3 subclassification of renal pelvic UTUC in a large international cohort of patients treated with RNU. pT3b UTUC is associated with features of aggressive tumour biology, disease recurrence and cancer‐specific mortality. However, pT3 subclassification is not an independent predictor of clinical outcomes.

OBJECTIVE

• ? To externally validate the prognostic value of subclassification of pT3 renal pelvic upper tract urothelial carcinoma (UTUC) in a large international cohort of patients treated with radical nephroureterectomy (RNU).

PATIENTS AND METHODS

• ? The RNU specimens with pT3 UTUC of the renal pelvis from 284 patients at 11 centres located in Asia, North America and Europe were retrospectively evaluated. All specimens were reviewed by genitourinary pathologists at each institution. Tumours were categorized as pT3a (microscopic infiltration of the renal parenchyma) or pT3b (macroscopic infiltration of the renal parenchyma and/or infiltration of peripelvic adipose tissue).

RESULTS

• ? Overall, 148 (52%) tumours were classified as pT3a and 136 (48%) as pT3b. Patients with pT3b disease were more likely to have high‐grade tumours and sessile tumour architecture (all P≤ 0.02). Patients with pT3b tumours were at increased risk of disease recurrence (5‐year estimates: 55% versus 42%, P= 0.012) and cancer‐specific mortality (CSM) (5‐year estimates: 48% versus 40%, P= 0.04). Lymph node status, tumour architecture and tumour grade were independently associated with disease recurrence, whereas lymph node status, tumour architecture and lymphovascular invasion were independently associated with CSM. Subclassification of pT3 tumours was not associated with recurrence or CSM in multivariable analyses.

CONCLUSION

• ? Patients with pT3b UTUC were more likely to have tumours with aggressive pathological features and were at higher risk of disease recurrence and CSM after RNU compared with patients with pT3a disease. However, the pT3 subclassification did not remain an independent predictor of disease recurrence or CSM after controlling for tumour grade, lymph node status, tumour architecture and lymphovascular invasion.

     

Prospective Evaluation of a Molecular Marker Panel for Prediction of Recurrence and Cancer-specific Survival After Radical Cystectomy

Background

Retrospective studies demonstrated that cell cycle–related and proliferation biomarkers add information to standard pathologic tumor features after radical cystectomy (RC). There are no prospective studies validating the clinical utility of markers in bladder cancer.

Objective

To prospectively determine whether a panel of biomarkers could identify patients with urothelial carcinoma of the bladder (UCB) who were likely to experience disease recurrence or mortality.

Design, setting, and participants

Between January 2007 and January 2012, every patient with high-grade bladder cancer, including 216 patients treated with RC and lymphadenectomy, underwent immunohistochemical staining for tumor protein p53 (Tp53); cyclin-dependent kinase inhibitor 1A (p21, Cip1) (CDKN1A); cyclin-dependent kinase inhibitor 1B (p27, Kip1); antigen identified by monoclonal antibody Ki-67 (MKI67); and cyclin E1.

Intervention

Every patient underwent RC and lymphadenectomy, and marker staining.

Outcome measurements and statistical analysis

Cox regression analyses tested the ability of the number of altered biomarkers to predict recurrence or cancer-specific mortality (CSM).

Results and limitations

Pathologic stage among the study population was pT0 (5%), pT1 (35%), pT2 (19%), pT3 (29%), and pT4 (13%); lymphovascular invasion (LVI) was seen in 34%. The median number of removed lymph nodes was 23, and 60 patients had lymph node involvement (LNI). Median follow-up was 20 mo. Expression of p53, p21, p27, cyclin E1, and Ki-67 were altered in 54%, 26%, 46%, 15%, and 75% patients, respectively. In univariable analyses, pT stage, LNI, LVI, perioperative chemotherapy (CTx), margin status, and number of altered biomarkers predicted disease recurrence. In a multivariable model adjusting for pathologic stage, margins, LNI, and adjuvant CTx, only LVI and number of altered biomarkers were independent predictors of recurrence and CSM. The concordance index of a baseline model predicting CSM (including pathologic stage, margins, LVI, LNI, and adjuvant CTx) was 80% and improved to 83% with addition of the number of altered markers.

Conclusions

Molecular markers improve the prediction of recurrence and CSM after RC. They may identify patients who might benefit from additional treatments and closer surveillance after cystectomy.     

Lymphovascular invasion is an independent predictor of oncological outcomes in patients with lymph node‐negative urothelial bladder cancer treated by radical cystectomy: a multicentre validation trial

Study Type – Prognosis (inception cohort)
Level of Evidence 1b

OBJECTIVES

To validate the association of lymphovascular invasion (LVI) with disease recurrence and cancer‐specific survival (CSS) in a multicentre cohort of patients treated with radical cystectomy (RC) for urothelial bladder cancer (UBC).

PATIENTS AND METHODS

We collected pathological and clinical data on 1099 lymph node‐negative patients treated with RC at six German institutions. LVI was defined as the presence of tumour cells within an unequivocal endothelium‐lined space in haematoxylin and eosin‐stained sections.

RESULTS

LVI was present in 295 (26.8%) patients; the presence of LVI correlated significantly with increasing tumour stage, i.e. pT1, 65 (29.4%); pT2, 88 (31.5%); pT3 110 (31.8%); and pT4 32 (38.1%) (P= 0.002) and grade (P < 0.001). In univariable analysis the presence of LVI was significantly associated with reduced recurrence‐free survival (P= 0.008) and reduced CSS (P= 0.039). On multivariable Cox regression analysis tumour stage (P < 0.001), age (>75 vs ≥75 years; P= 0.018) and LVI (P < 0.001) were identified as independent predictors of CSS.

CONCLUSIONS

Our large multicentre study confirms the independent prognostic value of LVI in patients with node‐negative UBC. LVI can be regarded as a surrogate variable for lymphatic micrometastasis in node‐negative UBC. Assessment of LVI might improve the selection of patients who are likely to benefit from adjuvant therapy after RC. The identification of factors involved in the process of LVI could reveal new therapeutic targets for UBC.     

Contemporary outcomes of 2287 patients with bladder cancer who were treated with radical cystectomy: a Canadian multicentre experience

Study Type – Therapy (case series) Level of Evidence 4

OBJECTIVE

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.

MATERIALS AND METHODS

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.

RESULTS

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 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.

CONCLUSIONS

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.     

Impact of several histopathological prognosticators and local tumour extension on oncological outcome in pT3b/c N0M0 renal cell carcinoma

OBJECTIVE

To investigate the prognostic relevance of different histopathological features and local tumour extension in patients with pT3b/c N0M0 renal cell carcinoma (RCC), as recently new proposals of reclassifying tumour fat invasion in pT3b/c RCC have been made but the effect of other histopathological tumour characteristics and combinations thereof with tumour invasion has yet to be determined in these patients.

PATIENTS AND METHODS

Between 1990 and 2006, 1943 patients underwent surgical treatment for renal tumours in our institution, of which 175 patients (8.7%) had pT3b/c RCC. After exclusion of 57 patients (32.6%) with lymph node and/or distant metastases at the time of diagnosis, 118 (67.4%) remained for retrospective analysis. Different histopathological features and local tumour extension were studied for their association with cancer‐specific‐survival (CSS) and progression‐free‐survival (PFS) by univariate and multivariate analyses. Histopathology was reviewed and revised according to the 2002 Tumour‐Nodes‐Metastasis (TNM) classification system by one pathologist (S.B.). CSS and PFS were estimated by the Kaplan–Meier method.

RESULTS

Follow‐up data were obtained from 110 patients at a median (range) of 3.2 (0.3–16.1) years. In univariate analysis, microvascular invasion (MVI) and capsular invasion increased the risk of tumour progression by 2.05‐ and 2.72‐times (P = 0.037 and P < 0.001). Overall, tumour fat invasion (TFI) and the presence of areas composed by cells with eosinophilic cytoplasm were associated with a higher risk of progression (P = 0.001 and P = 0.011) and reduced CSS (P = 0.037 and P = 0.017). In multivariate analysis, MVI and capsular invasion were associated with a two‐fold increased risk of dying from cancer (hazard risk ratio, HR 2.22, P = 0.045 and HR 2.31, P = 0.011). TFI in general (P = 0.004) and specifically coexistent perirenal fat invasion (PFI) and renal sinus fat invasion (RSFI) were associated with a three‐fold increased risk of developing tumour progression (HR 3.36, P = 0.001). The 10‐year CSS and PFS rates were 39% and 36% for all patients, 47% and 45% for pT3b/c RCC with no PFI or RSFI, and 25% and 10% for PFI + RSFI.

CONCLUSION

Patients with pT3b/c RCC with MVI, capsular invasion, TFI and especially PFI + RSFI, have a markedly reduced prognosis compared with patients with pT3b/c RCC without these features. When these results are corroborated by additional studies and external validation, modification of the TNM classification system would be a sensible consequence.