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.     

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.     

p53 expression in patients with advanced urothelial cancer of the urinary bladder

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

OBJECTIVE

To test whether assessing p53 expression could improve the ability to predict disease recurrence and disease‐specific survival in a multi‐institutional cohort of patients with advanced urothelial carcinoma of the urinary bladder (UCB).

PATIENTS AND METHODS

The study comprised 692 patients with pT3–4 N0 or pTany N+ UCB treated with radical cystectomy and lymphadenectomy. The predictive accuracy (PA) was quantified using the 200 bootstrap‐corrected concordance index. The base model comprised age, gender, stage, grade, lymphovascular invasion, number of lymph nodes removed, number of lymph nodes positive, concomitant carcinoma in situ, and adjuvant chemotherapy.

RESULTS

p53 expression was altered in 341 (49.3%) patients. In multivariable analyses, p53 expression was independently associated with disease recurrence (hazard ratio, 1.66; P < 0.001) and cancer‐specific mortality (hazard ratio 1.65, P < 0.001). Overall, adding p53 did not significantly improve the PA of the base model (recurrence +0.7%, P = 0.085, and cancer‐specific mortality +1.2%, P = 0.050). In the subgroups of pT3N0 (280) and pT4N0 (83) patients, p53 slightly improved the PA of the base model by a statistically significant degree (recurrence +1.7% and +3.6%, respectively; cancer‐specific mortality +1.9% and +3.5%, respectively; all P < 0.001). In 329 patients with pTany N+ disease p53 status did not improve the PA of the base model.

CONCLUSION

While assessing p53 expression has limited utility in patients with lymph node‐positive UCB, it marginally improves prognostication in patients with advanced non‐metastatic UCB. Integration of p53 into a panel of biomarkers might be necessary to capture a more accurate picture of the biological potential of advanced UCB.     

The significance of lymphovascular invasion in transurethral resection of bladder tumour and cystectomy specimens on the survival of patients with urothelial bladder cancer

OBJECTIVE

To test the hypothesis that patients with bladder cancer who had evidence of lymphovascular invasion (LVI) in their transurethral resection of bladder tumour (TURBT) and radical cystectomy (RC) specimens would have a worse prognosis and higher likelihood of clinical understaging, and to assess the effect of LVI discovered at RC on subsequent disease‐related mortality, as the prognostic significance of LVI in TURBT or RC specimens of patients treated for urothelial carcinoma of the bladder is not completely established.

PATIENTS AND METHODS

We retrospectively reviewed the records of 163 patients with urothelial carcinoma of the bladder seen at our institution, and who had TURBT (69) or RC (94) between 1995 and 2005. We compared patients with LVI on TURBT and/or RC specimens to a group of controls who did not have LVI on TURBT (34) or RC (32).

RESULTS

Patients with LVI present in their TURBT specimen had a shorter disease‐specific survival than those without LVI, with a 5‐year survival of 33.6% vs 62.9% (log‐rank test P = 0.027; hazard ratio 2.21). LVI at TURBT varied with clinical stage (P = 0.049). Patients with LVI and who were clinical stage I or II had lower survival than those without LVI (P = 0.049; hazard ratio 2.68). LVI did not affect survival among those with clinical stage III or IV (P = 0.29). There was a trend for patients with LVI at TURBT to be clinically understaged compared to those without LVI (75% vs 46%) but the difference was not significant (P = 0.086). Patients with LVI detected in their RC specimen were significantly more likely to have cancer recurrence than were those with no evidence of LVI (48% vs 19%, P = 0.006). For the RC group there was also a significant difference in survival distribution between patients with evidence of LVI vs those without (5‐year survival 45.5% vs 78.4%, P = 0.017). Those with LVI were significantly more likely to die from the disease than those without LVI (P = 0.017; hazard ratio 2.92).

CONCLUSIONS

Our findings suggest that LVI is a histological feature that might be associated with a poorer prognosis in patients with urothelial carcinoma of the bladder. The presence of LVI in TURBT specimens predicts shorter survival for patients with stage I or II disease. The presence of LVI in RC specimens predicts recurrence of disease and shorter survival. Further studies are needed to determine whether this group of patients would benefit from early RC and/or perioperative chemotherapy to improve clinical outcomes.     

The presence of lymphovascular invasion in radical cystectomy specimens from patients with urothelial carcinoma portends a poor clinical prognosis

OBJECTIVES

To assess the prognostic significance of lymphovascular invasion (LVI) on clinical outcomes in patients with transitional cell carcinoma of the bladder treated with radical cystectomy (RC).

PATIENTS AND METHODS

We retrospectively evaluated a prospectively maintained and authorised cystectomy database; the presence or absence of LVI was determined by pathological examination of the RC specimen. Cox regression analysis and Kaplan‐Meier tables were developed to evaluate the contribution of LVI to clinical outcomes.

RESULTS

In all, we analysed 356 patients treated with RC and urinary diversion between 1988 and 2006, with a mean follow‐up of 45.6 months. Of these patients, 242 (68%) had no evidence of LVI in the RC specimen, whereas 114 (32%) had LVI. Patients with LVI tended to present with higher pathological stage; 84 (74%) had pT3 or pT4 disease. On univariable analysis the presence of LVI conferred a significant risk for decreased overall, cancer‐specific and recurrence‐free survival (P < 0.001); the mean values for LVI‐negative patients were 96.8, 157.4, and 135.0 months, respectively, vs LVI‐positive patients, whose survival times were 52.3, 82.7 and 75.2 months, respectively. The multivariable analysis showed significant independent risk for cancer‐specific and overall survival for patients who were LVI‐positive and had no lymph‐node metastases. The hazard ratios (95% confidence interval) were 1.63 (1.06–2.51, P < 0.026) and 1.81 (1.06–3.08, P < 0.03) for overall and disease‐specific survival, respectively.

CONCLUSIONS

The presence of LVI in the pathological RC specimen confers significant independent risk for reduced bladder cancer‐specific and overall survival. This variable could be used to prospectively stratify patients who would benefit from adjuvant chemotherapy.     

Multicenter validation of the prognostic value of patient age in patients treated with radical cystectomy

Purpose

Small studies have suggested that older patients have worse outcomes following radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). We evaluated the association of patient age with clinical outcomes in a large multi-institutional RC series.

Methods

Data were collected from 4,429 patients treated with RC and lymphadenectomy for UCB without neoadjuvant chemotherapy. Age at RC was analyzed both as a continuous and categorical variable.

Results

Higher age at RC, analyzed as a continuous or categorical variable, was associated with advanced pathologic stage (P?<?0.001), higher tumor grade (P?=?0.045), presence of lymphovascular invasion (P?=?0.018), and positive soft-tissue surgical margin status (P?=?0.004). Elderly patients were less likely to receive postoperative chemotherapy (P?<?0.001). In multivariable analyses, higher age was associated with disease recurrence, cancer-specific, and overall mortality (P?<?0.001). Patients ??80?years had a significantly greater risk of cancer-specific mortality than patients <50?years (HR 1.763, P?<?0.001). Age minimally improved the accuracy of a base model that included standard pathologic features for prediction of disease recurrence (+0.2?C0.3%) and cancer-specific survival (+0.3%). Conversely, age improved the predictive accuracy for overall survival by a sizeable margin (+4.2?C4.5%).

Conclusions

This large external validation study confirms that advanced patient age is minimally but significantly associated with worse prognosis after RC. Nevertheless, a large proportion of elderly patients benefitted from RC with curative intent. We need to improve our understanding of the reasons for the worse UCB outcomes in this growing segment of the population and to develop strategies to improve cancer care in the elderly.     

Longitudinal evaluation of the concordance and prognostic value of lymphovascular invasion in transurethral resection and radical cystectomy specimens

THIS IS A COMMENT MODERATED PAPER
available at http://www.bjui.org/commentary Study Type – Therapy (case series)
Level of Evidence 4 What’s known on the subject? and What does the study add? Lymphovascular invasion (LVI) is a prognostic marker for biologically aggressive disease in numerous tumour types. Indeed, numerous studies have documented the negative prognostic value of LVI in bladder cancer patients who have undergone radical cystectomy, however few studies have evaluated the prognostic value of LVI at TURBT. The current study examines both the concordance between the presence of LVI at TURBT and radical cystectomy specimens and furthermore examines the survival implications of the presence of LVI at both TURBT and radical cystectomy.

OBJECTIVE

To evaluate the concordance transurethral resection of bladder tumour (TURBT) and radical cystectomy (RC) specimens with regard to the presence of lymphovascular invasion (LVI). Additionally, to evaluate the prognostic value of LVI in the prediction of lymph node metastases, overall survival, disease‐specific survival and recurrence‐free survival following RC.

PATIENTS AND METHODS

The records of 487 patients who underwent RC at our institution between 1987 and 2008 were retrospectively reviewed and evaluated for the presence or absence of LVI as determined by pathological evaluation. The presence or absence of LVI was then evaluated on previous transrectal resection specimens of this cohort of patients undergoing RC. Cox regression and Kaplan–Meier analysis were undertaken to evaluate the contribution of LVI to various outcomes.

RESULTS

Of 474 patients with complete LVI data, 60 (12.3%) were found to have LVI at TURBT compared to 161 (33.1%) at RC. Although the presence of LVI at TURBT was more significantly associated with the presence of LVI at RC, only 42.9% of patients in whom LVI was documented at TURBT were found to harbour LVI at RC. The risk of nodal disease was higher in those patients with LVI at TURBT than in those with no evidence of LVI at TURBT (48.3% vs 25.0%, P < 0.001). Additionally, LVI at TURBT was associated with an increasing risk of pathological upstaging and the receipt of adjuvant chemotherapy. Survival analysis showed a significant decrement in overall and recurrence‐free survival among those with LVI at TURBT compared to those with no evidence of LVI.

CONCLUSIONS

Lymphovascular invasion at TURBT provides useful prognostic information that should be incorporated into clinical decision‐making, particularly with regard to cystectomy for nonmuscle‐invasive carcinoma and the administration of neoadjuvant chemotherapy.     

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.     

Commentary on “Detection and oncological effect of circulating tumor cells in patients with variant urothelial carcinoma histology treated with radical cystectomy.”

Objectives

To investigate for the presence of circulating tumor cells (CTC) in patients with variant urothelial carcinoma of the bladder (UCB) histology treated with radical cystectomy (RC), and to determine their impact on oncological outcomes.

Gender-specific Differences in Clinicopathologic Outcomes Following Radical Cystectomy: An International Multi-institutional Study of More Than 8000 Patients

Background

The impact of gender on the staging and prognosis of urothelial carcinoma of the bladder (UCB) is insufficiently understood.

Objective

To assess gender-specific differences in pathologic factors and survival of UCB patients treated with radical cystectomy (RC).

Design, setting, and participants

Data from 8102 patients treated with RC (6497 men [80%] and 1605 women [20%]) for UCB between 1971 and 2012 were analyzed.

Outcome measurements and statistical analysis

Multivariable competing-risk regression analyses were performed to evaluate the relationship of gender on disease recurrence (DR) and cancer-specific mortality (CSM). We also tested the interaction of gender and tumor stage, nodal status, and lymphovascular invasion (LVI).

Results and limitations

Female patients were older at the time of RC (p = 0.033) and had higher rates of pathologic stage T3/T4 disease (p < 0.001). In univariable, but not in multivariable analysis, female gender was associated with a higher risk of DR (p = 0.022 and p = 0.11, respectively). Female gender was an independent predictor for CSM (p = 0.004). We did not find a significant interaction between gender and stage, nodal metastasis, or LVI (all p values >0.05).

Conclusions

We found female gender to be associated with a higher risk of CSM following RC. However, these findings do not appear to be explained by gender differences in pathologic stage, nodal status, or LVI. This gender disparity may be due to differences in care and/or the biology of UCB.     

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.     

Upstaging of urothelial cancer at the time of radical cystectomy: factors associated with upstaging and its effect on outcome

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The reported discordance between staging on transurethral bladder resection and on radical cystectomy pathology in the literature ranges from 20 to 80%.Correct staging in bladder cancer has direct implications for its management. The upstaging from organ‐confined (OC) to non‐organ‐confined (nOC) disease has been reported in 40% of cases. Lymphovascular invasion (LVI) is a factor known to be associated with poor clinical outcome. Pathological upstaging was observed in our cohort in 40% of cases and most cases (80%) were upstaged from OC to nOC disease. During the study period the frequency of upstaging observed increased. We found LVI (hazard ratio [HR]= 5.07, 95% CI = 3.0–8.3, P < 0.001) and any histological variant variant (HR = 2.77, 95% CI = 1.6–4.8, P < 0.001) to be strong independent predictors of upstaging. Patients with clinical T2 bladder cancer found with upstaging at the time of radical cystectomy had a poorer outcome than patients with no upstaging. Identification of patients at high risk of upstaging at radical cystectomy is key to improving their management and outcome.

OBJECTIVES

• ? To analyse the details of bladder cancer (BC) staging in a large combined radical cystectomy (RC) database from two academic centres.
• ? To study rate and time trends, as well as risk factors for upstaging, especially clinical factors associated with staging errors after RC.

PATIENTS AND METHODS

• ? Characteristics of patients undergoing RC at University Health Network, Toronto, Canada (1992–2010) and University of Turku, Turku, Finland (1986–2005) were analysed.

RESULTS

• ? Among 602 patients undergoing RC, 306 (51%) had a discordance in clinical and pathological stages. Upstaging occurred in 240 (40%) patients and 192 (32%) patients were upstaged from organ‐confined (OC) to non‐organ‐confined (nOC) disease.
• ? During the study period, upstaging became more common in both centres.
• ? In multivariate analyses, T2 disease at initial presentation (P= 0.001, odds ratio [OR]= 2.62, 95% confidence interval [CI]: 1.44–4.77), high grade disease (P= 0.01, OR = 2.85, 95% CI: 1.21–6.7), lymphovascular invasion (LVI) (P < 0.001, OR = 5.17, 95% CI: 3.48–7.68), female gender (P= 0.038, OR = 0.6, 95% CI: 0.38–0.97, and histological variants (P < 0.001, OR = 2.77, 95% CI: 1.6–4.8) were associated with a risk of upstaging from OC to nOC disease.
• ? Upstaged patients had worse survival rates than patients with correct staging. This was especially significant among patients with carcinoma invading bladder muscle before undergoing RC (16% vs 46% 10‐year disease‐specific mortality, P < 0.001).

CONCLUSIONS

• ? Upstaging is a common problem and unfortunately no improvements have been observed during the last two decades.
• ? LVI and the presence of histological variants are strong predictors of upstaging at the time of RC.
• ? Pathologists should be encouraged to report LVI and any histological variant at the time of TURBT.

     

Nephrectomy improves survival in patients with invasion of adjacent viscera and absence of nodal metastases (stage T4N0 renal cell carcinoma)

OBJECTIVE

To examine the cancer‐specific mortality (CSM) of patients with T4N0–2M0 renal cell carcinoma (RCC) treated with either nephrectomy (RN) or no surgery (NS).

PATIENTS AND METHODS

Of 43 143 patients with RCC identified in the Surveillance, Epidemiology and End Results database, 310 had tumours involving adjacent organs with no evidence of distant metastases (T4NanyM0) and had RN (246, 79.4%) or NS (64, 20.6%). Kaplan‐Meier analyses, Cox regression and competing‐risks regression models were used to compare the effect of RN vs NS on CSS.

RESULTS

In patients with T4N0 disease the median survival benefit associated with RN vs NS was 42 months (48 vs 6 months, P < 0.001). Conversely, the median survival in patients T4N1‐2 was no different between RN and NS (9.3 vs 9.1 months, P = 0.9). Multivariable analyses in T4N0 cases indicated a substantial survival disadvantage for patients having NS vs RN (hazard ratio 4.8, P < 0.001). Conversely, in patients with N1‐2 stages, the CSS was virtually the same for NS and RN (hazard ratio 0.9, P = 0.9). Competing‐risks regression models confirmed the benefit of RC in patients with T4N0 and the lack of benefit in those with T4N1‐2 disease, after controlling for other‐cause mortality.

CONCLUSION

Our data suggest a survival benefit in patients with T4N0 RCC treated with RC. By contrast, RN seems to have no effect on survival in patients with evidence of nodal metastases.     

A systematic review and meta-analysis of lymphovascular invasion in patients treated with radical cystectomy for bladder cancer

Purpose

Lymphovascular invasion (LVI) is an important step in bladder cancer cell dissemination. We aimed to perform a systematic review and meta-analysis of the literature to assess the prognostic value of LVI in radical cystectomy (RC) specimens.

Prognostic significance of lymphovascular or perineural invasion in patients with locally advanced colorectal cancer

Background

This study was designed to evaluate the prognostic significance of the positivity of lymphovascular (LVI) and perineural invasion (PNI) in patients with locally advanced colorectal cancer.

Methods

From January 1999 to December 2009, 1,437 consecutive patients who underwent curative surgery for stage II or III colorectal cancer were analyzed. Patients were then categorized into 4 groups: LVI−/PNI− (n = 850), LVI+ only (n = 178), PNI+ only (n = 271), and LVI+/PNI+ (n = 138).

Results

With a median follow-up period of 56 months, the 5-year overall survival rates of patients with LVI−/PNI−, LVI+ only, PNI+ only, and LVI+/PNI+ were 82%, 73%, 71%, and 56%, respectively (P < .001), and the 5-year disease-free survival rates of patients with LVI−/PNI−, LVI+ only, PNI+ only, and LVI+/PNI+ were 80%, 70%, 65%, and 46%, respectively (P < .001). In multivariate analysis, LVI+/PNI+ was an independent prognostic factor for both overall survival (P < .001) and disease-free survival (P < .001).

Conclusions

Positivity of both LVI and PNI is a strong predictor of overall and disease-free survival in patients with stages II and III colorectal cancer.     

Oncological and safety profiles in patients undergoing simultaneous transurethral resection (TUR) of bladder tumour and TUR of the prostate

Objectives

To determine the oncological impact and adverse events of performing simultaneous transurethral resection of bladder tumour (TURB) and transurethral resection of the prostate (TURP), as evidence on the outcomes of simultaneous TURB for bladder cancer and TURP for obstructive benign prostatic hyperplasia is limited and contradictory.

Patients and Methods

Patients from 12 European hospitals treated with either TURB alone or simultaneous TURB and TURP (TURB+TURP) were retrospectively analysed. A propensity score matching (PSM) 1:1 was performed with patients from the TURB+TURP group matched to TURB-alone patients. Associations between surgery approach with recurrence-free (RFS) and progression-free (PFS) survivals were assessed in Cox regression models before and after PSM. We performed a subgroup analysis in patients with risk factors for recurrence (multifocality and/or tumour size >3 cm).

Results

A total of 762 men were included, among whom, 76% (581) underwent a TURB alone and 24% (181) a TURB+TURP. There was no difference in terms of tumour characteristics between the groups. We observed comparable length of stay as well as complication rates including major complications (Clavien–Dindo Grade ≥III) for the TURB-alone vs TURB+TURP groups, while the latest led to longer operative time (P < 0.001). During a median follow-up of 44 months, there were more recurrences in the TURB-alone (47%) compared to the TURB+TURP group (28%; P < 0.001). Interestingly, there were more recurrences at the bladder neck/prostatic fossa in the TURB-alone group (55% vs 3%, P < 0.001). TURB+TURP procedures were associated with improved RFS (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.29–0.53; P < 0.001), but not PFS (HR 1.63, 95% CI 0.90–2.98; P = 0.11). Within the PSM cohort of 254 patients, the simultaneous TURB+TURP was still associated with improved RFS (HR 0.33, 95% CI 0.22–0.49; P < 0.001). This was also true in the subgroup of 380 patients with recurrence risk factors (HR 0.41, 95% CI 0.28–0.62; P < 0.001).

Conclusion

In our contemporary cohort, simultaneous TURB and TURP seems to be an oncologically safe option that may, even, improve RFS by potentially preventing disease recurrence at the bladder neck and in the prostatic fossa.     

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.     

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.

     

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.     

Clinicopathological outcomes after radical cystectomy for clinical T2 urothelial carcinoma: further evidence to support the use of neoadjuvant chemotherapy

Study Type – Therapy (case series)
Level of Evidence 4 What’s known on the subject? and What does the study add? Systemic chemotherapy for muscle‐invasive bladder cancer is underutilized. Currently, debate centers on whether patients should be given neoadjuvant chemotherapy or be given chemotherapy after surgery, depending on the pathology of the specimen. In this paper, we found that greater than 73% of patients had evidence of bladder cancer that was locally advanced, a criteria that would designate these patients for adjuvant chemotherapy. Using this evidence and the knowledge that neoadjuvant chemotherapy confers a survival advantage, we argue that neoadjuvant chemotherapy should be the standard of care.

OBJECTIVE

To evaluate the clinicopathological outcomes for patients with clinical T2 (cT2) urothelial carcinoma treated with radical cystectomy (RC) without neoadjuvant chemotherapy (NC).

PATIENTS AND METHODS

We identified 212 patients with cT2 tumours who underwent RC at our institution without NC. Pathological assessment of RC specimens was correlated with clinical stage. The impact of various clinicopathological factors on the outcome of patients with cT2 disease was analysed.

RESULTS

In total, 153/212 (73.2%) patients with cT2 bladder cancer had either pT3/T4 or pN+ tumours at RC. Moreover, only 58/153 (37.9%) of these patients received adjuvant chemotherapy. The median follow‐up was 28 (months 0.6–107.5) (range). The 5‐year recurrence‐free survival and cancer‐specific survival (CSS) was 56.5% and 59.5%, respectively. On multivariate analysis, increasing age (hazard ratio [HR] 1.04; P= 0.04), advanced pathological stage (HR 1.83; P= 0.02), and positive lymph nodes (HR 3.72; P= 0.001) were adversely associated with CSS, while receipt of adjuvant chemotherapy was protective of disease‐specific mortality (HR 0.45; P= 0.04).

CONCLUSIONS

Pathological upstaging is prevalent and survival remains modest in patients with cT2 tumours treated with RC without NC. Unfortunately, only 40% of patients that had locally advanced and/or regionally metastatic disease received adjuvant treatment. These data further support the value of NC for patients with muscle‐invasive bladder cancer, even in those with apparent clinically organ‐confined tumours.