Mario Zacharias

Lymph Node Density Affects Cancer-Specific Survival in Patients with Lymph Node–Positive Urothelial Bladder Cancer Following Radical Cystectomy

BACKGROUND The prognosis for patients with lymph node (LN)-positive bladder cancer (BCa) is likely affected by the extent of lymphadenectomy in radical cystectomy (RC) cases. Specifically, the prognostic significance of the LN density (ratio of positive LNs to the total number removed) has been demonstrated. OBJECTIVE To evaluate the prognostic signature of lymphadenectomy variables, including the LN density, for a large, multicentre cohort of RC patients with LN-positive BCa. DESIGN, SETTING, AND PARTICIPANTS The clinical and histopathologic data from 477 patients with LN-positive urothelial BCa (pN1-2) were analysed. The median follow-up period for all living patients was 28 mo. MEASUREMENTS Multivariable Cox regression analysis was used to test the effect of various pelvic lymph node dissection (PLND) variables on cancer-specific survival (CSS) based on colinearity in various models. RESULTS AND LIMITATIONS The median number of LNs removed was 12 (range: 1-66), and the median number of positive LNs was 2 (range: 1-25). Two hundred ninety (60.8%) of the patients presented with stage pN2 disease. The median and mean LN density was 17.6% and 29% (range: 2.3-100), respectively, where 268 (56.2%) and 209 (43.8%) patients exhibited am LN density of ≤20% and >20%, respectively. In separate multivariable Cox regression models adjusted for age, sex, pTN stage, grade, associated Tis, and adjuvant chemotherapy, the interval-scaled LN density (hazard ratio [HR]: 1.01; p=0.002) and the LN density, ordinal-scaled by 20% (HR: 1.65; p<0.001) exhibit independent effects on CSS. In addition, an independent contribution appears from the pT but not the pN stage. Limitations include surgeon selection bias when determining the extent of lymphadenectomy. CONCLUSIONS Our results support the prognostic relevance of LN density in patients with LN-positive BCa, where a threshold value of 20% stratifies the population into two prognostically distinct groups. Before LN density is integrated into the clinical decision-making process, these results should be validated by prospective studies with defined LN templates and standardised histopathologic methods.

Biochemical recurrence after radical prostatectomy: multiplicative interaction between surgical margin status and pathological stage.

PURPOSE A positive surgical margin after radical prostatectomy is considered an adverse prognostic feature. However, few groups have explored the potential interaction between surgical margin status and other cancer characteristics, specifically pathological stage. We addressed the first degree of interaction between positive surgical margins and other established adverse predictors of biochemical recurrence after radical prostatectomy. MATERIALS AND METHODS We used univariate and multivariate analysis to test the effect of surgical margin status on biochemical recurrence in 4,490 patients treated at a single institution between 1992 and 2008. We systematically tested all first-degree interactions between surgical margin status, and pretreatment prostate specific antigen, pT and pN stage, and radical prostatectomy Gleason sum. If interactions were significant, we quantified the effect on the biochemical recurrence rate. RESULTS Overall 850 patients (18.9%) had positive surgical margins. In those with negative vs positive surgical margins the 5-year biochemical recurrence-free survival rate was 95% vs 83%, 74% vs 62% and 47% vs 29% for pT2, pT3a and pT3b disease, respectively. In multivariate models only the pT stage-surgical margin status interaction achieved independent predictor status (p = 0.003). Negative vs positive surgical margin multivariate HRs were 1 vs 2.9, 2.3 vs 4.3 and 4.1 vs 5.6 in pT2, pT3a and pT3b cases, respectively. CONCLUSIONS Compared to negative surgical margins, positive surgical margins increase the absolute biochemical recurrence 5-year rate by 12% to 18%. More importantly, positive surgical margins may substantially worsen the prognosis beyond that of the original pathological disease stage.

Analysis of sex differences in cancer-specific survival and perioperative mortality following radical cystectomy: results of a large German multicenter study of nearly 2500 patients with urothelial carcinoma of the bladder.

BACKGROUND Outcome of patients with urothelial carcinoma of the bladder (UCB) varies between sexes. Although overall incidence is higher in men, cancer-specific survival (CSS) has been suggested to be lower in women. Although the former effect is attributed to greater exposure to carcinogens in men, the latter has not been elucidated. OBJECTIVES The aim of the study was to identify sex-specific outcomes based on one of the largest databases of patients with UCB who underwent radical cystectomy (RC). METHODS This retrospective multicenter series comprised 2483 patients in Stage M0 who underwent RC for UCB from 1989 to 2008; 20.4% of patients were women. The impact of sex on CSS in the entire study group and in specific subgroups was analyzed. The median follow-up time was 42 months (interquartile range, 21-79). RESULTS Histopathologic criteria of pathologic tumor (pT), pathologic nodal (pN), grade, lymphovascular invasion (LVI), and associated carcinoma in situ (CIS) of the study did not differ between sexes. The percentage of female patients increased over time. Five-year CSS in female patients was significantly lower than in male patients (60% vs 66%; P = 0.005). In multivariate analysis adjusted to other covariates, tumor stage ≥pT3 (hazard ratio [HR] = 2.44; P < 0.001), positive pN status (HR = 1.91; P < 0.001), LVI (HR = 1.48; P < 0.001), lower count of lymph nodes removed (HR = 0.98; P = 0.002), older age (HR = 1.01; P < 0.001), and female gender (HR = 1.26; P = 0.011) had an independent impact on CSS. Deterioration of CSS in female patients was pronounced when LVI was present (HR = 1.57; P < 0.001) and when RC was performed in the earlier time period (HR = 2.44; P < 0.001). However, women showed significantly lower perioperative mortality (within 90 days after RC) compared with men. CONCLUSIONS After RC for UCB, cancer-specific mortality was higher in female patients; this disadvantage was more pronounced in earlier time periods. In addition, worse outcome of women with verified LVI was shown to be comparable with men. These findings were suggestive of different tumor biology and potentially unequal access to timely RC in earlier time periods because of reduced awareness of UCB in women. Further studies are required to improve UCB outcome in both sexes, notably in female patients.

Prospective non-randomized evaluation of four mediators of the systemic response after extraperitoneal laparoscopic and open retropubic radical prostatectomy.

Associate Editor

Gender-specific differences in cancer-specific survival after radical cystectomy for patients with urothelial carcinoma of the urinary bladder in pathologic tumor stage T4a

BACKGROUND Bladder cancer (UCB) staged pT4a show heterogeneous outcome after radical cystectomy (RC). No risk model has been established to date. Despite gender-specific differences, no comparative studies exist for this tumor stage. MATERIALS AND METHODS Cancer-specific survival (CSS) of 245 UCB patients without neoadjuvant chemotherapy staged pT4a, pN0-2, M0 after RC were analyzed in a retrospective multi-center study. Seventeen patients were excluded from further analysis due to carcinoma in situ (CIS) of the prostatic urethra and/or positive surgical margins. Average follow-up period was 30 months (IQR: 14-45). The influence of different clinical and histopathologic variables on CSS was determined through uni- and multivariate Cox regression analyses. Two risk groups were generated using factors with independent effect in multivariate models. Internal validity of the prediction model was evaluated by bootstrapping. RESULTS Eighty-four percent of the patients (n = 192) were male; 72% (n = 165) showed lymphovascular invasion (LVI). The 5-year CSS rate was 31%, and significantly different between male and female (35% vs. 15%, P = 0.003). Multivariate Cox regression modeling, female gender (HR = 1.83, P = 0.008), LVI (HR = 1.92, P = 0.005), and absence of adjuvant chemotherapy (HR = 0.61, P = 0.020) significantly worsened CSS. Two risk groups were generated using these 3 criteria, which differed significantly between each other in CSS (5-year-CSS: 46% vs. 12%, P < 0.001). The c-index value of the risk model was 0.61 (95% CI: 0.53-0.68, P < 0.001). CONCLUSIONS Prognosis in UCB staged pT4a is heterogeneous. Female gender and LVI are adverse factors. Adjuvant chemotherapy seems to improve outcome. The present analysis establishes the first risk model for this demanding tumor stage.

Unilateral Prostate Cancer Cannot be Accurately Predicted in Low-Risk Patients

PURPOSE Hemiablative therapy (HAT) is increasing in popularity for treatment of patients with low-risk prostate cancer (PCa). The validity of this therapeutic modality, which exclusively treats PCa within a single prostate lobe, rests on accurate staging. We tested the accuracy of unilaterally unremarkable biopsy findings in cases of low-risk PCa patients who are potential candidates for HAT. METHODS AND MATERIALS The study population consisted of 243 men with clinical stage <or=T2a, a prostate-specific antigen (PSA) concentration of <10 ng/ml, a biopsy-proven Gleason sum of <or=6, and a maximum of 2 ipsilateral positive biopsy results out of 10 or more cores. All men underwent a radical prostatectomy, and pathology stage was used as the gold standard. Univariable and multivariable logistic regression models were tested for significant predictors of unilateral, organ-confined PCa. These predictors consisted of PSA, % fPSA (defined as the quotient of free [uncomplexed] PSA divided by the total PSA), clinical stage (T2a vs. T1c), gland volume, and number of positive biopsy cores (2 vs. 1). RESULTS Despite unilateral stage at biopsy, bilateral or even non-organ-confined PCa was reported in 64% of all patients. In multivariable analyses, no variable could clearly and independently predict the presence of unilateral PCa. This was reflected in an overall accuracy of 58% (95% confidence interval, 50.6-65.8%). CONCLUSIONS Two-thirds of patients with unilateral low-risk PCa, confirmed by clinical stage and biopsy findings, have bilateral or non-organ-confined PCa at radical prostatectomy. This alarming finding questions the safety and validity of HAT.

Prognostic significance of a positive surgical margin in pathologically organ-confined prostate cancer

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

Multicenter evaluation of the prognostic value of pT0 stage after radical cystectomy due to urothelial carcinoma of the bladder.

Study Type – Therapy (case series)

[Influence of older age on survival after radical cystectomy due to urothelial carcinoma of the bladder: survival analysis of a German multi-centre study after curative treatment of urothelial carcinoma of the bladder].

BACKGROUND The therapeutic gold standard of muscle-invasive tumour stages is radical cystectomy (RC), but there are still conflicting reports about associated morbidity and mortality and the oncologic benefit of RC in elderly patients. The aim of the present study was the comparison of overall (OS) and cancer-specific survival (CSS) in patients <75 and >75 years of age (median follow-up was 42 months). PATIENTS AND METHODS Clinical and histopathological data of 2,483 patients with urothelial carcinoma and consecutive RC were collated. The study group was dichotomized by the age of 75 years at RC. Statistical analyses comprising an assessment of postoperative mortality within 90 days, OS and CSS were assessed. Multivariate logistic regression and survival analyses were performed. RESULTS The 402 patients (16.2%) with an age of ≥75 years at RC showed a significantly higher local tumour stage (pT3/4 and/or pN+) (58 vs 51%; p=0.01), higher tumour grade (73 vs 65%; p=0.003) and higher rates of upstaging in the RC specimen (55 vs 48%; p=0.032). Elderly patients received significantly less often adjuvant chemotherapy (8 vs 15%; p<0.001). The 90-day mortality was significantly higher in patients ≥75 years (6.2 vs 3.7%; p=0.026). When adjusted for different variables (gender, tumour stage, adjuvant chemotherapy, time period of RC), only in male patients and locally advanced tumour stages was an association with 90-day mortality noticed. The multivariate analysis showed that patients ≥75 years of age have a significantly worse OS (HR=1.42; p<0.001) and CSS (HR=1.27; p=0.018). CONCLUSIONS An age of ≥75 years at RC is associated with a worse outcome. Prospective analyses including an assessment of the role of comorbidity and possibly age-dependent tumour biology are warranted.

Pathological upstaging detected in radical cystectomy procedures is associated with a significantly worse tumour-specific survival rate for patients with clinical T1 urothelial carcinoma of the urinary bladder

Abstract Objective. Due to their variable oncological course, clinical stage T1 (cT1) urothelial carcinomas of the bladder (UCBs) are the subject of controversial discussion with regard to indication for radical cystectomy (RC).This study aimed to evaluate the frequency and prognosis of upstaging in patients undergoing RC due to UCB. Material and methods. Clinical and pathological records of 607 patients, having undergone RC for treatment of UCB in cT1N0M0, were summarized in a multi-institutional database. Cancer-specific survival (CSS) and overall survival (OS) rates were calculated. A multivariable prognostic model predicting the possibility of an upstaging in RC specimens was developed based on clinical information. Results. In 210patients (35%) an upstaging (> pT1 and/or pN+) was detected in the RC specimen. Five-year CSS was 86%, 78%, 60%and 34%, respectively, for tumour stages < pT2N0 (n = 397), pT2N0 (n = 78), > pT2N0 (n = 63)and pN+ (n = 69) (p < 0.001). In a multivariable Cox regression model, pN stage, pT stage and lymphovascular invasion (LVI) revealed an independent influence on CSS (OS: pN, pT, age). An upstaging of cT1 tumours was enhanced by the criteria of G3 tumour grading and absent Tis in the transurethral resection of the bladder (TURB)specimen. Detection of LVI in RC specimens was also independently associated with an upstaging and, therefore, is recommended as a relevant prognostic parameter for the histopathological evaluation of TURB specimens. Conclusions. More than one-third of patients with cT1 tumours had an upstaging that was associated with significant prognosis deterioration. Further valid markers are required for an early identification of these patients. LVI represents such a criterion and, therefore, should be evaluated in prospectively designed trials with accurate histopathological assessment of TURB specimens.