Umberto Capitanio

Updated Nomogram Predicting Lymph Node Invasion in Patients with Prostate Cancer Undergoing Extended Pelvic Lymph Node Dissection: The Essential Importance of Percentage of Positive Cores

BACKGROUND Few predictive models aimed at predicting the presence of lymph node invasion (LNI) in patients with prostate cancer (PCa) treated with extended pelvic lymph node dissection (ePLND) are available to date. OBJECTIVE Update a nomogram predicting the presence of LNI in patients treated with ePLND at the time of radical prostatectomy (RP). DESIGN, SETTING, AND PARTICIPANTS The study included 588 patients with clinically localised PCa treated between September 2006 and October 2010 at a single tertiary referral centre. INTERVENTION All patients underwent RP and ePLND invariably including removal of obturator, external iliac, and hypogastric nodes. MEASUREMENTS Prostate-specific antigen, clinical stage, and primary and secondary biopsy Gleason grade as well as percentage of positive cores were included in univariable (UVA) and multivariable (MVA) logistic regression models predicting LNI and formed the basis for the regression coefficient-based nomogram. The area under the curve (AUC) method was used to quantify the predictive accuracy (PA) of the model. RESULTS AND LIMITATIONS The mean number of lymph nodes removed and examined was 20.8 (median: 19; range: 10-52). LNI was found in 49 of 588 patients (8.3%). All preoperative PCa characteristics differed significantly between LNI-positive and LNI-negative patients (all p<0.001). In UVA predictive accuracy analyses, percentage of positive cores was the most accurate predictor of LNI (AUC: 79.5%). At MVA, clinical stage, primary biopsy Gleason grade, and percentage of positive cores were independent predictors of LNI (all p≤0.006). The updated nomogram demonstrated a bootstrap-corrected PA of 87.6%. Using a 5% nomogram cut-off, 385 of 588 patients (65.5%) would be spared ePLND. and LNI would be missed in only 6 patients (1.5%). The sensitivity, specificity, and negative predictive value associated with the 5% cut-off were 87.8%, 70.3%, and 98.4%, respectively. The relatively low number of patients included as well as the lack of an external validation represent the main limitations of our study. CONCLUSIONS We report the first update of a nomogram predicting the presence of LNI in patients treated with ePLND. The nomogram maintained high accuracy, even in more contemporary patients (87.6%). Because percentage of positive cores represents the foremost predictor of LNI, its inclusion should be mandatory in any LNI prediction model. Based on our model, those patients with a LNI risk<5% might be safely spared ePLND.

Radical versus partial nephrectomy: effect on overall and noncancer mortality.

Relative to radical nephrectomy (RN), partial nephrectomy (PN) performed for renal cell carcinoma (RCC) may protect from non‐cancer‐related deaths. The authors tested this hypothesis in a cohort of PN and RN patients.

Pelvic/Retroperitoneal Salvage Lymph Node Dissection for Patients Treated With Radical Prostatectomy With Biochemical Recurrence and Nodal Recurrence Detected by [11C]Choline Positron Emission Tomography/Computed Tomography

BACKGROUND The management of patients with clinical recurrence of prostate cancer after radical prostatectomy (RP) remains challenging. OBJECTIVE To determine whether the removal of positive lymph nodes at [11C]choline positron emission tomography/computed tomography (PET/CT) scan may have an impact on the prognosis of patients with biochemical recurrence (BCR) and nodal recurrence after RP. DESIGN, SETTING, AND PARTICIPANTS Prospective analysis of 72 patients affected by BCR after RP associated with a nodal pathologic [11C]choline PET/CT scan. INTERVENTION Patients underwent salvage lymph node dissection (LND). MEASUREMENTS Biochemical response (BR) to treatment was defined as prostate-specific antigen (PSA) <0.2 ng/ml at 40 d after salvage LND. Kaplan-Meier and Cox regression analyses addressed time to and predictors of clinical recurrence (CR) after salvage LND, respectively. RESULTS AND LIMITATIONS Overall, 56.9% of patients achieved BR. Mean and median follow-up after LND were 39.4 and 39.8 mo, respectively. The 5-yr BCR-free survival rate was 19%. Preoperative PSA <4 ng/ml (hazard ratio [HR]: 0.12; p = 0.005), time to BCR <24 mo (HR: 7.52; p = 0.005), and negative lymph nodes at previous RP (HR: 0.19; p=0.04) represented independent predictors of BR. Overall, 5-yr CR-free and cancer-specific survival were 34% and 75%, respectively. At multivariable analyses, only PSA >4 ng/ml (HR: 2.13; p=0.03) and the presence of retroperitoneal uptake at PET/CT scan (HR=2.92; p=0.004) represented independent preoperative predictors of CR. Similarly, the presence of pathologic nodes in the retroperitoneum (HR: 2.78; p=0.02), higher number of positive lymph nodes (HR: 1.04; p=0.006), and complete BR to salvage LND (HR: 0.31; p=0.002) represented postoperative independent predictors of CR. Main limitations consisted of the lack of a control group and the heterogeneity of patients included in the analyses. CONCLUSIONS Salvage LND is feasible in patients with BCR after RP and nodal pathologic uptake at [11C]choline PET/CT scan. Biochemical response after surgery can be achieved in a consistent proportion of patients. Although most patients invariably progressed to BCR after surgery at longer follow-up, 35% of patients showed the absence of CR at 5 yr.

Combination of Adjuvant Hormonal and Radiation Therapy Significantly Prolongs Survival of Patients With pT2–4 pN+ Prostate Cancer: Results of a Matched Analysis

BACKGROUND Previous prospective randomised trials have shown a positive impact of adjuvant radiation therapy (RT) in patients with locally advanced prostate cancer. However, none of these trials included patients with lymph node invasion (LNI). OBJECTIVE The aim of this study was to assess the impact of combination adjuvant hormonal therapy (HT) and RT on the survival of patients with prostate cancer and histologically documented lymph node metastases (pN+). DESIGN, SETTING, AND PARTICIPANTS Data on 703 consecutive patients with LNI treated with radical prostatectomy, pelvic lymph node dissection, and adjuvant treatments between September 1986 and November 2002 at two large academic institutions were reviewed. MEASUREMENTS For study purposes, patients treated with adjuvant HT plus RT and patients treated with adjuvant HT alone were matched for age at surgery, pathologic T stage and Gleason score, number of nodes removed, surgical margin status, and length of follow-up. Differences in cancer-specific survival (CSS) and overall survival (OS) were compared using the Kaplan-Meier method and life table analyses. RESULTS AND LIMITATIONS Following the matching process, 117 pT2-4 pN1 patients of 171 (68.4%) treated with adjuvant HT plus RT (group 1) were compared with 247 pT2-4 pN1 patients of 532 (46.4%) receiving adjuvant HT alone (group 2). After matching, the two groups of patients were comparable in terms of pre- and postoperative characteristics (all p ≥ 0.07). Mean follow-up was 100.8 mo (median: 95.1 mo; range: 3.5-229.3 mo). Overall, prostate CSS and OS rates at 5, 8, and 10 yr were 90%, 82%, and 75%, and 85%, 70%, and 60%, respectively. Patients treated with adjuvant RT plus HT had significantly higher CSS and OS rates compared with patients treated with HT alone at 5, 8, and 10 yr after surgery (95%, 91%, and 86% vs 88%, 78%, and 70%, and 90%, 84%, and 74% vs 82%, 65%, and 55%, respectively; p = 0.004 and p<0.001, respectively). Similarly, higher survival rates associated with the combination of HT plus RT were found when patients were stratified according to the extent of nodal invasion (namely, two or fewer vs more than two positive nodes; all p ≤ 0.006). Lack of standardised HT and RT protocols represents the main limitations of our retrospective study. CONCLUSIONS Adjuvant RT plus HT significantly improved CSS and OS of pT2-4 pN1 patients, regardless of the extent of nodal invasion. These results reinforce the need for a multimodal approach in the treatment of node-positive prostate cancer.

Comparison of Oncologic Outcomes for Open and Laparoscopic Nephroureterectomy: A Multi-Institutional Analysis of 1249 Cases

BACKGROUND Data regarding the oncologic efficacy of laparoscopic nephroureterectomy (LNU) compared to open nephroureterectomy (ONU) are scarce. OBJECTIVE We compared recurrence and cause-specific mortality rates of ONU and LNU. DESIGN, SETTING, AND PARTICIPANTS Thirteen centers from three continents contributed data on 1249 patients with nonmetastatic upper tract urothelial carcinoma (UTUC). MEASUREMENTS Univariable and multivariable survival models tested the effect of procedure type (ONU [n=979] vs LNU [n=270]) on cancer recurrence and cancer-specific mortality. Covariables consisted of institution, age, Eastern Cooperative Oncology Group (ECOG) performance status score, pT stage, pN stage, tumor grade, lymphovascular invasion, tumor location, concomitant carcinoma in situ, ureteral cuff management, previous urothelial bladder cancer, and previous endoscopic treatment. RESULTS AND LIMITATIONS Median follow-up for censored cases was 49 mo (mean: 62). Relative to ONU, LNU patients had more favorable pathologic stages (pT0/Ta/Tis: 38.1% vs 20.8%, p<0.001) and less lymphovascular invasion (14.8% vs 21.3%, p=0.02) and less frequently had tumors located in the ureter (64.5 vs 71.1%, p=0.04). In univariable recurrence and cancer-specific mortality models, ONU was associated with higher cancer recurrence and mortality rates compared to LNU (hazard ratio [HR]: 2.1 [p<0.001] and 2.0 [p=0.008], respectively). After adjustment for all covariates, ONU and LNU had no residual effect on cancer recurrence and mortality (p=0.1 for both). CONCLUSIONS Short-term oncologic data on LNU are comparable to ONU. Since LNU was selectively performed in favorable-risk patients, we cannot state with certainty that ONU and LNU have the same oncologic efficacy in poor-risk patients. Long-term follow-up data and morbidity data are necessary before LNU can be considered as the standard of care in patients with muscle-invasive or high-grade UTUC.

Soft Tissue Surgical Margin Status is a Powerful Predictor of Outcomes After Radical Cystectomy: A Multicenter Study of More Than 4,400 Patients

PURPOSE We evaluated the association of soft tissue surgical margins with characteristics and outcomes of patients treated with radical cystectomy for urothelial carcinoma of the bladder. MATERIALS AND METHODS We retrospectively collected the data of 4,410 patients treated with radical cystectomy and pelvic lymphadenectomy without neoadjuvant chemotherapy at 12 academic centers in the United States, Canada and Europe. A positive soft tissue surgical margin was defined as presence of tumor at inked areas of soft tissue on the radical cystectomy specimen. RESULTS Positive soft tissue surgical margins were identified in 278 patients (6.3%). On univariate analysis positive soft tissue surgical margin was significantly associated with advanced pT stage, higher tumor grade, lymphovascular invasion and lymph node metastasis (p <0.001). Actuarial 5-year recurrence-free and cancer specific survival probabilities were 62.8% +/- 0.8% and 69% +/- 0.8% for patients without soft tissue surgical margins vs 21.6% +/- 3.1% and 26.4% +/- 3.3% for those with positive soft tissue surgical margins (p <0.001). On multivariable analyses adjusting for the effect of standard clinicopathological features and adjuvant chemotherapy positive soft tissue surgical margin was an independent predictor of disease recurrence and cancer specific mortality (HR 1.52 and HR 1.51, p <0.001, respectively). Soft tissue surgical margin retained independent predictive value in subgroups with advanced disease such as pT3Nany, pT4Nany or Npositive. CONCLUSIONS Positive soft tissue surgical margin is a strong predictor of recurrence and eventual death from urothelial carcinoma of the bladder. Soft tissue surgical margin status should always be reported in the pathological reports after radical cystectomy. Due to uniformly poor outcomes patients with positive soft tissue surgical margins should be considered for studies on adjuvant local and/or systemic therapy.

Combination of Multiple Molecular Markers Can Improve Prognostication in Patients With Locally Advanced and Lymph Node Positive Bladder Cancer

PURPOSE We tested whether the combination of 4 established cell cycle regulators (p53, pRB, p21 and p27) could improve the ability to predict clinical outcomes in a large multi-institutional collaboration of patients with pT3-4N0 or pTany Npositive urothelial carcinoma of the bladder. We also assessed whether the combination of molecular markers is superior to any individual biomarker. MATERIALS AND METHODS The study comprised 692 patients with pT3-4N0 or pTany Npositive urothelial carcinoma of the bladder treated with radical cystectomy and bilateral lymphadenectomy (median followup 5.3 years). Scoring was performed using advanced cell imaging and color detection software. The base model incorporated patient age, gender, stage, grade, lymphovascular invasion, number of lymph nodes removed, number of positive lymph nodes, concomitant carcinoma in situ and adjuvant chemotherapy. RESULTS Individual molecular markers did not improve the predictive accuracy for disease recurrence and cancer specific mortality. Combination of all 4 molecular markers into number of altered molecular markers resulted in significantly higher predictive accuracy than any single biomarker (p <0.001). Moreover addition of number of altered molecular markers to the base model significantly improved the predictive accuracy for disease recurrence (3.9%, p <0.001) and cancer specific mortality (4.3%, p <0.001). Addition of number of altered molecular markers retained statistical significance for improving the prediction of clinical outcomes in the subgroup of patients with pT3N0 (280), pT4N0 (83) and pTany Npositive (329) disease (p <0.001). CONCLUSIONS While the status of individual molecular markers does not add sufficient value to outcome prediction in patients with advanced urothelial carcinoma of the bladder, combinations of molecular markers may improve molecular staging, prognostication and possibly prediction of response to therapy.

Multi-Institutional Validation of the Predictive Value of Ki-67 Labeling Index in Patients With Urinary Bladder Cancer

Several small single-center studies have reported a prognostic role for Ki-67 labeling index in advanced urothelial carcinoma of the urinary bladder. To investigate whether Ki-67 was a useful biomarker of oncological outcome after radical cystectomy for urothelial carcinoma, we assessed its expression in tumor tissue from 713 patients treated with radical cystectomy and bilateral lymphadenectomy at six centers. A high Ki-67 labeling index was independently associated with established features of aggressive urothelial carcinoma, disease recurrence, and cancer-specific survival. Addition of Ki-67 labeling index improved the accuracy of standard multivariate outcome prediction models, as measured by Harrell concordance index, by 2.9% for disease recurrence and 2.4% for bladder cancer-specific survival (P < .001, two-sided Mantel-Haenszel) -- a statistically and potentially clinically significant margin. In conclusion, routine assessment of Ki-67 expression status along with assessment of other established predictors of urothelial carcinoma outcome has the potential to improve identification of patients who are at increased risk for disease progression after radical cystectomy and thus may benefit from perioperative systemic chemotherapy.

The extent of lymphadenectomy seems to be associated with better survival in patients with nonmetastatic upper-tract urothelial carcinoma: how many lymph nodes should be removed?

BACKGROUND The role and extent of lymphadenectomy in patients with upper-tract urothelial carcinoma (UTUC) is debated. OBJECTIVE To establish whether the number of lymph nodes (LNs) removed might be associated with better cause-specific survival in patients with UTUC. DESIGN, SETTING, AND PARTICIPANTS The study included 552 consecutive patients who underwent radical nephroureterectomy (RNU) and lymphadenectomy between 1992 and 2006. INTERVENTION Patients were treated with RNU and lymphadenectomy. MEASUREMENTS Univariable and multivariable Cox proportional hazards regression models addressed the association between the number of LNs removed and cause-specific mortality (CSM). The number of LNs removed was coded as a cubic spline to allow for nonlinear effects. Finally, the most informative cut-off for the number of removed LNs was identified. RESULTS AND LIMITATIONS In the entire population, the number of LNs removed was not associated with CSM in univariable (hazard ratio [HR]: 0.99; p=0.16) or in multivariable (HR: 0.97; p=0.12) analyses. In contrast, in the subgroup of pN0 patients (n=412), the number of LNs removed achieved the independent predictor status of CSM (HR: 0.93; p=0.02). Eight LNs removed was the most informative cut-off in predicting CSM (HR: 0.42; p=0.004). The inclusion of the variable defining dichotomously the number of removed LNs (< 8 vs > or = 8) in the base model (age, Eastern Cooperative Oncology Group performance status, pathologic stage, grade, architecture, and lymphovascular invasion) significantly increased the accuracy in predicting CSM (+1.7%; p<0.001). CONCLUSIONS The extension of the lymphadenectomy in pN0 UTUC patients seems to be associated with CSM. Longer survival was observed in patients in whom at least eight LNs had been removed.

Prognostic Value of Lymph Node Dissection in Patients with Muscle-Invasive Transitional Cell Carcinoma of the Upper Urinary Tract

OBJECTIVES To analyze the prognostic role of lymphadenectomy (LND) in patients with muscle-invasive transitional cell carcinoma (TCC) of the upper urinary tract (UUT) managed with radical surgery. METHODS From 1986 to 2003, 132 consecutive patients with muscle-invasive TCC of the UUT underwent radical surgery. LND was performed in 95 cases. Patients were stratified according to the presence of LND and lymph node (LN) status. Univariable and multivariable Cox regression models determined the effect of age, pT, grade, nodal status (pN), number of LNs removed, year of surgery, and postoperative chemotherapy on disease-free survival (DFS) and cancer-specific survival (CSS) in the overall population and in patients who underwent LND. RESULTS The actuarial 5-yr CSS in pNx patients was significantly worse than in pN0 patients (48% vs. 73%, p=0.001) and comparable to pN+ outcome (48% vs. 39%, p=0.476). In the entire population, multivariable Cox regression analyses indicated that pT and pN status were independent predictors of DFS (p=0.04, hazard ratio [HR]=1.82 and p<0.01, HR=1.34, respectively) and CSS (p<0.01, HR=2.42 and p=0.04, HR=1.32, respectively). In patients who underwent LND, the number of LNs removed was an independent predictor of DFS (p=0.03, HR=0.928) and of CSS (p=0.007, HR=0.903). The extent of LND again resulted in an independent predictor either of DFS or CSS (p=0.04, HR=0.904 and p=0.01, HR=0.867, respectively) in the subgroup of pN0 patients. CONCLUSIONS LND emerged as a strong independent predictor of DFS and CSS in patients surgically managed for a muscle-invasive TCC of the UUT.