Giovanni Lughezzani

Prognostic Factors in Upper Urinary Tract Urothelial Carcinomas: A Comprehensive Review of the Current Literature

CONTEXT The heterogeneity of upper tract urothelial carcinoma (UTUC) biology and prognosis, as well as the presence of different treatment options, makes the clinical decision-making process extremely challenging. OBJECTIVE Provide an overview of the currently available prognostic factors for UTUC, focusing on clinical and pathologic characteristics, as well as on molecular markers. EVIDENCE ACQUISITION A systematic literature search was conducted using the PubMed, Scopus, and Embase databases to identify original articles, review articles, and editorials regarding prognostic factors in patients with UTUC. Keywords included urothelial carcinoma, renal pelvis, ureter, upper urinary tract urothelial carcinoma, upper urinary tract transitional cell carcinoma, prognosis, prognostic factors, markers, and survival. Articles published between 2000 and 2011 were reviewed and selected with the consensus of all the authors. EVIDENCE SYNTHESIS Prognostic factors can be divided into four different categories: preoperative/clinical factors, intraoperative/surgical factors, postoperative/pathologic factors, and molecular markers. Because of the rarity of the disease, only a small amount of level 1 evidence information from prospective randomized trials is available. Conversely, several single-institutional and multi-institutional studies have been published providing level 3 evidence information on various prognostic factors. Tumor stage and grade represent the best-established predictors of prognosis in patients with UTUC, but controversies still exist regarding the prognostic impact of tumor location and tumor necrosis. Several promising biomarkers have also been evaluated, but further studies evaluating their prognostic role are still needed. Finally, few prognostic models have been developed to provide clinicians with accurate estimates of the outcome of interest. CONCLUSIONS In the past few years, several prognostic factors have been identified to help clinicians dealing with patients with UTUC in the decision-making process. However, well-designed multi-institutional studies are still needed to provide stronger evidence and to promote the use of these prognostic factors in clinical practice.

Age-Adjusted Incidence, Mortality, and Survival Rates of Stage-Specific Renal Cell Carcinoma in North America: A Trend Analysis

BACKGROUND The rising incidence of renal cell carcinoma (RCC) has been largely attributed to the increasing use of imaging procedures. OBJECTIVE Our aim was to examine stage-specific incidence, mortality, and survival trends of RCC in North America. DESIGN, SETTING, AND PARTICIPANTS We computed age-adjusted incidence, survival, and mortality rates using the Surveillance Epidemiology and End Results database. Between 1988 and 2006, 43,807 patients with histologically confirmed RCC were included. MEASUREMENTS We calculated incidence, mortality, and 5-yr survival rates by year. Reported findings were stratified according to disease stage. RESULTS AND LIMITATIONS Age-adjusted incidence rate of RCC rose from 7.6 per 100,000 person-years in 1988 to 11.7 in 2006 (estimated annual percentage change [EAPC]: +2.39%; p<0.001). Stage-specific age-adjusted incidence rates increased for localized stage: 3.8 in 1988 to 8.2 in 2006 (EAPC: +4.29%; p<0.001) and decreased during the same period for distant stage: 2.1 to 1.6 (EAPC: -0.57%; p=0.01). Stage-specific survival rates improved over time for localized stage but remained stable for regional and distant stages. Mortality rates varied significantly over the study period among localized stage, 1.3 in 1988 to 2.4 in 2006 (EAPC: +3.16%; p<0.001), and distant stage, 1.8 in 1988 to 1.6 in 2006 (EAPC: -0.53%; p=0.045). Better detailed staging information represents a main limitation of the study. CONCLUSIONS The incidence rates of localized RCC increased rapidly, whereas those of distant RCC declined. Mortality rates significantly increased for localized stage and decreased for distant stage. Innovation in diagnosis and management of RCC remains necessary.

Serum Isoform [−2]proPSA Derivatives Significantly Improve Prediction of Prostate Cancer at Initial Biopsy in a Total PSA Range of 2–10 ng/ml: A Multicentric European Study

BACKGROUND Strategies to reduce prostate-specific antigen (PSA)-driven prostate cancer (PCa) overdiagnosis and overtreatment seem to be necessary. OBJECTIVE To test the accuracy of serum isoform [-2]proPSA (p2PSA) and its derivatives, percentage of p2PSA to free PSA (fPSA; %p2PSA) and the Prostate Health Index (PHI)-called index tests-in discriminating between patients with and without PCa. DESIGN, SETTING, AND PARTICIPANTS This was an observational, prospective cohort study of patients from five European urologic centers with a total PSA (tPSA) range of 2-10 ng/ml who were subjected to initial prostate biopsy for suspected PCa. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point was to evaluate the specificity, sensitivity, and diagnostic accuracy of index tests in determining the presence of PCa at prostate biopsy in comparison to tPSA, fPSA, and percentage of fPSA to tPSA (%fPSA) (standard tests) and the number of prostate biopsies that could be spared using these tests. Multivariable logistic regression models were complemented by predictive accuracy analysis and decision curve analysis. RESULTS AND LIMITATIONS Of >646 patients, PCa was diagnosed in 264 (40.1%). Median tPSA (5.7 vs 5.8 ng/ml; p=0.942) and p2PSA (15.0 vs 14.7 pg/ml) did not differ between groups; conversely, median fPSA (0.7 vs 1 ng/ml; p<0.001), %fPSA (0.14 vs 0.17; p<0.001), %p2PSA (2.1 vs 1.6; p<0.001), and PHI (48.2 vs 38; p<0.001) did differ significantly between men with and without PCa. In multivariable logistic regression models, p2PSA, %p2PSA, and PHI significantly increased the accuracy of the base multivariable model by 6.4%, 5.6%, and 6.4%, respectively (all p<0.001). At a PHI cut-off of 27.6, a total of 100 (15.5%) biopsies could have been avoided. The main limitation is that cases were selected on the basis of their initial tPSA values. CONCLUSIONS In patients with a tPSA range of 2-10 ng/ml, %p2PSA and PHI are the strongest predictors of PCa at initial biopsy and are significantly more accurate than tPSA and %fPSA.

Prostate-Specific Antigen (PSA) Isoform p2PSA Significantly Improves the Prediction of Prostate Cancer at Initial Extended Prostate Biopsies in Patients with Total PSA Between 2.0 and 10 ng/ml: Results of a Prospective Study in a Clinical Setting

BACKGROUND Total prostate-specific antigen (tPSA), ratio of free PSA (fPSA) to tPSA (%fPSA), and PSA density (PSAD) testing have a very low accuracy in the detection of prostate cancer (PCa). There is an urgent need for more accurate biomarkers. OBJECTIVE To compare the diagnostic accuracy of PSA isoform p2PSA and its derivatives in determining the presence of PCa at initial biopsy with the accuracy of other predictors in patients with tPSA 2.0-10 ng/ml. DESIGN, SETTING, AND PARTICIPANTS We conducted an observational prospective study in a real clinical setting of consecutive men with tPSA 2.0-10 ng/ml and negative digital rectal examination who were scheduled for prostate biopsy at a tertiary academic center. INTERVENTION Outpatient transrectal ultrasound-guided prostate biopsies were performed according to a standardized institutional saturation scheme (18-22 cores). MEASUREMENTS We determined the diagnostic accuracy of serum tPSA, %fPSA, PSAD, p2PSA, %p2PSA [(p2PSA/fPSA)×100] and the Beckman Coulter Prostate Health Index (phi; [p2PSA/fPSA×√tPSA]). RESULTS AND LIMITATIONS Overall, 107 of 268 patients (39.9%) were diagnosed with PCa at extended prostate biopsies. Statistically significant differences between patients with and without PCa were observed for age, prostate and transition zone volume, PSAD, %p2PSA, and phi (all p values<0.05). In univariate accuracy analysis, phi and %p2PSA were the most accurate predictors of PCa (area under the curve: 75.6% and 75.7%, respectively), followed by transition zone volume (66%), prostate volume (65%), patient age (63%), PSAD (61%), %fPSA (58%), and tPSA (53%). In multivariate accuracy analyses, both phi (+11%) and %p2PSA (+10%) significantly improved the accuracy of established predictors in determining the presence of PCa at biopsy (p<0.001). Although %p2PSA and phi were significantly associated with Gleason score (Spearman ρ: 0.303 and 0.387, respectively; p ≤ 0.002), they did not improve the prediction of Gleason score ≥7 PCa in multivariable accuracy analyses (p > 0.05). CONCLUSIONS In patients with a tPSA between 2.0 and 10 ng/ml, %p2PSA and phi are the strongest predictors of PCa at initial extended biopsies and are significantly more accurate than the currently used tests (tPSA, %fPSA, and PSAD) in determining the presence of PCa at biopsy.

The European Network for the Study of Adrenal Tumors staging system is prognostically superior to the international union against cancer-staging system: A North American validation

BACKGROUND A reclassification of the International Union Against Cancer (UICC) staging system for adrenocortical carcinoma (ACC) patients has recently been proposed by the European Network for the Study of Adrenal Tumors (ENSAT) to better discriminate between cancer-specific mortality (CSM) risk strata. We formally tested the validity of the modified staging system in a large North American population-based cohort. METHODS Kaplan-Meier survival curves depicted CSM rates in the overall population and after stratification according to the 2004 UICC or the 2008 ENSAT-staging system. Cox regression models addressing CSM tested the prognostic value of respectively the UICC or the ENSAT-staging system. Harrells concordance index quantified the accuracy of the standard versus the modified staging system. RESULTS In the overall population (n=573), the CSM-free survival rates at 1, 3, and 5 years were, respectively, 62.9%, 47.0%, and 38.1%. No statistically significant differences in survival were recorded between 2004 UICC stages II and III patients (p=0.1). Conversely, a statistically significant difference was observed between 2008 ENSAT stage II and stage III patients (p<0.001). The 2008 ENSAT-staging system showed higher accuracy (83.0%) in predicting 3-year CSM rates, relative to the 2004 UICC-staging system (79.5%) (p<0.001). CONCLUSION Our study corroborates the superior accuracy of the ENSAT-staging system for ACC relative to the 2004 UICC-staging system. In consequence, the 2008 ENSAT-staging system may warrant consideration in the next update of staging manuals.

Preoperative pelvic floor muscle exercise for early continence after radical prostatectomy: a randomised controlled study.

BACKGROUND Despite improvements in surgical techniques, urinary incontinence (UI) is not uncommon after radical prostatectomy (RP), and it may dramatically worsen quality of life (QoL). OBJECTIVE To determine the benefit of starting pelvic floor muscle exercise (PFME) 30d before RP and of continuing PFME postoperatively for early recovery of continence. DESIGN, SETTING, AND PARTICIPANTS A randomised, prospective study was designed. Men with localised prostate cancer (PCa) who underwent an open radical retropubic prostatectomy (RRP) at our department of urology were included. INTERVENTION Patients were randomised to start PFME preoperatively and continue postoperatively (active group: A) or to start PFME postoperatively alone (control group: B). MEASUREMENTS The primary outcome measure was self-reported continence after surgery. Secondary outcome measures were assessed by degree of UI based on a 24-h pad test and QoL instruments (International Continence Society [ICS] male short form [SF]). RESULTS AND LIMITATIONS Of 143 men evaluated for the study, 118 were randomised either to start PFME preoperatively and continue postoperatively (group A; n=59) or to start postoperative PFME (group B; n=59). After 1 mo, 44.1% (26 of 59) of patients were continent in group A, while 20.3% (12 of 59) were continent in group B (p=0.018). At 3 mo, 59.3% (35 of 59) and 37.3% (22 of 59) patients were continent in group A and group B, respectively (p=0.028). The ICS male SF mean score showed better results in group A than in group B patients at both 1 mo (14.6 vs 18.3) and 3 mo (8.1 vs 12.2) after RP (p=0.002). In age-adjusted logistic regression analyses, patients who performed preoperative PFME had a 0.41-fold lower risk of being incontinent 1 mo after RP and a 0.38-fold lower risk of being incontinent 3 mo after RP (p≤0.001). CONCLUSIONS Preoperative PFME may improve early continence and QoL outcomes after RP. Further studies are needed to corroborate our results.

Treatment of metastatic renal cell carcinoma

The median survival of patients with metastatic renal cell carcinoma (mRCC) has increased from 10 months to more than 40 months since the advent of targeted therapy. Sunitinib and bevacizumab represent the first-line standards of care for patients with clear cell mRCC. Temsirolimus is the standard of care for those with poor-risk features. Additionally, exploratory analyses of the temsirolimus data indicate important benefits for those with non-clear-cell mRCC. Everolimus has proved its efficacy in second-line therapy. Sunitinib and sorafenib are also effective for non-clear-cell histological subtypes and after failure of first-line treatment. Potential survival benefits can also be derived from cytoreductive nephrectomy (CNT) in patients previously exposed to sunitinib or bevacizumab. Phase III studies are ongoing to address the importance of CNT in the targeted therapy era. Such information is crucial to ensure timely delivery of a combination of medical and surgical therapies to this patient population.

Location of the Primary Tumor is Not an Independent Predictor of Cancer Specific Mortality in Patients With Upper Urinary Tract Urothelial Carcinoma

PURPOSE The prognostic significance of renal pelvis vs ureteral upper urinary tract urothelial carcinoma tumor location is controversial. We assessed the prognostic significance of upper urinary tract urothelial carcinoma tumor location in a large, population based data set. MATERIALS AND METHODS Our analyses relied on 2,824 patients treated with nephroureterectomy for upper urinary tract urothelial carcinoma within 9 SEER registries between 1988 and 2004. Univariable and multivariable models tested the effect of tumor location on cancer specific mortality rates. Covariates consisted of age, race, SEER registry, gender, type of surgery (nephroureterectomy with vs without bladder cuff removal), pT stage, pN stage, grade and year of surgery. RESULTS Relative to ureteral tumors renal pelvis tumors were of higher stage (T3/T4 disease 38.4% vs 57.9%, p <0.001) and had a higher rate of lymph node metastases (6.0% vs 9.8%, p = 0.003) at nephroureterectomy. The respective 5-year cancer specific mortality-free survival estimates were 81.0% vs 75.5% (p = 0.007). However, after multivariable adjustment tumor location failed to reach independent predictor status of cancer specific mortality (p = 0.8). CONCLUSIONS To our knowledge this is the largest cohort in which the impact of upper urinary tract urothelial carcinoma tumor location on cancer specific mortality was examined. At nephroureterectomy renal pelvis tumors had significantly more advanced T and N stages compared to ureteral tumors. However, after adjustment for stage, grade and other covariates tumor location did not independently predict cancer specific mortality. Thus, the biological behavior of renal pelvis vs ureteral tumors is the same after nephroureterectomy as long as stage, grade, and other patient and tumor characteristics are accounted for.

Preoperative Prostate-Specific Antigen Isoform p2PSA and Its Derivatives, %p2PSA and Prostate Health Index, Predict Pathologic Outcomes in Patients Undergoing Radical Prostatectomy for Prostate Cancer

BACKGROUND Currently available predictive models fail to assist clinical decision making in prostate cancer (PCa) patients who are possible candidates for radical prostatectomy (RP). New biomarkers would be welcome. OBJECTIVE Test the hypothesis that prostate-specific antigen (PSA) isoform p2PSA and its derivates, percentage of p2PSA to free PSA (%p2PSA) and the Prostate Health Index (PHI), predict PCa characteristics at final pathology after RP. DESIGN, SETTING, AND PARTICIPANTS An observational prospective study was performed in 350 consecutive men diagnosed with clinically localised PCa who underwent RP. MEASUREMENTS We determined the predictive accuracy of serum total PSA (tPSA), free PSA (fPSA), fPSA-to-tPSA ratio (%fPSA), p2PSA, %p2PSA, and PHI. The primary end point was to determine the accuracy of these biomarkers in predicting the presence of pT3 disease, pathologic Gleason sum≥7, Gleason sum upgrading, and tumour volume<0.5 ml. INTERVENTION Open retropubic and robot-assisted laparoscopic RP was performed. Pelvic lymphadenectomy was performed according to baseline oncologic parameters and the surgeons judgement. RESULTS AND LIMITATIONS The %p2PSA and PHI levels were significantly higher in patients with pT3 disease, pathologic Gleason sum≥7, and Gleason sum upgrading (all p values<0.001). Conversely, %p2PSA and PHI levels were significantly lower in patients with tumour volume<0.5 ml (p<0.001). By univariate analysis, both %p2PSA and PHI were accurate predictors of pT3 disease, pathologic Gleason sum≥7, Gleason sum upgrading, and tumour volume<0.5 ml. By multivariate analyses, the inclusion of both %p2PSA and PHI significantly increased the predictive accuracy of a base multivariate model (excluding the tumour volume prediction for both variables, and Gleason sum upgrading for the model including %p2PSA) that included patient age, tPSA, fPSA, f/tPSA, clinical stage, and biopsy Gleason sum. CONCLUSIONS We found that p2PSA and its derivatives are predictors of PCa characteristics at final pathology after RP and are more accurate than currently available markers.

Segmental Ureterectomy Can Safely be Performed in Patients With Transitional Cell Carcinoma of the Ureter

PURPOSE To date no study to our knowledge has compared cancer control outcomes of segmental ureterectomy relative to nephroureterectomy, which represents the standard of care for ureteral transitional cell carcinoma. We compared cancer specific mortality rates according to surgery type (nephroureterectomy vs segmental ureterectomy) in a large population based cohort of patients with ureteral transitional cell carcinoma. MATERIALS AND METHODS Our analyses involved 2,044 patients with pathological T1-T4 N0M0 ureteral transitional cell carcinoma from the Surveillance, Epidemiology and End Results database. Survival plots and Cox regression models compared cancer specific mortality after segmental ureterectomy, or nephroureterectomy with or without bladder cuff removal. Covariates consisted of pathological stage and grade, age, race, gender and year of surgery. RESULTS Median followup of censored patients was 30.0 months. Overall 569 (27.8%) patients underwent segmental ureterectomy vs 1,222 (59.8%) nephroureterectomy with bladder cuff removal and 253 (12.4%) nephroureterectomy without bladder cuff removal. At 5 years cancer specific mortality-free rates for segmental ureterectomy vs nephroureterectomy with bladder cuff removal vs nephroureterectomy without bladder cuff removal were 86.6% vs 82.2% vs 80.5%, respectively (all pairwise log rank comparisons p >or=0.05). On univariable and multivariable analyses of the entire cohort, as well as after stratification according to pT1-2 vs pT3-4 stage, the type of surgery (segmental ureterectomy vs nephroureterectomy with bladder cuff removal vs nephroureterectomy without bladder cuff removal) failed to affect cancer specific mortality rates (p >or=0.2). CONCLUSIONS In patients with ureteral transitional cell carcinoma segmental ureterectomy does not undermine cancer control outcomes relative to nephroureterectomy (with or without bladder cuff removal). Therefore, segmental ureterectomy may be offered to virtually all patients with ureteral transitional cell carcinoma when it is technically feasible, which also includes carefully selected patients with T3 or even T4 lesions.