Prognostic impact of subclassification of radical prostatectomy positive margins by linear extent and Gleason grade.

PURPOSE: We evaluated the relationship of progression to positive surgical margin linear length and Gleason grade at a positive surgical margin. MATERIALS AND METHODS: We studied 2,150 prostatectomies done for pT2 or pT3a disease to determine grade, stage and surgical margin status. In patients with positive surgical margins we recorded the location, number, positive margin linear length and highest Gleason grade at a positive margin. The Kaplan-Meier method and log rank test were used to determine differences in progression-free probability among positive margin features. The concordance index was used to discriminate the accuracy of grouping surgical margin status as negative/positive vs positive margin linear length/highest Gleason grade. RESULTS: A total of 207 cases (10%) showed positive surgical margins, including 93 (45%) that were pT2+ and 114 (55%) that were pT3a. Patients with pT3a and positive margins had greater prostate specific antigen and tumor volume, and Gleason score 7 or greater than those with pT2+. A total of 45 patients with positive margins progressed. We then subcategorized positive margins. Of the patients 164 (79%) had 1 positive margin. Positive margin linear length was 1 mm or less, 1.1 to 3 and greater than 3 in 104 (50%), 55 (27%) and 48 cases (23%), respectively. Two-year progression-free probability was 95%, 91%, 83% and 47% in patients with negative margins and the 3 positive margin linear length groups, respectively (p <0.001). Gleason grade at a positive margin was 3 and 4/5 in 154 (74%) and 53 patients (26%), respectively. The latter group was significantly more likely to progress (p <0.001). The overall margin status concordance index was 0.636. It was not considerably enhanced by categorizing by positive surgical margin linear length/highest Gleason grade at positive margins. CONCLUSIONS: The linear extent of and highest Gleason grade at a positive surgical margin are associated with progression. However, subcategorization does not importantly add to predictive models using margin status only. More robust markers are needed in patients with positive surgical margins to warrant routine reporting and identify those at risk for biochemical recurrence.

Lymph node-positive bladder cancer treated with radical cystectomy and lymphadenectomy: effect of the level of node positivity.

BACKGROUND: The extent of lymphadenectomy needed to optimize oncologic outcomes after radical cystectomy (RC) for patients with regionally advanced bladder cancer (BCa) is unclear. OBJECTIVE: Evaluate the effect of the location of lymph node metastasis on recurrence-free survival (RFS) and cancer-specific survival (CSS) for patients undergoing RC with a mapping pelvic lymph node dissection (PLND). DESIGN, SETTING, AND PARTICIPANTS: A study of 591 patients undergoing RC with mapping PLND was completed between 2000 and 2010. Median follow-up was 30 mo. INTERVENTION: RC with mapping PLND. MEASUREMENTS: We evaluated the impact of lymph node involvement by location on disease outcomes using the 2010 TNM staging system. Survival estimates were described using Kaplan-Meier methods. Gender, age, pathologic stage, histology, number of positive nodes, location of positive nodes, node density, use of perioperative chemotherapy, and grade were evaluated as predictors of RFS and CSS using multivariate Cox proportional hazard regression. RESULTS AND LIMITATIONS: Overall, 114 patients (19%) had lymph node involvement, and 42 patients (7%) had pN3 disease. On multivariate analysis, the number of positive lymph nodes (one or two or more) was significantly associated with increased risk of cancer-specific death (hazard ratio [HR]: 1.9 [95% confidence interval (CI), 1.04-3.46], p=0.036; versus HR: 4.3 [95% CI, 2.25-8.34], p<0.0005). Positive lymph node location was not an independent predictor of RFS or CSS. Five-year RFS for pN3 patients undergoing RC with PLND was 25% (95% CI, 10-42). This finding was not statistically different from our pN1 and pN2 patients (38% [95% CI, 22-54] and 35% [95% CI, 11-60], respectively). This study is limited by the lack of prospective randomization and a control group. CONCLUSIONS: The outcome for patients with involved common iliac lymph nodes was similar to the outcome for patients with primary nodal basin disease. These data support inclusion of the common iliac lymph nodes (pN3) in the nodal staging system for BCa. Lymph node location was not an independent predictor of outcome, whereas the number of positive lymph nodes was an independent predictor of worse oncologic outcome (pN1, pN2). Further refinements of the TNM system to provide improved prognostication are warranted.

Evaluation of multiple risk-associated single nucleotide polymorphisms versus prostate-specific antigen at baseline to predict prostate cancer in unscreened men.

BACKGROUND: Although case-control studies have identified numerous single nucleotide polymorphisms (SNPs) associated with prostate cancer, the clinical role of these SNPs remains unclear. OBJECTIVE: Evaluate previously identified SNPs for association with prostate cancer and accuracy in predicting prostate cancer in a large prospective population-based cohort of unscreened men. DESIGN, SETTING, AND PARTICIPANTS: This study used a nested case-control design based on the Malmö Diet and Cancer cohort with 943 men diagnosed with prostate cancer and 2829 matched controls. Blood samples were collected between 1991 and 1996, and follow-up lasted through 2005. MEASUREMENTS: We genotyped 50 SNPs, analyzed prostate-specific antigen (PSA) in blood from baseline, and tested for association with prostate cancer using the Cochran-Mantel-Haenszel test. We further developed a predictive model using SNPs nominally significant in univariate analysis and determined its accuracy to predict prostate cancer. RESULTS AND LIMITATIONS: Eighteen SNPs at 10 independent loci were associated with prostate cancer. Four independent SNPs at four independent loci remained significant after multiple test correction (p<0.001). Seven SNPs at five independent loci were associated with advanced prostate cancer defined as clinical stage≥T3 or evidence of metastasis at diagnosis. Four independent SNPs were associated with advanced or aggressive cancer defined as stage≥T3, metastasis, Gleason score≥8, or World Health Organization grade 3 at diagnosis. Prostate cancer risk prediction with SNPs alone was less accurate than with PSA at baseline (area under the curve of 0.57 vs 0.79), with no benefit from combining SNPs with PSA. This study is limited by our reliance on clinical diagnosis of prostate cancer; there are likely undiagnosed cases among our control group. CONCLUSIONS: Only a few previously reported SNPs were associated with prostate cancer risk in the large prospective Diet and Cancer cohort in Malmö, Sweden. SNPs were less useful in predicting prostate cancer risk than PSA at baseline.

Evaluating the utility of a preoperative nomogram for predicting 90-day mortality following radical cystectomy for bladder cancer.

OBJECTIVE: To evaluate the performance of the Isbarn nomogram for predicting 90-day mortality following radical cystectomy in a contemporary series. PATIENTS AND METHODS: We identified 1141 consecutive radical cystectomy patients treated at our institution between 1995 and 2005 with at least 90 days of follow-up. We applied the published nomogram to our cohort, determining its discrimination, with the area under the receiver operating characteristic curve (AUC), and calibration. We further compared it with a simple model using age and the Charlson comorbidity score. RESULTS: Our cohort was similar to that used to develop the Isbarn nomogram in terms of age, gender, grade and histology; however, we observed a higher organ-confined (≤pT2, N0) rate (52% vs 24%) and a lower overall 90-day mortality rate [2.8% (95% confidence interval 1.9%, 3.9%) vs 3.9%]. The Isbarn nomogram predicted individual 90-day mortality in our cohort with moderate discrimination [AUC 73.8% (95% confidence interval 64.4%, 83.2%)]. In comparison, a model using age and Charlson score alone had a bootstrap-corrected AUC of 70.2% (95% confidence interval 67.2%, 75.4%). CONCLUSIONS: The Isbarn nomogram showed moderate discrimination in our cohort; however, the exclusion of important preoperative comorbidity variables and the use of postoperative pathological stage limit its utility in the preoperative setting. The use of a simple model combining age and Charlson score yielded similar discriminatory ability and underscores the significance of individual patient variables in predicting outcomes. An accurate tool for predicting postoperative morbidity/mortality following radical cystectomy would be valuable for treatment planning and counselling. Future nomogram design should be based on preoperative variables including individual risk factors, such as comorbidities.

Salvage radical prostatectomy for radiation-recurrent prostate cancer: a multi-institutional collaboration.

BACKGROUND: Oncologic outcomes in men with radiation-recurrent prostate cancer (PCa) treated with salvage radical prostatectomy (SRP) are poorly defined. OBJECTIVE: To identify predictors of biochemical recurrence (BCR), metastasis, and death following SRP to help select patients who may benefit from SRP. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective, international, multi-institutional cohort analysis. There was a median follow-up of 4.4 yr following SRP performed on 404 men with radiation-recurrent PCa from 1985 to 2009 in tertiary centers. INTERVENTION: Open SRP. MEASUREMENTS: BCR after SRP was defined as a serum prostate-specific antigen (PSA) ≥ 0.1 or ≥ 0.2 ng/ml (depending on the institution). Secondary end points included progression to metastasis and cancer-specific death. RESULTS AND LIMITATIONS: Median age at SRP was 65 yr of age, and median pre-SRP PSA was 4.5 ng/ml. Following SRP, 195 patients experienced BCR, 64 developed metastases, and 40 died from PCa. At 10 yr after SRP, BCR-free survival, metastasis-free survival, and cancer-specific survival (CSS) probabilities were 37% (95% confidence interval [CI], 31-43), 77% (95% CI, 71-82), and 83% (95% CI, 76-88), respectively. On preoperative multivariable analysis, pre-SRP PSA and Gleason score at postradiation prostate biopsy predicted BCR (p = 0.022; global p < 0.001) and metastasis (p = 0.022; global p < 0.001). On postoperative multivariable analysis, pre-SRP PSA and pathologic Gleason score at SRP predicted BCR (p = 0.014; global p < 0.001) and metastasis (p < 0.001; global p < 0.001). Lymph node involvement (LNI) also predicted metastasis (p = 0.017). The main limitations of this study are its retrospective design and the follow-up period. CONCLUSIONS: In a select group of patients who underwent SRP for radiation-recurrent PCa, freedom from clinical metastasis was observed in >75% of patients 10 yr after surgery. Patients with lower pre-SRP PSA levels and lower postradiation prostate biopsy Gleason score have the highest probability of cure from SRP.

Intraoperative conversion from partial to radical nephrectomy at a single institution from 2003 to 2008.

PURPOSE: Little information exists on conversion from partial to radical nephrectomy. We assessed the intraoperative reasons and predictive factors for conversion in a contemporary series of patients undergoing partial nephrectomy. MATERIALS AND METHODS: We identified all patients at our institution who underwent open or laparoscopic partial nephrectomy with conversion to radical nephrectomy between 2003 and 2008. Renal function was assessed by the glomerular filtration rate using the modification of diet in renal disease equation. We used logistic regression analysis to determine whether tumor site, tumor size, body mass index, American Society of Anesthesiologists score, age or gender was associated with the conversion risk. RESULTS: The rate of conversion to radical nephrectomy was 6% (61 of 1,029 patients). In the open partial nephrectomy group 59 of 865 cases (7%, 95% CI 5-9) and in the laparoscopic partial nephrectomy group 2 of 164 (1.2%, 95% CI 0.01-4) were converted. The most common reasons for conversion were invasion of hilar structures, size discrepancy and insufficient residual kidney. Patients with conversion were more likely to have larger tumors (per 1 cm increase OR 1.41, 95% CI 1.24-1.59), a central site (central vs peripheral OR 7.74, 95% CI 3.98-15) and a lower preoperative glomerular filtration rate (per 10 ml/minute/1.73 m(2) OR 0.78, 95% CI 0.67-0.91), and present with symptoms (any vs none OR 2.78, 95% CI 1.54-5.04) than those without conversion. The median postoperative glomerular filtration rate was 46 vs 61 ml/minute/1.73 m(2) in patients with vs without conversion. CONCLUSIONS: Conversion to radical nephrectomy was rare in patients undergoing partial nephrectomy in this series. Increasing tumor size, central site, lower preoperative glomerular filtration rate and symptoms at presentation were associated with an increased risk of conversion, which increases the likelihood of chronic kidney disease postoperatively.

Intra-individual short-term variability of prostate-specific antigen and other kallikrein markers in a serial collection of blood from men under evaluation for prostate cancer.

STUDY TYPE: Diagnostic (exploratory cohort). LEVEL OF EVIDENCE: 2b. OBJECTIVE: To assess variation of total prostate-specific antigen (tPSA), free PSA (fPSA), percent fPSA, human glandular kallikrein 2 (hK2) and intact PSA measured three times within 2 weeks. Knowledge of the variation in an individual's PSA level is important for clinical decision-making. PATIENTS AND METHODS: Study participants were 149 patients referred for prostate biopsy, of which 97 had benign disease and 52 had prostate cancer. Three blood samples were drawn with a median of 4 h between first and second samples and 12 days between first and third samples. Variability was described by absolute differences, ratios and intra-individual coefficients of variation. Total PSA, fPSA, hK2 and intact PSA were measured in anticoagulated blood plasma. RESULTS: At baseline, the median tPSA was 6.8 (interquartile range, 4.5-9.6) ng/mL. The intra-individual variation was low for all biomarkers, and lowest for tPSA. For 80% of participants, the ratio between first and second time points for tPSA was in the range 0.91-1.09 and the ratio for percent fPSA was in the range 0.89-1.15. Total coefficients of variation between time 1 and 2 for tPSA, fPSA, percent fPSA, hK2 and intact PSA were 4.0%, 6.6%, 6.0%, 9.2% and 9.5%, respectively. The measurements taken several days apart varied more than those taken on the same day, although the variation between both time points was not large. CONCLUSIONS: The intra-individual variation for all the kallikrein-like markers studied was relatively small, especially for samples drawn the same day. Few cases are reclassified between the time points. This indicates the high short-term biological and technical reproducibility of the tests in clinical use.

Surgery confounds biology: the predictive value of stage-, grade- and prostate-specific antigen for recurrence after radical prostatectomy as a function of surgeon experience.

Statistical models predicting cancer recurrence after surgery are based on biologic variables. We have shown previously that prostate cancer recurrence is related to both tumor biology and to surgical technique. Here, we evaluate the association between several biological predictors and biochemical recurrence across varying surgical experience. The study included two separate cohorts: 6,091 patients treated by open radical prostatectomy and an independent replication set of 2,298 patients treated laparoscopically. We calculated the odds ratios for biological predictors of biochemical recurrence-stage, Gleason grade and prostate-specific antigen (PSA)-and also the predictive accuracy (area under the curve, AUC) of a multivariable model, for subgroups of patients defined by the experience of their surgeon. In the open cohort, the odds ratio for Gleason score 8+ and advanced pathologic stage, though not PSA or Gleason score 7, increased dramatically when patients treated by surgeons with lower levels of experience were excluded (Gleason 8+: odds ratios 5.6 overall vs. 13.0 for patients treated by surgeons with 1,000+ prior cases; locally advanced disease: odds ratios of 6.6 vs. 12.2, respectively). The AUC of the multivariable model was 0.750 for patients treated by surgeons with 50 or fewer cases compared to 0.849 for patients treated by surgeons with 500 or more. Although predictiveness was lower overall for the independent replication set cohort, the main findings were replicated. Surgery confounds biology. Although our findings have no direct clinical implications, studies investigating biological variables as predictors of outcome after curative resection of cancer should consider the impact of surgeon-specific factors.

A panel of kallikrein marker predicts prostate cancer in a large, population-based cohort followed for 15 years without screening.

BACKGROUND: Prostate-specific antigen (PSA) has modest specificity for prostate cancer. A panel of four kallikrein markers (total PSA, free PSA, intact PSA, and kallikrein-related peptidase 2) is a highly accurate predictor of biopsy outcome. The clinical significance of biopsy-detectable cancers in men classified as low-risk by this panel remains unclear. METHODS: The Malmö Diet and Cancer study is a population-based cohort of 11,063 Swedish men aged 45 to 73 providing a blood sample at baseline during 1991-1996. The Swedish Cancer Registry was used to identify 943 men diagnosed with prostate cancer by December 31, 2006. PSA testing was low. We assessed the predictive accuracy of our published statistical model to predict subsequent prostate cancer diagnosis in men with a total PSA level of 3.0 ng/mL or more at baseline. RESULTS: Compared with total PSA and age, the full kallikrein panel enhanced the predictive accuracy for clinically diagnosed prostate cancer (concordance index 0.65 vs. 0.75; P < 0.001). For every 1,000 men with a total PSA level of 3 ng/mL or more at baseline, the model would classify as high-risk 131 of 152 (86%) of the cancer cases diagnosed clinically within 5 years; 421 men would be classified as low-risk by the panel and recommended against biopsy. Of these, only 2 would be diagnosed with advanced prostate cancer (clinical T3-T4 or metastases) within 5 years. CONCLUSIONS: Men with a PSA level of 3 ng/mL or more but defined as low-risk by the panel of four kallikrein markers are unlikely to develop incurable prostate cancer. IMPACT: Use of the panel to determine referral to biopsy could substantially reduce the number of unnecessary prostate biopsies.

Prognostic significance of lymphovascular invasion in radical prostatectomy specimens.

UNLABELLED: 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.

Evaluation of prediagnostic prostate-specific antigen dynamics as predictors of death from prostate cancer in patients treated conservatively.

Prostate-specific antigen (PSA) dynamics have been proposed to predict outcome in men with prostate cancer. We assessed the value of PSA velocity (PSAV) and PSA doubling time (PSADT) for predicting prostate cancer-specific mortality (PCSM) in men with clinically localized prostate cancer undergoing conservative management or early hormonal therapy. From 1990 to 1996, 2,333 patients were identified, of whom 594 had two or more PSA values before diagnosis. We examined 12 definitions for PSADT and 10 for PSAV. Because each definition required PSA measurements at particular intervals, the number of patients eligible for each definition varied from 40 to 594 and number of events from 10 to 119. Four PSAV definitions, but no PSADT, were significantly associated with PCSM after adjustment for PSA in multivariable Cox proportional hazards regression. All four could be calculated only for a proportion of events, and the enhancements in predictive accuracy associated with PSAV had very wide confidence intervals. There was no clear benefit of PSAV in men with low PSA and Gleason grade 6 or less. Although evidence that certain PSAV definitions help to predict PCSM in the cohort exist, the value of incorporating PSAV in predictive models to assist in determining eligibility for conservative management is, at best, uncertain.

Validation study of a web-based assessment of functional recovery after radical prostatectomy.

BACKGROUND: Good clinical care of prostate cancer patients after radical prostatectomy depends on careful assessment of post-operative morbidities, yet physicians do not always judge patient symptoms accurately. Logistical problems associated with using paper questionnaire limit their use in the clinic. We have implemented a web-interface ("STAR") for patient-reported outcomes after radical prostatectomy. METHODS: We analyzed data on the first 9 months of clinical implementation to evaluate the validity of the STAR questionnaire to assess functional outcomes following radical prostatectomy. We assessed response rate, internal consistency within domains, and the association between survey responses and known predictors of sexual and urinary function, including age, time from surgery, nerve sparing status and co-morbidities. RESULTS: Of 1581 men sent an invitation to complete the instrument online, 1235 responded for a response rate of 78%. Cronbach's alpha was 0.84, 0.86 and 0.97 for bowel, urinary and sexual function respectively. All known predictors of sexual and urinary function were significantly associated with survey responses in the hypothesized direction. CONCLUSIONS: We have found that web-based assessment of functional recovery after radical prostatectomy is practical and feasible. The instrument demonstrated excellent psychometric properties, suggested that validity is maintained when questions are transferred from paper to electronic format and when patients give responses that they know will be seen by their doctor and added to their clinic record. As such, our system allows ready implementation of patient-reported outcomes into routine clinical practice.

Prostate specific antigen velocity does not aid prostate cancer detection in men with prior negative biopsy.

PURPOSE: Prostate specific antigen velocity has been proposed as a marker to aid in prostate cancer detection. We determined whether prostate specific antigen velocity could predict repeat biopsy results in men with persistently increased prostate specific antigen after initial negative biopsy. MATERIALS AND METHODS: We identified 1,837 men who participated in the Göteborg or Rotterdam section of the European Randomized Screening study of Prostate Cancer and who underwent 1 or more subsequent prostate biopsies after an initial negative finding. We evaluated whether prostate specific antigen velocity improved predictive accuracy beyond that of prostate specific antigen alone. RESULTS: Of the 2,579 repeat biopsies 363 (14%) were positive for prostate cancer, of which 44 (1.7%) were high grade (Gleason score 7 or greater). Prostate specific antigen velocity was statistically associated with cancer risk but had low predictive accuracy (AUC 0.55, p <0.001). There was some evidence that prostate specific antigen velocity improved AUC compared to prostate specific antigen for high grade cancer. However, the small increase in risk associated with high prostate specific antigen velocity (from 1.7% to 2.8% as velocity increased from 0 to 1 ng/ml per year) had questionable clinical relevance. CONCLUSIONS: Men with prior negative biopsy are at lower risk for prostate cancer at subsequent biopsies with high grade disease particularly rare. We found little evidence to support prostate specific antigen velocity to aid in decisions about repeat biopsy for prostate cancer.

Clinical outcomes of primary bladder carcinoma in situ in a contemporary series.

PURPOSE: The natural history of primary bladder carcinoma in situ has not been well described. We describe patterns of disease recurrence and progression, and identify clinical outcome predictors of primary carcinoma in situ after bacillus Calmette-Guerin therapy. MATERIALS AND METHODS: We performed a retrospective analysis of 155 patients diagnosed with isolated primary high grade carcinoma in situ at a tertiary center from 1990 to 2008 who underwent transurethral resection followed by intravesical bacillus Calmette-Guerin therapy. The end points included time to disease recurrence, time to progression to invasive disease (cT1 or higher) or to muscle invasive disease (cT2 or higher), or early radical cystectomy. Predictors included gender, age, race, smoking history, presenting symptoms, carcinoma in situ pattern (focal, multiple or diffuse) and response to bacillus Calmette-Guerin. RESULTS: A total of 155 patients received bacillus Calmette-Guerin therapy within 6 months. The 5-year cumulative incidence of progression to cT1 or higher was 45% (95% CI 37-55) and to cT2 or higher was 17% (95% CI 12-25) adjusting for the competing risk of radical cystectomy. Of 130 patients evaluated for response to bacillus Calmette-Guerin 81 (62%) were considered responders. Response to bacillus Calmette-Guerin was significantly associated with progression to cT1 or higher/radical cystectomy (HR 0.59, 95% CI 0.36-0.95, p = 0.029) and to cT2 or higher/radical cystectomy (HR 0.53, 95% CI 0.32-0.88, p = 0.015). This association was largely driven by the higher rate of early radical cystectomy among nonresponders. CONCLUSIONS: Despite bacillus Calmette-Guerin therapy and early radical cystectomy, patients with primary carcinoma in situ had a high rate of disease progression. Response to bacillus Calmette-Guerin was significantly associated with a lower rate of disease progression or early radical cystectomy.

A four-kallikrein panel predicts prostate cancer in men with recent screening: data from the European Randomized Study of Screening for Prostate Cancer, Rotterdam.

PURPOSE: We have developed a statistical prediction model for prostate cancer based on four kallikrein markers in blood: total, free, and intact prostate-specific antigen (PSA), and kallikrein-related peptidase 2 (hK2). Although this model accurately predicts the result of biopsy in unscreened men, its properties for men with a history of PSA screening have not been fully characterized. EXPERIMENTAL DESIGN: A total of 1,501 previously screened men with elevated PSA underwent initial biopsy during rounds 2 and 3 of the European Randomized Study of Screening for Prostate Cancer, Rotterdam, with 388 cancers diagnosed. Biomarker levels were measured in serum samples taken before biopsy. The prediction model developed on the unscreened cohort was then applied and predictions compared with biopsy outcome. RESULTS: The previously developed four-kallikrein prediction model had much higher predictive accuracy than PSA and age alone (area under the curve of 0.711 versus 0.585, and 0.713 versus 0.557 with and without digital rectal exam, respectively; both P < 0.001). Similar statistically significant enhancements were seen for high-grade cancer. Applying the model with a cutoff of 20% cancer risk as the criterion for biopsy would reduce the biopsy rate by 362 for every 1,000 men with elevated PSA. Although diagnosis would be delayed for 47 cancers, these would be predominately low-stage and low-grade (83% Gleason 6 T(1c)). CONCLUSIONS: A panel of four kallikreins can help predict the result of initial biopsy in previously screened men with elevated PSA. Use of a statistical model based on the panel would substantially decrease rates of unnecessary biopsy.

Empirical estimates of the lead time distribution for prostate cancer based on two independent representative cohorts of men not subject to prostate-specific antigen screening.

BACKGROUND: Lead time, the estimated time by which screening advances the date of diagnosis, is used to calculate the risk of overdiagnosis. We sought to describe empirically the distribution of lead times between an elevated prostate-specific antigen (PSA) and subsequent prostate cancer diagnosis. METHODS: We linked the Swedish cancer registry to two independent cohorts: 60-year-olds sampled in 1981-1982 and 51- to 56-year-olds sampled in 1982-1985. We used univariate kernel density estimation to characterize the lead time distribution. Linear regression was used to model the lead time as a function of baseline PSA and logistic regression was used to test for an association between lead time and either stage or grade at diagnosis. RESULTS: Of 1,167 older men, 132 were diagnosed with prostate cancer, of which 57 had PSA>or=3 ng/mL at baseline; 495 of 4,260 younger men were diagnosed with prostate cancer, of which 116 had PSA>or=3 ng/mL at baseline. The median lead time was slightly longer in the younger men (12.8 versus 11.8 years). In both cohorts, wide variation in lead times followed an approximately normal distribution. Longer lead times were significantly associated with a lower risk of high-grade disease in older and younger men [odds ratio, 0.82 (P=0.023) and 0.77 (P<0.001)]. CONCLUSION: Our findings suggest that early changes in the natural history of the disease are associated with high-grade cancer at diagnosis. IMPACT: The distinct differences between the observed distribution of lead times and those used in modeling studies illustrate the need to model overdiagnosis rates using empirical data.

The total number of retroperitoneal lymph nodes resected impacts clinical outcome after chemotherapy for metastatic testicular cancer.

OBJECTIVES: To evaluate the prognostic significance of the total number of lymph nodes obtained at postchemotherapy retroperitoneal lymph node dissection (PC-RPLND). After the multidisciplinary management of metastatic germ cell tumor, approximately 10%-15% of patients with the histologic finding of fibrosis or teratoma will suffer disease recurrence. METHODS: Between 1989 and 2006, a total of 628 patients underwent PC-RPLND and were found to have either fibrosis or teratoma. After Institutional Review Board approval, complete clinical and pathologic data were obtained from our prospective testis cancer surgical database. A Cox proportional hazards regression model was constructed to evaluate the association of the total number of lymph nodes obtained at PC-RPLND on disease recurrence. RESULTS: On pathologic evaluation, 248 (57%) patients had fibrosis and 184 (43%) patients had teratoma. The median number of lymph nodes resected was 25 (interquartile range, 15-37). On multivariable analysis, increasing postchemotherapy nodal size and decreasing lymph node counts were significant predictors of disease recurrence (P=.01, .04, respectively). For patients with 10 nodes removed, the predicted 2-year relapse free probability was 90%, compared with 97% when 50 nodes were removed. CONCLUSIONS: Our data suggest that the total number of lymph nodes removed and analyzed is an independent predictor of disease recurrence after PC-RPLND. This has implications both for the urologist to assure completeness of resection and for the pathologist to meticulously assess the pathologic specimens.

Finasteride to prevent prostate cancer: should all men or only a high-risk subgroup be treated?

PURPOSE Finasteride has been shown to reduce the incidence of prostate cancer. Yet the use of finasteride remains low, likely because of the risk of adverse effects. We sought to determine whether prostate-specific antigen (PSA) levels could identify a high-risk subgroup for which the benefits of finasteride treatment outweigh the potential harms. PATIENTS AND METHODS Raw data from the Prostate Cancer Prevention Trial were used to model chemopreventive treatment strategies: treat all men, treat no men, or treat a high-risk subgroup based on PSA level. We weighted the benefits (reduction in cancer rate) and harms (treatment rate) of each strategy using numbers-needed-to-treat thresholds-the maximum number of men a clinician would treat with finasteride to prevent one cancer. Results Of 9,058 men, 1,957 were diagnosed with prostate cancer during the 7-year study. For the end point of all cancers, including both for-cause and end-of-study biopsies, the optimal strategy is to treat all or nearly all men. To reduce risk of cancers detected through routine care, treating men with PSA > 1.3 or > 2 ng/mL is optimal. For example, treating only men with PSA > 2 ng/mL reduced the treatment rate by 83% and resulted in a cancer rate only 1.1% higher than treating all men. CONCLUSION Clinicians wishing to reduce the risk of any biopsy-detectable prostate cancer should recommend finasteride to all men. Clinicians who believe that it is unnecessary to prevent all cancers, but that preventing those readily detectable by screening would be desirable, would be best off recommending finasteride only to a high-risk subgroup.

Focal treatment or observation of prostate cancer: pretreatment accuracy of transrectal ultrasound biopsy and T2-weighted MRI.

OBJECTIVES: To test the hypothesis that men with prostate cancer (PCA) and preoperative disease features considered favorable for focal treatment would be accurately characterized with transrectal biopsy and prostate magnetic resonance imaging (MRI) by performing a retrospective analysis of a selected cohort of such patients treated with radical prostatectomy (RP). METHODS: A total of 202 patients with PCA who had preoperative MRI and low-risk biopsy criteria (no Gleason grade 4/5, 1 involved core, < 2 mm, PSA density < or = 0.10, clinical stage < or = T2a) were included in the study. Indolent RP pathology was defined as no Gleason 4/5, organ confined, tumor volume < 0.5 mL, and negative surgical margins. MRI ability to locate and determine the tumor extent was assessed. RESULTS: After RP, 101 men (50%) had nonindolent cancer. Multifocal and bilateral tumors were present in 81% and 68% of patients, respectively. MRI indicated extensive disease in 16 (8%). MRI sensitivity to locate PCA ranged from 2% to 20%, and specificity from 91% to 95%. On univariate analysis, MRI evidence of extracapsular extension (P = .027) and extensive disease (P = .001) were associated with nonindolent cancer. On multivariate analysis, only the latter remained as significant predictor (P = .0018). CONCLUSIONS: Transrectal biopsy identified men with indolent tumors favorable for focal treatment in 50% of cases. MRI findings of extracapsular extension and extensive tumor involving more than half of the gland are associated with unfavorable features, and may be useful in excluding patients from focal treatment. According to these data, endorectal MRI is not sufficient to localize small tumors for focal treatment.

Critical evaluation of perioperative complications in laparoscopic partial nephrectomy.

OBJECTIVES: To analyze our experience with laparoscopic partial nephrectomy (LPN) to detail postoperative adverse events and identify factors that may contribute to adverse surgical outcomes. Complications from LPN result from a variety of factors, both technical and inherent. METHODS: Single-center review of 144 consecutive LPN (4 surgeons) performed between November 2002 and January 2008 was conducted. Identified complications were graded using standard reporting criteria. Univariate and multivariate statistical analysis of variables and their association with complication event and blood loss was performed. RESULTS: A total of 39 complications occurred in 29 (20%) cases. Of these, 20 (51%) were urologic and 19 (49%) were nonurologic. Individual adverse events by grade were as follows: grade I, 6 (15.4%); grade II, 19 (48.7%), grade III, 11 (28.2%), and grade IV, 3 (7.7%). No grade V complications occurred. The median tumor size and ischemia time were 2.7 cm and 35 minutes, respectively. Univariate analysis identified increased American Society of Anesthesiologists risk score (odds ratio 2.99, 95% confidence interval [CI] 1.28, 6.94) and ischemia time (odds ratio 1.31; 95% CI 1.00, 1.71) as associated with complication risk. On multivariate analysis, longer ischemia time was associated with increased estimated blood loss (95% CI 3, 57; P = .03). Hospital readmission and reintervention was required in 15 (10.4%) and 9 (6.2%) patients, respectively. CONCLUSIONS: Complications from LPN occur in a meaningful proportion of procedures although the majority does not require reintervention and half are not urologic. Increasing ischemia time and American Society of Anesthesiologists score are associated with risk for unfavorable surgical outcomes.