The Efficient and Effective Use of Exfoliative Urinary Markers.

INTRODUCTION: Multiple exfoliative urinary markers are available and commonly used in various clinical settings. However despite an abundance of primary data and reviews an evidence-based application in the detection and monitoring of bladder cancer is lacking. We provide a framework in which the clinician caring for patients at risk for and diagnosed with bladder cancer can easily understand and incorporate these tools into routine practice. METHODS: We reviewed the English language literature regarding voided urinary markers for bladder cancer, focusing on prior systematic reviews published since 2003. Available data on sensitivity and specificity were analyzed in the context of 3 scenarios of application, including screening for bladder cancer, evaluating patients with hematuria and monitoring disease after a bladder cancer diagnosis. We defined and applied the relevant statistical tools, and provide rational recommendations for clinical application. We also summarized issues of cost-effective utilization of these tests. RESULTS: Consistent with existing opinions there is no current role for any urinary marker in screening for bladder cancer. This is the result of low disease prevalence even in purportedly high risk groups. In patients with microscopic hematuria a negative urinary biomarker may spare further evaluation with cystoscopy while regardless of the urinary marker result those with gross hematuria are at sufficient risk to justify cystoscopy. Patients with lower risk bladder urothelial carcinoma may require less frequent cystoscopy if urinary markers are negative. Patients at high risk are at low risk for undetected cancer if cystoscopy and voided marker are negative. CONCLUSIONS: Available information on exfoliative urinary markers suggests a clear role in bladder cancer diagnosis and monitoring. We provide an evidence-based practical approach to application in routine clinical practice. Our approach must be considered in the context of current practice guidelines. Additional studies are required to determine the most cost-effective algorithms and novel markers that may further enhance the role of these biomarkers.

Outcomes in a multi-institutional cohort of patients treated with intraoperative radiation therapy for advanced or recurrent renal cell carcinoma.

PURPOSE/OBJECTIVE(S): This study aimed to analyze outcomes in a multi-institutional cohort of patients with advanced or recurrent renal cell carcinoma (RCC) who were treated with intraoperative radiation therapy (IORT). METHODS AND MATERIALS: Between 1985 and 2010, 98 patients received IORT for advanced or locally recurrent RCC at 9 institutions. The median follow-up time for surviving patients was 3.5 years. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were estimated with the Kaplan-Meier method. Chained imputation accounted for missing data, and multivariate Cox hazards regression tested significance. RESULTS: IORT was delivered during nephrectomy for advanced disease (28%) or during resection of locally recurrent RCC in the renal fossa (72%). Sixty-nine percent of the patients were male, and the median age was 58 years. At the time of primary resection, the T stages were as follows: 17% T1, 12% T2, 55% T3, and 16% T4. Eighty-seven percent of the patients had a visibly complete resection of tumor. Preoperative or postoperative external beam radiation therapy was administered to 27% and 35% of patients, respectively. The 5-year OS was 37% for advanced disease and 55% for locally recurrent disease. The respective 5-year DSS was 41% and 60%. The respective 5-year DFS was 39% and 52%. Initial nodal involvement (hazard ratio [HR] 2.9-3.6, P<.01), presence of sarcomatoid features (HR 3.7-6.9, P<.05), and higher IORT dose (HR 1.3, P<.001) were statistically significantly associated with decreased survival. Adjuvant systemic therapy was associated with decreased DSS (HR 2.4, P=.03). For locally recurrent tumors, positive margin status (HR 2.6, P=.01) was associated with decreased OS. CONCLUSIONS: We report the largest known cohort of patients with RCC managed by IORT and have identified several factors associated with survival. The outcomes for patients receiving IORT in the setting of local recurrence compare favorably to similar cohorts treated by local resection alone suggesting the potential for improved DFS with IORT.

Long-term follow-up of International Prostate Symptom Score (IPSS) in men following prostate brachytherapy.

OBJECTIVE: To investigate variation in the International Prostate Symptom Score (IPSS) in men following prostate brachytherapy. METHODS: From January 2004 to November 2009, 524 consecutive patients underwent prostate brachytherapy either alone or in combination with external beam radiation therapy for T1c-T3b prostate cancer. The IPSS was assessed preimplant and at 1, 6, 12, 24, 36, and 48 months after treatment. Clinical and treatment-related factors were assessed for correlations with the IPSS increase. RESULTS: The mean preimplant IPSS was 7.4, with the greatest mean score of 16.0 at 1 month. At 6 months, the mean total IPSS had decreased to 11.5, but it was still statistically significantly greater than that at baseline (<0.001). At 12 months, the IPSS was decreased to 8.6, slightly greater than baseline (p = 0.001). The IPSS of 45.4 % (69/152) patients gradually returned to preimplant levels and that of 71.1 % (108/152) patients returned to within 3 points of the baseline at 24 months. At 24, 36, and 48 months after seed implantation, the IPSS was 8.6, 7.7, and 8.2, respectively, and none of these values differed statistically significantly from baseline (p > 0.05). Sixteen patients (3.1 %) showed AUR, and 11 patients required catheterization. On univariate and multivariate analyses, the IPSS increase was best predicted by lower preimplant IPSS. CONCLUSION: In our series, IPSS after prostate brachytherapy peaked at 1 month and gradually returned to approximately baseline at 24 months. The IPSS increase was best predicted by lower preimplant IPSS.

Natural history of untreated renal cell carcinoma with venous tumor thrombus.

OBJECTIVES: The natural history of untreated renal cell carcinoma (RCC) with venous tumor thrombus (VTT) is poorly characterized. We aimed to describe the natural history of this disease, and to identify prognostic factors associated with disease-specific survival. MATERIALS AND METHODS: We identified patients in the Surveillance, Epidemiology, and End Results (SEER) database with untreated renal cell carcinoma and venous tumor thrombi. Disease-specific median and 1-year survival rates were determined, and disease-free survival curves were plotted using the Kaplan-Meier method. Multivariable Cox regression analyses were performed to identify factors associated with disease-specific and overall survival in this patient group. RESULTS: Of 2,265 patients with RCC and VTT, 390 (17%) underwent no treatment; 278 (71%) patients died during follow-up; of these, 243 deaths (87%) were due to RCC. Median and 1-year disease-specific survival for this group was 5 months and 29%, respectively. On multivariable analysis, the extent of tumor thrombus (HR 1.7 for T3c vs. T3b, 95% CI 1.0-2.7) and the presence of metastases (HR 3.1 for M+ vs. M0, 95% CI 1.7-5.5) were most strongly associated with disease-specific mortality. CONCLUSIONS: Prognosis is poor for the majority of untreated patients with RCC and VTT. Supradiaphragmatic thrombi and distant metastases are adverse prognostic factors in this patient group. This information is important when counseling patients as to the risk and benefits of surgical vs. nonoperative management of RCC and VTT.

Factors associated with downgrading in patients with high grade prostate cancer.

OBJECTIVE: To determine the factors associated with downgrading between biopsy and prostatectomy in the contemporary era using extended-template biopsy techniques. MATERIALS AND METHODS: The UCSF Urologic Oncology Database was used to identify subjects diagnosed with high grade prostate cancer (primary pattern 4 or 5) in at least one core on extended-pattern biopsy. Multivariable logistic regression analysis was performed to identify independent factors associated with downgrading at radical prostatectomy, defined as a change from primary pattern 4 or 5 to primary pattern 3. RESULTS: Downgrading occurred in 68 (34%) of 202 subjects who met the study criteria. Fourteen (47%) of 30 subjects with ≤25% of cores that were high grade and 9 (43%) of 21 subjects with <10% of total tissue containing cancer were downgraded. In a multivariable model, patients with mixed grade cores had much higher odds of downgrading than those with all high grade cores (OR 3.0 95% 1.3-7.1), P < 0.01). The proportion (per 10% increment) of positive cores containing high grade cancer (OR 0.8 95% CI 0.7-0.9 P < 0.01) and the percent (per 10% increment) of total tissue containing cancer (OR 0.7 95% CI 0.6-0.9 P = 0.01) were significantly associated with lower odds of downgrading. CONCLUSIONS: Downgrading following radical prostatectomy is a common event. Biopsy over-grading may preclude men from active surveillance or lead to unnecessary lymphadenectomy, excess radiation, or prolonged hormone therapy. The proportion of positive biopsy cores that are high grade and the percent of total tissue containing cancer should be incorporated into decision making.

Population based analysis of survival in patients with renal cell carcinoma and venous tumor thrombus.

OBJECTIVES: To identify prognostic factors for renal cell carcinoma (RCC) with venous tumor thrombus (VTT) and determine the significance of thrombus level on survival. MATERIALS AND METHODS: Patients within the Surveillance, Epidemiology, and End Results (SEER) database with RCC and VTT were identified and included if managed surgically. The Kaplan-Meier method and Cox regression analyses were performed to identify factors associated with disease-specific survival. RESULTS: A total of 1,875 patients met the inclusion criteria. One-year survival for patients undergoing surgery was 60% for patients with metastases and 90% for those without. Factors associated with worse survival included larger tumor size (HR 1.2, 95% CI 1.0-1.4), medullary, collecting duct, or sarcomatoid histology (HR 2.2, 95% CI 1.5-3.3), Fuhrman grade 3 (HR 2.2, 95% CI 1.5-3.3) or grade 4 (HR 2.9, 95% CI 1.8-4.5) tumors, positive lymph nodes (HR 1.5, 95% CI 1.0-2.0), and metastases (HR 3.5, 95% CI 2.6-4.8). Thrombus level above the diaphragm (T3c) was not significantly associated with worse survival (HR 1.4, 95% CI 0.8-2.5). CONCLUSIONS: In this large, population-based study of patients with RCC and VTT, we identify several disease-specific factors strongly associated with cancer-specific mortality. After controlling for adverse prognostic factors, thrombus level was not associated with worse outcome.

The impact of serial prostate biopsies on sexual function in men on active surveillance for prostate cancer.

PURPOSE: NCCN Guidelines® recommend annual prostate biopsies for men with low risk prostate cancer on active surveillance. We determined whether erectile function decreases with the number of biopsies experienced. MATERIALS AND METHODS: During a median 3.2-year followup after prostate cancer diagnosis in 2003 to 2010 at our institution 427 men on active surveillance underwent a total of 1,197 biopsies and provided 1,398 erectile function evaluations via the Sexual Health Inventory for Men questionnaire. For analysis we decomposed the 25-point questionnaire responses into a 5-point erectile function score and a 3-level sexual activity status. We used separate models adjusted for patient characteristics to determine whether either outcome varied with biopsy exposure. RESULTS: At diagnosis the median age was 61 years and median prostate specific antigen was 5.3 ng/ml. Of the cases 70% were clinical stage cT1 and 93% were Gleason score less than 7. Of biopsies followed by evaluations 40% were the first undergone by the patient and 9% were the fifth to ninth. At the first erectile function evaluation 15% of men were inactive, 8% engage in stimulation and 77% engaged in intercourse. Sexual activity level changed in greater than 20% of respondents between evaluations. Adjusted erectile function scores were not associated with biopsy exposure cross-sectionally or longitudinally but they corresponded with the 50th, 63rd and 80th percentiles of erectile function by increasing sexual activity level. Similarly, sexual activity was not associated with biopsy exposure. Separated outcomes were more accurate and informative than Sexual Health Inventory for Men scores. CONCLUSIONS: Our study had high power to detect erectile function-biopsy associations but it estimated that the effects were negligible. We recommend erectile function scores over Sexual Health Inventory for Men scores to avoid biased assessment of erectile function.

Population-based comparative effectiveness of nephron-sparing surgery vs ablation for small renal masses.

OBJECTIVE: To determine, in a population-based cohort, if disease-specific survival (DSS) was equivalent in patients undergoing ablation vs nephron-sparing surgery (NSS) for clinical stage T1a renal cell carcinoma (RCC). PATIENTS AND METHODS: A retrospective cohort study was performed using patients from the Surveillance, Epidemiology and End Results cancer registry with RCC < 4 cm and no evidence of distant metastases, who underwent ablation or NSS. Kaplan-Meier and Cox regression analyses were performed to determine if treatment type was independently associated with DSS. RESULTS: Between 1998 and 2007, a total of 8818 incident cases of RCC were treated with either NSS (7704) or ablation (1114). The median (interquartile range) follow-up was 2.8 (1.2-4.7) years in the NSS group and 1.6 (0.7-2.9) years in the ablation group, although 10% of each cohort were followed up beyond 5 years. After multivariable adjustment, ablation was associated with a twofold greater risk of kidney cancer death than NSS (hazard ratio 1.9, 95% confidence interval 1.1-3.3, P= 0.02). Age, gender, marital status and tumour size were also significantly associated with outcome. The predicted probability of DSS at 5 years was 98.3% with NSS and 96.6% with ablation. CONCLUSION: After controlling for age, gender, marital status and tumour size, the typical patient presenting with clinical stage T1a RCC, who undergoes ablation rather than NSS, has a twofold increase in the risk of kidney cancer death; however, at 5 years the absolute difference is small, and may only be realized by patients with long life expectancies.

Under-grading of <4 cm renal masses on renal biopsy.

UNLABELLED: What's known on the subject? and What does the study add? It is well documented that biopsy of small renal masses is inaccurate and tends to under-estimate tumour grade compared with surgical specimens. To our knowledge there has not been a study showing grading discrepancy between biopsy and surgical excision in a large population-based cohort. OBJECTIVE: To determine whether differences exist in tumour grade between patients who undergo partial nephrectomy (PN) and those who undergo ablation for renal tumours. PATIENTS AND METHODS: Data was obtained using the Surveillance, Epidemiology and End Results database. Patients with solitary renal tumours of <4 cm treated with ablation or PN and with renal cell carcinoma (RCC) histopathology were identified. Tissue diagnosis in the ablation specimens was obtained from biopsy reports, whereas tissue from PN specimens was determined from surgical pathology. Variables analysed included: year of diagnosis, age, sex, race/ethnicity, marital status, population density, education, poverty level, and tumour size. Stacked bar graphs were created to compare the distributions of grade and histology between the groups. Multinomial logistic regression was used to determine factors independently associated with grade. RESULTS: In all, 7704 (87.4%) patients underwent PN and 1114 (12.6%) underwent either radiofrequency ablation or cryoablation. The PN patients were younger at diagnosis (59 vs 68 years, P < 0.001), more likely to be married (70% vs 64%, P < 0.001), and had smaller tumours (2.4 vs 2.6 cm, P < 0.001). There were no differences in the distribution of histology between the PN and ablation groups. Tumour grade was significantly lower in tumours treated with ablation. Compared with grade 1 disease, those undergoing ablation were 30% less likely to have grade 2 (P < 0.001), 30% less likely to have grade 3 (P < 0.001), and 92% less likely to have grade 4 disease (P < 0.01) than those having PN. CONCLUSIONS: There is a strong association between grade and treatment type in patients with small renal masses after controlling for baseline characteristics. As grade is determined by different methods, we think that this shows systematic under-grading in biopsy of small renal masses.

Evolving practice patterns for the management of small renal masses in the USA.

UNLABELLED: What's known on the subject? and What does the study add? Treatment options for small renal masses include radical nephrectomy (RN), partial nephrectomy (PN), ablation, and surveillance. PN provides equivalent oncological as RN for small tumours, but long-term outcomes for ablation and surveillance are poorly defined. Due to changing techniques and technology, treatment patterns for small renal masses are rapidly developing. Prior studies had analysed utilisation trends for PN and RN to 2006, revealing a relative rise in the rate of PN. However, overall treatment trends including surveillance and ablation had not been studied using a population-based cohort. It has become increasingly clear that RN is associated with greater renal and cardiovascular deterioration than nephron-sparing treatments. Thus, it is important to understand current population-based practice patterns for the treatment of small renal masses to assess whether practitioners are adhering to ever-changing principles in this field. The present study provides up-to-date treatment trends in the USA using a large population-based cohort. OBJECTIVE: To describe the changing practice patterns in the management of small renal masses, including the use of surveillance and ablative techniques. PATIENTS AND METHODS: All patients in the Surveillance, Epidemiology and End Results (SEER) registry treated for renal masses of ≤7 cm in diameter, from 1998 to 2008, were included for analysis. Annual trends in the use of surveillance, ablation, partial nephrectomy (PN), and radical nephrectomy (RN) were calculated. Multinomial logistic regression was used to determine the association of demographic and clinical characteristics with treatment method. RESULTS: In all, 48 148 patients from 17 registry sites with a mean age of 63.4 years were included for analysis. Between 1998 and 2008, for masses of <2 cm and 2.1-4 cm, there was a dramatic increase in the proportion of patients undergoing PN (31% vs 50%, 16% vs 33%, respectively) and ablation (1% vs 11%, 2% vs 9%, respectively). In multivariable analysis, later year of diagnosis, male gender, being married, clinically localised disease, and smaller tumours were associated with increased use of PN vs RN. Later year of diagnosis, male gender, being unmarried, smaller tumour, and the presence of bilateral masses were associated with increased use of ablation and surveillance vs RN. CONCLUSIONS: PN is now used in half of all patients with the smallest renal masses, and its use continues to increase over time. Ablation and surveillance are less common overall, but there is increased usage over time in select populations.

Transrectal ultrasonography-guided biopsy does not reliably identify dominant cancer location in men with low-risk prostate cancer.

UNLABELLED: Study Type - Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? The widespread use of serum PSA testing followed by TRUS-guided biopsy have resulted in profound prostate cancer stage migration with many patients presenting with focal rather than multifocal disease. There is increasing interest in the use of focal rather than whole-gland treatment. However, current biopsy schemes may still miss cancer or, even when cancer is identified, its extent or grade might not be accurately characterized. In order for focal therapy to be effective, the area of highest tumour volume and/or grade needs to localized accurately. The aim of this study was to assess how well biopsy, as currently performed, locates the focus of highest prostate cancer volume and/or grade. OBJECTIVE: To evaluate the ability of transrectal ultrasonography (TRUS)-guided extended core biopsy to identify the dominant tumour accurately in men with early stage prostate cancer. PATIENTS AND METHODS: Patients with early stage, low-risk prostate cancer who subsequently underwent radical prostatectomy (RP) and had complete surgical specimens were identified. Re-review was performed by a single uropathologist using ImageJ software to identify tumour location, dominant grade (DG) and dominant volume (DV). Pathology findings were then compared with biopsy results. RESULTS: A total of 51 men with early stage, low-risk prostate cancer, who had undergone RP, had complete specimens for review and a median of 15 biopsy cores taken for diagnosis and grading. Sixteen men had a single diagnostic biopsy, 21 had one repeat biopsy, and 14 had two or more repeat biopsies. Compared with surgical findings, biopsy correctly identified the sextant with the largest tumour volume in 55% (95% CI 0.5-0.6) of specimens and the highest grade in 37% (95 CI 0.3-0.5). No demographic or clinical factors were significantly associated with identification of DG. Interval between last biopsy and RP, total tissue length taken and total length of tumour identified were significantly associated with correct identification of DV. CONCLUSIONS: Our findings show that TRUS-guided biopsy detects and localizes DV better than it does DG. Even with an extended scheme, TRUS-guided biopsy does not reliably identify dominant cancer location in this low-risk cohort of men with early stage prostate cancer. TRUS-guided biopsy may perform better in similar men with low stage, but higher volume disease.

Poor agreement of prostate specific antigen doubling times calculated using ultrasensitive versus standard prostate specific antigen values: important impact on risk assessment.

PURPOSE: In men with biochemical recurrence after radical prostatectomy, a rapid prostate specific antigen doubling time is associated with adverse outcomes, and is often used to guide the type and timing of salvage therapy. It is unknown whether prostate specific antigen doubling time calculated in the ultrasensitive range (prostate specific antigen less than 0.2 ng/ml) accurately reflects measures performed in the traditional range (prostate specific antigen greater than 0.2 ng/ml). MATERIALS AND METHODS: We studied 394 men in a national disease registry of men with prostate cancer (CaPSURE™) who underwent radical prostatectomy, experienced biochemical failure, and had prostate specific antigen doubling time assessed using ultrasensitive and traditional prostate specific antigen values. Agreement between these measurements was assessed using Cohen's kappa score. RESULTS: Median ultrasensitive prostate specific antigen doubling time was 11.9 months (IQR 6-29) and median traditional prostate specific antigen doubling time was 240 months (IQR 18-240). Agreement between ultrasensitive and traditional prostate specific antigen doubling time was poor, with a weighted Cohen's kappa score of 0.04 (95% CI -0.02-0.10). Using a dichotomous prostate specific antigen doubling time cutoff of 9 months, there was a statistically significant difference between ultrasensitive and standard prostate specific antigen doubling time (exact McNemar p <0.01). Ultrasensitive prostate specific antigen doubling time was more or less rapid than traditional prostate specific antigen doubling time by more than 15 months in 244 (62%) and 35 (9%) patients, respectively. CONCLUSIONS: Agreement between prostate specific antigen doubling time calculated using ultrasensitive vs traditional prostate specific antigen values is poor. Ultrasensitive prostate specific antigen doubling time is often significantly more rapid than traditional prostate specific antigen doubling time, potentially overestimating the risk of clinical recurrence. Until the significance of ultrasensitive prostate specific antigen doubling time is better characterized, the decision to proceed with salvage therapy should not be based on prostate specific antigen doubling time calculated using ultrasensitive prostate specific antigen values.