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Introduction:Our goal was to assess temporal changes in the race-specific rates of prostate specific antigen (PSA) screening, prostate biopsy, overall prostate cancer detection, and metasta...

PURPOSE In 2016, Kaiser Permanente Northern California began regionalizing testicular cancer care using population-based tumor board review. This mixed methods evaluation describes implementation outcomes and learnings. METHODS We conducted in-depth interviews with key stakeholders, administered surveys to local oncologists and urologists, and used clinical data to evaluate changes in care delivery during 2015-2018. RESULTS An average of 135 patients with testicular cancer were diagnosed each year. Interviews with 16 key stakeholders provided several insights. Implementation resulted in high levels of satisfaction, was dependent on leadership and staff at various levels, and required technology and consulting solutions aligned to user agreements and clinical workflows. Of 123 local oncologists and urologists who completed surveys, 97% understood why care was regionalized and 89% agreed that tumor board review improved treatment decisions. Among 177 patients with stage I seminoma, the percentage appropriately observed rather than treated with adjuvant chemotherapy or radiation therapy increased from 48% (95% CI, 35 to 62) in 2015 to 87% (75 to 99) in 2018. Review altered care based on pathology and radiology re-review in 14.5 % of cases. CONCLUSION Regionalization was feasible and effective.

To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (HOXB13), as well as a novel candidate gene (ILDR1), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at HOXB13 and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th–60th percentile OR = 2.62, P = 2.55 × 10−191). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits. Significance: This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer. See related commentary by Lachance, p. 1637

Purpose To prospectively validate a new prostate cancer risk calculator in a racially diverse population. Materials and Methods We recently developed, internally validated and published the Kaiser Permanente Prostate Cancer Risk Calculator. This study is a prospective validation of the calculator in a separate, referral population over a 21-month period. All patients were tested with a uniform PSA assay and a standardized systematic, ultrasound-guided biopsy scheme. We report on 3 calculator models: Model 1 included age, race, PSA, prior biopsy status, body mass index, and family history of prostate cancer; Model 2 added digital rectal exam to Model 1 variables; Model 3 added prostate volume to Model 2 variables. We considered three outcomes: high-grade disease (Gleason score ≥7), low-grade disease (Gleason score=6), and no cancer. Predictive discrimination and calibration were calculated. How each model might alter biopsy frequency and outcomes at various thresholds of risk was assessed. We compared the performance of our calculator with two other calculators. Results In 4178 patients (16.2% Asian, 11.3% African American, 13.5% Hispanic), cancer was found in 53%; 62% were Gleason score ≥7. Using a high-grade risk threshold for biopsy of ≥10%, Model 2 predictions would result in 9% of men avoiding a biopsy, while only missing 2% of high-grade cancers. At the same threshold, Model 3 predictions would result in 26% of men avoiding a biopsy, while only missing 5% of high-grade cancers. The c-statistics for Models 1, 2, and 3 to predict high-grade disease vs. low-grade or no cancer were 0.76, 0.79 and 0.85, respectively. The c-statistics for Models 1, 2, and 3 to predict any prostate cancer vs. no cancer were 0.70, 0.72 and 0.80, respectively. All models were well calibrated for all outcomes. Our Model 3 calculator had superior discrimination for high grade disease (c-statistic=0.85, 0.84-0.86) and any cancer (0.80, 0.79-0.82) compared to the PBCG calculator [(0.79, 0.78-0.80); 0.72 (0.70-0.73)] and the PCPT calculator [(0.75, 0.74-0.77); 0.69 (0.67-0.70)], respectively. In the high-grade cancer predicted risk range of 0-30%, our Model 2 was better calibrated than the PCPT and PBCG calculators. Conclusions This validation of our calculator showed excellent performance characteristics.

Purpose To prospectively develop a prostate cancer (CaP) risk calculator in a racially diverse population. Materials and Methods All patients referred for prostate biopsy due to an elevated prostate-specific antigen or abnormal digital rectal exam in a 19-months period at Kaiser Permanente Northern California underwent a standardized systematic, ultrasound-guided biopsy scheme (14-cores for initial biopsy, 18–20 cores for repeat biopsy). All pertinent clinical variables were prospectively collected. The highest Gleason score for each patient was recorded for all positive biopsies. We used a split sample design to develop and validate 3 multivariable prediction models using multinomial logistic regression with the least absolute shrinkage and selection operator. All models included these core variables: age, race, prostate-specific antigen, prior biopsy status, body mass index, and family history of CaP. Model 1 included only the core variables, Model 2 added digital rectal exam, and Model 3 added digital rectal exam and prostate volume. We considered 3 outcomes: high-grade disease (Gleason score ≥7), low-grade disease (Gleason score = 6), and no cancer. Predictive discrimination was quantified using the c-statistic. Results Complete data were available for 2,967 patients. Cancer was found in 50% of patients: of these, 58% were Gleason score ≥7 and 42% were low grade. Compared to Caucasians, African Americans were at a higher risk while Asians and Hispanics were at a lower risk for overall and high-grade cancer detection. The number of prior negative biopsies was also protective for these outcomes. The c-statistics for Model 1, 2, and 3 to predict high-grade disease vs. low-grade or no cancer were 0.76, 0.79, and 0.85, respectively. The c-statistics for Model 1, 2, and 3 to predict any CaP vs. no cancer were 0.69, 0.70, and 0.79, respectively. All models were well calibrated for all outcomes. Conclusions In men with elevated PSA levels, our calculator provides useful information that may enhance the shared decision-making process regarding the need for biopsy.

The potential association between rare germline genetic variants and prostate cancer (PrCa) susceptibility has been understudied due to challenges with assessing rare variation. Furthermore, although common risk variants for PrCa have shown limited individual effect sizes, their cumulative effect may be of similar magnitude as high penetrance mutations. To identify rare variants associated with PrCa susceptibility, and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we analyzed large population-based cohorts, custom genotyping microarrays, and imputation reference panels in an integrative study of PrCa genetic etiology. In particular, 11,649 men (6,196 PrCa cases, 5,453 controls) of European ancestry from the Kaiser Permanente Research Program on Genes, Environment and Health, ProHealth Study, and California Men’s Health Study were genotyped and meta-analyzed with 196,269 European-ancestry male subjects (7,917 PrCa cases, 188,352 controls) from the UK Biobank. Six novel loci were genome-wide significant in our meta-analysis, including two rare variants (minor allele frequency < 0.01, at 3p21.31 and 8p12). Gene-based rare variant tests implicated a previously discovered PrCa gene (HOXB13) as well as a novel candidate (ILDR1) highly expressed in prostate tissue. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants atHOXB13and other loci, reflecting their evolutionary history. Furthermore, a polygenic risk score (PRS) of 187 known, largely common PrCa variants was strongly associated with risk in non-Hispanic whites (90thvs. 10thdecile OR = 7.66,P= 1.80*10-239). Many of the 187 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a six-fold difference in log-probability of Androgen Receptor binding at the variant rs2680708 (17q22). Our finding of two novel rare variants associated with PrCa should motivate further consideration of the role of low frequency polymorphisms in PrCa, while the considerable effect of PrCa PRS profiles should prompt discussion of their role in clinical practice.

Prostate cancer screening is associated with low specificity, unnecessary biopsies, and overdiagnosis. We have previously shown that the Stockholm-3 model (S3M) can reduce biopsies compared with using prostate-specific antigen (PSA) ≥3ng/ml as an indication for biopsy. Urologists in today's current prostate cancer testing (CPT) have access to numerous variables in addition to PSA (eg, age, ethnicity, family history, free PSA, PSA velocity, digital rectal examination, and prostate volume) to support biopsy decisions. We estimated the number of prostate cancers diagnosed and prostate biopsies performed if S3M replaced CPT in Stockholm, Sweden, by comparing biopsy results in 56 282 men who underwent PSA testing according to CPT in Stockholm in 2011 with the 47 688 men enrolled in the STHLM3 validation cohort 2012–2015. With the same sensitivity as CPT to diagnose Gleason score ≥7 prostate cancer, S3M was estimated to reduce the number of men biopsied by 53% (95% confidence interval [CI]: 41–65%), avoid 76% (95% CI: 67–81%) of negative biopsies, and reduce Gleason score 6 cancers by 23% (95% CI: 6–40%). S3M has the potential to improve prostate cancer diagnostics by better selecting men with high risk of GS ≥7 prostate cancer. Patient summary We modeled the effect the Stockholm-3 model would have on prostate cancer diagnostics if it replaced current clinical practice. We found that Stockholm-3 model may substantially reduce the number of biopsies, while maintaining the same sensitivity to diagnose clinically significant prostate cancer.

A 17-gene biopsy-based reverse transcription polymerase chain reaction assay, which provides a Genomic Prostate Score (GPS-scale 0-100), has been validated as an independent predictor of adverse pathology and biochemical recurrence after radical prostatectomy (RP) in men with low- and intermediate-risk prostate cancer (PCa).To evaluate GPS as a predictor of PCa metastasis and PCa-specific death (PCD) in a large cohort of men with localized PCa and long-term follow-up.A retrospective study using a stratified cohort sampling design was performed in a cohort of men treated with RP within Kaiser Permanente Northern California. RNA from archival diagnostic biopsies was assayed to generate GPS results.We assessed the association between GPS and time to metastasis and PCD in prespecified uni- and multivariable statistical analyses, based on Cox proportional hazard models accounting for sampling weights.The final study population consisted of 279 men with low-, intermediate-, and high-risk PCa between 1995 and 2010 (median follow-up 9.8 yr), and included 64 PCD and 79 metastases. Valid GPS results were obtained for 259 (93%). In univariable analysis, GPS was strongly associated with time to PCD, hazard ratio (HR)/20 GPS units=3.23 (95% confidence interval [CI] 1.84-5.65; p0.001), and time to metastasis, HR/20 units=2.75 (95% CI 1.63-4.63; p0.001). The association between GPS and both end points remained significant after adjusting for National Comprehensive Cancer Network, American Urological Association, and Cancer of the Prostate Risk Assessment (CAPRA) risks (p0.001). No patient with low- or intermediate-risk disease and a GPS of20 developed metastases or PCD (n=31). In receiver operating characteristic analysis of PCD at 10 yr, GPS improved the c-statistic from 0.78 (CAPRA alone) to 0.84 (GPS+CAPRA; p0.001). A limitation of the study was that patients were treated during an era when definitive treatment was standard of care with little adoption of active surveillance.GPS is a strong independent predictor of long-term outcomes in clinically localized PCa in men treated with RP and may improve risk stratification for men with newly diagnosed disease.Many prostate cancers are slow growing and unlikely to spread or threaten a man's life, while others are more aggressive and require treatment. Increasingly, doctors are using new molecular tests, such as the17-gene Genomic Prostate Score (GPS), which can be performed at the time of initial diagnosis to help determine how aggressive a given patient's cancer may be. In this study, performed in a large community-based healthcare network, GPS was shown to be a strong predictor as to whether a man's prostate cancer will spread and threaten his life after surgery, providing information that may help patients and their doctors decide on the best course of management of their disease.

BACKGROUND: Most guidelines recommend against PSA-based screening for prostate cancer in men ≥ 70 years of age. Adherence to these guidelines is variable. OBJECTIVE: To determine whether the use of a “Best Practice Advisory” (BPA) intervention within the electronic medical record (EMR) system can alter the rate of PSA screening in men ≥ 70 years of age. DESIGN: This is an interventional study spanning the years 2013 through 2017, in men ≥ 70 years of age in Kaiser Permanente Northern California with no prior history of prostate cancer. The BPA intervention was activated in the EMR system on October 15, 2015, with no prior notice or education. SETTING: Integrated healthcare system including all Kaiser Permanente Northern California facilities. PARTICIPANTS: A population-based sample that included all male members ≥ 70 years of age without a history of prostate cancer. MAIN MEASURES: The main outcome was the rate of PSA testing in men ≥ 70 years of age. We compared the rates of PSA testing between the pre-BPA period (January 1, 2013–October 14, 2015) and the post-BPA period (October 15, 2015–December 31, 2017). An interrupted time series analysis of PSA ordering rates was performed. KEY RESULTS: Following the 2015 BPA intervention, screening rates substantially declined from 36.0 per 100 person-years to 14.9 per 100 person-years (rate ratio = 0.415; 95% CI: 0.410–0.419). The effect of the BPA was comparable among all patient races and ordering provider specialties. The interrupted time series analysis showed a rapid, large, and sustained drop in the rate of PSA ordering, and much less temporal variation in test ordering after activation of the BPA. CONCLUSION: Following activation of a BPA within the EMR, the rates of inappropriate PSA testing significantly declined by 58.5% in men ≥ 70 years of age and temporal variation was reduced.

INTRODUCTION AND OBJECTIVES:To determine how the 2012 United States Preventive Services Task Force (USPSTF) Prostate Cancer Screening recommendations altered the rates of PSA screening, prostate bi...

BACKGROUND: In 2012, the US Preventive Services Task Force (USPSTF) recommended against PSA-based screening for prostate cancer in men of all ages. Following this change, screening declined yet the complete impact on clinical presentation is not well defined in the screen-eligible population. OBJECTIVE: To determine if the rates of PSA screening, prostate biopsy, incident prostate cancer detection, and stage IV at presentation in screen-eligible men in Kaiser Permanente Northern California changed following the 2012 USPSTF Prostate Cancer Screening recommendations. DESIGN: Retrospective study spanning the years 2010 to 2015, in screen-eligible Kaiser Permanente Northern California members (African American men ages 45–69 and all other men ages 50–69) with no prior history of prostate cancer. Participants All screen-eligible, male members during 2010 (n = 403,931) to 2015 (n = 483,286) without a history of prostate cancer within all Kaiser Permanente Northern California facilities. MAIN MEASURES: Annual rates of PSA testing, prostate biopsy, incident prostate cancer detection, and stage IV cancer at presentation were compared between the pre-guideline period, 2010 and 2011, and the post-guideline period, 2014 and 2015, in men under the age of 70. KEY RESULTS: Following the 2012 USPSTF guideline change, screening rates declined 23.4% (95% CI 23.0–23.8%), biopsy rates declined 64.3% (95% CI 62.9–65.6%), and incident prostate cancer detection rates declined 53.5% (95% CI 50.1–56.7%) resulting in 1871 fewer incident cancers detected, and metastatic cancer rates increased 36.9% (95% CI 9.5–71.0%) resulting in 75 more stage IV cancers detected. CONCLUSION: Less screening resulted in a large decrease in cancer detection, some of which may be beneficial as many cancers may be indolent, yet this decrease occurred at the expense of an increase in metastatic cancer rates. For every 25 fewer cancers detected, one metastatic cancer was diagnosed. This information may be valuable in the shared decision-making process around prostate cancer screening.

39 Background: Research priorities in germ cell tumor (GCT) management have moved sharply from therapeutic improvements to cancer care delivery research and biomarker-based decision making. Early intervention with centralized decision support and oversight by expert teams result in best therapeutic outcomes and survivorship with decreased resource utilization. We describe Kaiser Permanente Northern California’s (KPNC) re-organization of care delivery through rapid case ascertainment and early expert input, as well as early results of reduction in practice variation and system-wide practice change. Methods: In 2016, KPNC reorganized oncology from a distributed generalist model to a model led by a centralized multidisciplinary expert team to share in initial and ongoing care delivery for all GCT patients in the system. Central to the re-organization was rapid ascertainment of the entire population of patients with GCT within the system and early expert engagement in treatment decision-making. Results: Between May 2016 and June 2018, 274 GCT patients were recorded in the tumor registry, of whom 69% were < 40 years of age, 16% were non-white, 56% had seminoma and 63% had stage 1 disease. Rapid case ascertainment identified 89% (95% CI, 86-93%) of the cases, increasing from 79% in 2016 to 97% in 2018 as false negatives were identified and used to improve the case finding algorithm. The overall positive predictive value was 57% (52-62%) and number needed to detect was 1.75 (1.62-1.91). Of the 274 cases, 92% (89-95%) were engaged by the expert team. In addition, the team reviewed 61 testicular cancer patients who had recurrences or metastatic cancers. Among 177 patients with stage I seminoma, the preferred use of active surveillance over adjuvant chemotherapy or radiation therapy rose from 48% (95% CI, 35-62%) in 2015 to 87% (75-99%) in 2018 (p = 0.0005). For patients with nonseminoma, the rate of the preferred option of retroperitoneal lymphadenectomies being performed by a high volume urologic surgeon increased markedly from 62% in 2015 to 95% in 2018. Conclusions: To our knowledge, the KPNC re-organization of GCT care delivery with comprehensive rapid case ascertainment is unique for integrated health care delivery systems in the USA. While early, KPNC has a working platform for early, expert multidisciplinary review and bidirectional communication with local care teams for population-based care. Early evidence points to system-wide reductions in practice variation and improvements in practice.

A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 × 10−19 (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 × 10−23) and SLC22A3 (P = 3.2 × 10−52). At the known 19q13.33 locus, rs2659124 (P = 1.3 × 10−13; OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P < 1.0 × 10−8). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004). Significance: Taken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations. Cancer Discov; 5(8); 878–91. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 783

Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa—such as genetics—can impact PSA. Here we present findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P−8) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment.

Background The University of California, San Francisco, Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) score uses pathologic data from radical prostatectomy (RP) to predict prostate cancer recurrence and mortality. However, this clinical tool has never been validated externally. Objective To validate CAPRA-S in a large, multi-institutional, external database. Design, setting, and participants The Shared Equal Access Regional Cancer Hospital (SEARCH) database consists of 2892 men who underwent RP from 2001 to 2011. With a median follow-up of 58 mo, 2670 men (92%) had complete data to calculate a CAPRA-S score. Intervention RP. Outcome measurements and statistical analysis The main outcome was biochemical recurrence. Performance of CAPRA-S in detecting recurrence was assessed and compared with a validated postoperative nomogram by concordance index (c-index), calibration plots, and decision curve analysis. Prediction of cancer-specific mortality was assessed by Kaplan-Meier analysis and the c-index. Results and limitations The mean age was 62 yr (standard deviation: 6.3), and 34.3% of men had recurrence. The 5-yr progression-free probability for those patients with a CAPRA-S score of 0–2, 3–5, and 6–10 (defining low, intermediate, and high risk) was 72%, 39%, and 17%, respectively. The CAPRA-S c-index was 0.73 in this validation set, compared with a c-index of 0.72 for the Stephenson nomogram. Although CAPRA-S was optimistic in predicting the likelihood of being free of recurrence at 5 yr, it outperformed the Stephenson nomogram on both calibration plots and decision curve analysis. The c-index for predicting cancer-specific mortality was 0.85, with the caveat that this number is based on only 61 events. Conclusions In this external validation, the CAPRA-S score predicted recurrence and mortality after RP with a c-index >0.70. The score is an effective prognostic tool that may aid in determining the need for adjuvant therapy.

85 Background: Since 2013, both the United States Preventive Services Task Force and the Kaiser Permanente National Prostate Cancer Guidelines have recommended against PSA-based screening for prostate cancer in men ≥70 years of age. Adherence to these guidelines has been variable. A “Best Practice Alert” (BPA) was activated in the electronic medical record (EMR) system in October 2015 at Kaiser Permanente Northern California (KPNC). This alerted physicians, in real time, if they attempted to order a PSA test in a man ≥70 years of age with no history of prostate cancer. No additional physician training or education was used. The objective of the present study was to determine the impact of this BPA on the frequency of inappropriate PSA testing. Methods: This was a retrospective study spanning the years 2013 to 2017, in men ≥70 years of age in KPNC with no prior history of prostate cancer. We compared the annual rates of PSA testing between the pre-BPA period, 2013 and 2014; and the post-BPA period , 2016 and 2017 (the post-BPA period began 3 months after the BPA was instituted). The primary outcome was the annual rate of PSA testing. The percent change between the two time periods, the rate ratio and 95% confidence interval (CI) were calculated. Results: The annual number of eligible men (men ≥70 years of age and no history of prostate cancer) and annual number of these men undergoing PSA testing are shown in the Table. Annual screening rates declined from 34.3% in the pre-BPA era to 13.5% in the post BPA era. The rate ratio was 0.394 (95% CI, 0.390-0.398). Conclusions: Following the activation of a simple and inexpensive BPA within the EMR, the rate of inappropriate PSA testing decreased 61% in men ≥70 years of age. This change was durable over the study period, demonstrating that well-conceived, straightforward interventions can have a marked effect on physician behavior. [Table: see text]

To examine the ability of various postoperative nomograms to predict prostate cancer-specific mortality (PCSM) and to validate that they could predict aggressive biochemical recurrence (BCR). Prostate-specific antigen (PSA), grade, and stage are the classic triad used to predict BCR after radical prostatectomy (RP). Multiple nomograms use these to predict risk of BCR. A previous study showed that several nomograms could predict aggressive BCR (prostate-specific antigen doubling time [PSADT] 9 months) more accurately than BCR. However, it remains unknown if they can predict more definitive endpoints, such as PCSM.We performed Cox analyses to examine the ability of 4 postoperative nomograms, the Duke Prostate Center (DPC) nomogram, the Kattan postoperative nomogram, the Johns Hopkins Hospital (JHH) nomogram, and the joint Center for Prostate Disease Research(CPDR)/Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) nomogram to predict BCR and PCSM among 1778 men in the Shared Equal Access Regional Cancer Hospital (SEARCH) database who underwent RP between 1990 and 2009. We also compared their ability to predict BCR and aggressive BCR in a subset of men. We calculated the c-index for each nomogram to determine its predictive accuracy for estimating actual outcomes.We found that each nomogram could predict aggressive BCR and PCSM in a statistically significant manner and that they all predicted PCSM more accurately than they predicted BCR (ie, with higher c-index values).Currently available nomograms used to predict BCR accurately predict PCSM and other more clinically relevant endpoints. Moreover, not only do they significantly predict PCSM, but do so with generally greater accuracy than BCR.

What's known on the subject? and What does the study add? Diabetes is known to be associated with a slightly lower risk of prostate cancer. Only a limited number of studies have examined the impact of diabetes on prostate cancer outcomes, with mixed results. This study builds on our prior work showing that on the whole, diabetes is not a risk factor for progression to metastases after surgery. However, intriguingly we found a significant interaction with obesity for modifying the relationship between diabetes and progression. If confirmed in future studies, this suggests the mechanisms by which diabetes alters prostate cancer aggressiveness may differ in obese and non-obese men. Objective To examine the association between diabetes and metastasis risk after radical prostatectomy (RP) and to determine if race or obesity modifies this relationship. Patients and Methods Patients comprised 2058 US veterans with prostate cancer (PCa) enrolled in the Shared Equal-Access Regional Cancer Hospital (SEARCH) database and treated with RP between 1988 and 2010. The association of diabetes with metastasis risk or secondary treatment rates was examined using Cox proportional hazards, adjusting for preoperative and, separately, clinical and postoperative findings. The effect modification by race (black vs white) and obesity (body mass index [BMI] ≥30 vs

Background Obesity is associated with an increased risk of biochemical recurrence (BCR) after radical prostatectomy (RP). It is unclear whether this is due to technical challenges related to operating on obese men or other biologic factors. Objective To examine whether obesity predicts higher prostate-specific antigen (PSA) nadir (as a measure of residual PSA-producing tissue) after RP and if this accounts for the greater BCR risk in obese men. Design, setting, and participants A retrospective analysis of 1038 RP patients from 2001 to 2010 in the multicenter US Veterans Administration–based Shared Equal Access Regional Cancer Hospital database with median follow-up of 41 mo. Intervention All patients underwent RP. Outcome measurements and statistical analysis We evaluated the relationship between body mass index (BMI) and ultrasensitive PSA nadir within 6 mo after RP. Adjusted proportional hazards models were used to examine the association between BMI and BCR with and without PSA nadir. Results and limitations Mean BMI was 28.5kg/m 2 . Higher BMI was associated with higher PSA nadir on both univariable ( p =0.001) and multivariable analyses ( p p =0.007). Adjusting for PSA nadir slightly attenuated, but did not eliminate, this association (HR: 1.04, p =0.043). When stratified by PSA nadir, obesity only significantly predicted BCR in men with an undetectable nadir ( p =0.006). Unfortunately, other clinically relevant end points such as metastasis or mortality were not available. Conclusions Obese men are more likely to have a higher PSA nadir, suggesting that either more advanced disease or technical issues confound an ideal operation. However, even after adjusting for the increased PSA nadir, obesity remained predictive of BCR, suggesting that tumors in obese men are growing faster. This provides further support for the idea that obesity is biologically associated with prostate cancer progression.

INTRODUCTION Active surveillance (AS) is increasingly accepted as appropriate management for low-risk prostate cancer (PC) patients. It is unknown whether delaying radical prostatectomy (RP) is associated with increased risk of biochemical recurrence (BCR) for men with intermediate-risk PC. METHODS We performed a retrospective analysis of 1,561 low and intermediate-risk men from the Shared Equal Access Regional Cancer Hospital (SEARCH) database treated with RP between 1988 and 2011. Patients were stratified by interval between diagnosis and RP (≤3, 3–6, 6–9, or >9 months) and by risk using the D'Amico classification. Cox proportional hazard models were used to analyze BCR. Logistic regression was used to analyze positive surgical margins (PSM), extracapsular extension (ECE), and pathologic upgrading. RESULTS Overall, 813 (52%) men were low-risk, and 748 (48%) intermediate-risk. Median follow-up among men without recurrence was 52.9 months, during which 437 men (38.9%) recurred. For low-risk men, RP delays were unrelated to BCR, ECE, PSM, or upgrading (all P > 0.05). For intermediate-risk men, however, delays >9 months were significantly related to BCR (HR: 2.10, P = 0.01) and PSM (OR: 4.08, P 9 months were associated with BCR in subsets of intermediate-risk men with biopsy Gleason score ≤3 + 4 (HR: 2.51, P 9 months predicted greater BCR and PSM risk. If confirmed in future studies, this suggests delayed RP for intermediate-risk PC may compromise outcomes. Prostate 73: 409–417, 2013. © 2012 Wiley Periodicals, Inc.

BACKGROUND: The impact of race and socioeconomic status (SES) in prostate cancer (CaP) outcomes has been well-studied, but controversy remains. The associations of race/SES with intermediate CaP outcomes, including positive surgical margin (PSM) and biochemical recurrence (BCR), were explored in an equal-access setting. METHODS: Data were retrospectively collected from 2502 men in the Shared Equal Access Regional Cancer Hospitals (SEARCH) database who underwent radical prostatectomy from 1989 to 2010. SES (income, education, employment, and poverty) was estimated from linkage of home ZIP code to census data. Logistic regression with adjustment for pre- and postoperative covariates estimated risk for associations between race/SES and pathologic outcomes. Cox proportional hazards models estimated risk for associations between race/SES and time to BCR. RESULTS: Black men were more likely to have lower SES than white men (P < .001). On multivariate analysis, race was not associated with PSM, but higher SES was associated with less PSM and fewer Gleason sum ≥ 7 pathologic tumors when SES was assessed by education, employment, or poverty (P trend ≤ .051) and income, employment, or poverty (P trend ≤ 0.059), respectively. Crude Cox models showed black men had higher BCR risk (hazards ratio = 1.20, 95% confidence interval = 1.05-1.38, P = .009) that persisted after adjustment for covariates including SES (hazards ratio ≥ 1.18, P ≤ .040). Higher SES measured by income and poverty were associated with less BCR, but only for black men (P trend ≤ .048). CONCLUSIONS: Even in an equal-access setting, higher SES predicted lower PSM risk, and race persisted in predicting BCR despite adjustment for SES. Low SES black patients may be at greatest risk for postprostatectomy BCR. Cancer 2012. © 2012 American Cancer Society.

Bladder plasmacytoid carcinoma is an invasive urothelial carcinoma subtype that is emphasized for its morphological overlap with plasma cells and metastatic carcinoma. Our experience suggests frequent intraperitoneal spread that is not typical of conventional urothelial carcinoma.We identified cases of plasmacytoid urothelial carcinoma diagnosed on radical cystectomy. Patient age, gender, American Joint Committee on Cancer (7th edition) stage, metastatic spread/recurrence sites and clinical disease status at last followup were recorded.A total of 10 male and 5 female patients 42 to 81 years old were identified. One tumor was pT2, 11 pT3 and 3 pT4. Six of 15 patients (40%) presented with lymph node metastasis and 5 (33%) had intraperitoneal metastasis at cystectomy. These initial sites of metastatic spread included the prerectal space, ovary and vagina, ovary and fallopian tube, bowel serosa, and omentum and bowel serosa in 1 case each. Three patients had subsequent metastasis involving the prerectal space, pleural fluid and small bowel serosa, and bowel serosa in 1 each. Eight patients had followup information available, including 3 who died of disease, 3 with disease and 2 with no evidence of disease.Of the patients 33% with the plasmacytoid variant of urothelial carcinoma presented with intraperitoneal disease spread and 20% had subsequent metastasis involving serosal surfaces. The possibility of noncontiguous intraperitoneal spread involving serosal surfaces should be recognized to ensure proper intraoperative staging and clinical followup for patients with plasmacytoid carcinoma.

Purpose Hypofractionated radiotherapy has an intrinsically different normal tissue and tumor radiobiology. The results of a prospective trial of stereotactic body radiotherapy (SBRT) for prostate cancer with long-term patient-reported toxicity and tumor control rates are presented. Methods and Materials From 2003 through 2009, 67 patients with clinically localized low-risk prostate cancer were enrolled. Treatment consisted of 36.25 Gy in 5 fractions using SBRT with the CyberKnife as the delivery technology. No patient received hormone therapy. Patient self-reported bladder and rectal toxicities were graded on the Radiation Therapy Oncology Group scale (RTOG). Results Median follow-up was 2.7 years. There were no grade 4 toxicities. Radiation Therapy Oncology Group Grade 3, 2, and 1 bladder toxicities were seen in 3% (2 patients), 5% (3 patients), and 23% (13 patients) respectively. Dysuria exacerbated by urologic instrumentation accounted for both patients with Grade 3 toxicity. Urinary incontinence, complete obstruction, or persistent hematuria was not observed. Rectal Grade 3, 2, and 1 toxicities were seen in 0, 2% (1 patient), and 12.5% (7 patients), respectively. Persistent rectal bleeding was not observed. Low-grade toxicities were substantially less frequent with QOD vs. QD dose regimen ( p = 0.001 for gastrointestinal and p = 0.007 for genitourinary). There were two prostate-specific antigen (PSA), biopsy-proven failures with negative metastatic workup. Median PSA at follow-up was 0.5 ± 0.72 ng/mL. The 4-year Kaplan-Meier PSA relapse-free survival was 94% (95% confidence interval, 85%–102%). Conclusion Significant late bladder and rectal toxicities from SBRT for prostate cancer are infrequent. PSA relapse-free survival compares favorably with other definitive treatments. The current evidence supports consideration of stereotactic body radiotherapy among the therapeutic options for localized prostate cancer.

What's known on the subject? and What does the study add? Much of our understanding of the pathological basis of prostate cancer comes from our analysis of radical prostatectomy specimens. Prostate cancer diagnosed by transrectal ultrasonography-guided biopsy is more likely to be posterior and basal in orientation rather than anterior or apical. Quantitative tissue analyses have not been undertaken both with details and in an unselected population, e.g. prostate specimens from autopsy cystoprostatectomy series from bladder cancer. Quantitative tissue analysis of incidentally detected prostate cancer such as largest cancer surface area, volume, site of origin, multifocality and laterality could be of paramount importance when trying to understand the findings of screen-detected programmes and focal therapy. Cancers were found in 30% of prostates. In the 96 prostates, 215 cancer foci were identified (mean 2.24). Prostate cancer was multifocal in 60% and bilateral in 80% of cases. The site of origin was in the peripheral and transition zone (TZ) in 75% and 25%, respectively. Overall, 90% of cancer foci were clinically insignificant with volume of 2 mL (eight patients) were excluded from morphometric study. Quantitative tissue analysis of 3-mm step-sectioned glands included largest cancer surface area, volume, site of origin, multifocality and laterality. RESULTS • In the 96 prostates, 215 cancer foci were identified (mean 2.24). Prostate cancer was multifocal in 58% and bilateral in 79% of cases. • Of the 215 cancers, 90% were

Study Type – Prognosis (cohort series) Level of Evidence 2a What's known on the subject? and What does the study add? The incidence and prevalence of obesity in the USA and Europe is increasing. Higher body mass index is associated with a lower risk of overall prostate cancer diagnosis but also with an increased risk of high grade prostate cancer. Obese men undergoing primary therapy with radical prostatectomy or external beam radiation are more likely to experience a biochemical recurrence after treatment compared with normal weight men. Finally, obesity is associated with increased prostate-cancer-specific mortality. We hypothesized that obese men on androgen deprivation therapy may be at increased risk for prostate cancer progression. Previous studies have shown that obese men have lower levels of testosterone compared with normal weight men. Additionally, one previous study found that obese men have higher levels of testosterone on androgen deprivation therapy. Men with higher levels of testosterone on androgen deprivation therapy are at increased risk of prostate cancer progression. We found that men with higher body mass index were at increased risk of progression to castration-resistant prostate cancer, development of metastases and prostate-cancer-specific mortality. When we adjusted for various clinicopathological characteristics, obese men were at increased risk of progression to castration-resistant prostate cancer and development of metastases. The results of our study help generate hypotheses for further study regarding the mechanisms between obesity and aggressive prostate cancer. OBJECTIVE • To investigate whether obesity predicts poor outcomes in men starting androgen deprivation therapy (ADT) before metastasis, since previous studies found worse outcomes after surgery and radiation for obese men. METHODS • A retrospective review was carried out of 287 men in the SEARCH database treated with radical prostatectomy between 1988 and 2009. • Body mass index (BMI) was categorized to

Objectives: Positive surgical margins (PSM) have been associated with biochemical recurrence (BCR) after radical prostatectomy, but the significance of PSM length and location are debated. We assessed the impact of PSM lengths at specific locations for BCR in an open radical prostatectomy series. Methods: Detailed clinical and pathological data were collected from 117 post-prostatectomy patients with PSM from 1984 to 2004 at our institution. PSM locations were classified as apex, mid-gland, base, bladder neck, and anterior fibromuscular region with lengths measured at each site. Aggregate PSM length was obtained by summing lengths of all PSM areas in contact with the inked surface. BCR was defined as serum prostate specific antigen level 0.2 ng/mL or greater. Cox proportional hazards regression analyses of PSM lengths were conducted either as a continuous or categorical variable relative to location as a predictor of BCR. Results: Multivariate analyses demonstrated that as a continuous variable, PSM length at the anterior fibromuscular region (Hazard ratio [HR] = 1.17; P = 0.027) and bladder neck (HR = 1.29; P = 0.046) were significant predictors for BCR. As a categorical variable, PSM length ≥ 2 mm at the anterior fibromuscular area was significant for BCR (HR = 3.02; P = 0.036). Increasing Gleason grade and positive lymph node status were also found to be significant independent predictors for BCR. Conclusion: PSM length at the anterior fibromuscular region (continuous and categorical) and the bladder neck (continuous) was significantly associated with BCR. Site-specific PSM length, along with Gleason grade and lymph node status, can be predictive of BCR and assist in risk stratification of patients with PSM following radical prostatectomy.

To analyze the association between cigarette smoking and biochemical recurrence (BCR) after radical prostatectomy among men from the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort.We performed a retrospective analysis of 1267 subjects from the SEARCH cohort treated from 1998 to 2008 with smoking status available from the preoperative notes. A comparison of the baseline patient and disease characteristics between the current smokers and nonsmokers (past and never smokers combined) was performed using the chi-square and rank sum tests. The univariate and multivariate associations between smoking status and BCR-free survival were analyzed using Kaplan-Meier plots, the log-rank test, and Cox proportional hazard models.Of the 1267 patients, 408 (32%) were active smokers and 859 (68%) were nonsmokers at surgery. The current smokers were younger (P.001), more likely to be black (P.001), and had a lower body mass index (P.001), a greater percentage of positive biopsy cores (P = .039), a greater preoperative prostate-specific antigen level (P = .003), more extracapsular extension (P = .003) and seminal vesicle invasion (P = .029), and lower prostate volumes (P = .002). On univariate analysis, smokers had a risk of BCR similar to that of nonsmokers (hazard ratio 1.19, P = .129). On multivariate analysis, smoking was associated with an increased risk of BCR when adjusted for body mass index only (hazard ratio 1.37, P = .008). However, after adjustment for multiple preoperative characteristics, the association was attenuated and no longer statistically significant (hazard ratio 1.12, P = .325). After additional adjustment for postoperative features, such as tumor grade and stage, smoking was unrelated to the risk of BCR (hazard ratio 0.91, P = .502).Among patients undergoing radical prostatectomy in the SEARCH cohort, cigarette smoking was associated with slightly more advanced disease but a similar risk of BCR.

Study Type – Harm (cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Prior studies have shown that men undergoing ADT tend to gain weight, with a net increase in fat mass and decrease in bone density and lean body mass. We sought to characterize the natural history of weight gain on ADT by studying patients over a three-year interval, finding that most weight gain occurs within the first year of initiating therapy. Furthermore, we confirm these prior findings in a more racially heterogeneous population of men, an important finding given the different outcomes of prostate cancer in black and white men. OBJECTIVES • To better understand the natural history of weight change with androgen-deprivation therapy (ADT), we investigated the effect of ADT on body weight among men from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. • Men undergoing ADT lose lean muscle but gain fat mass, contributing to an overall gain in weight. PATIENTS AND METHODS • We identified 132 men in SEARCH who received ADT after radical prostatectomy. • ‘Weight change’ was defined as the difference in weight before starting ADT (6 months before ADT) and the on-ADT weight (between 6 and 18 months after starting ADT). • In a subanalysis, baseline characteristics of weight-gainers and -losers were analysed using univariate and multivariate analysis to test association with weight change. RESULTS • In all, 92 men (70%) gained weight, and 40 (30%) either lost or maintained a stable weight. • On average, weight on ADT was 2.2 kg higher than the weight before ADT, with the mean change for weight-gainers and -losers being +4.2 kg and −2.4 kg, respectively. • This compared with no significant weight change in the year before starting ADT (paired t-test, change −0.7 kg, P= 0.19) or in the second year on ADT (paired t-test, change −0.5 kg, P= 0.46) for 84 men in whom these additional weight values were recorded. • There was no significant association between any of the features examined and weight change on univariate and multivariate analysis. CONCLUSION • In this longitudinal study, ADT was accompanied by significant weight gain (+2.2 kg). This change occurred primarily in the first year of therapy, with men neither losing nor gaining additional weight thereafter.

Purpose Previous studies suggest that some common medications alter prostate-specific antigen (PSA) levels. It remains unclear whether these reported medication effects are due to clinicodemographic factors or concurrent use of other medications. We investigated the impact of individual and combinations of common medications on PSA in a large cross-sectional study of the United States population. Patients and Methods The study included men ≥ 40 years old without prostate cancer from the 2003 to 2004 and 2005 to 2006 cycles of the National Health and Nutrition Examination Survey (NHANES). Men with recent prostate manipulation, prostatitis, and those on hormone therapy were excluded. Weighted multivariate linear regression was performed on log-transformed total PSA to determine the effect of the 10 most commonly prescribed medication classes, adjusting for potential confounders including demographics, clinical characteristics, physical examination, laboratory studies, and duration of medication use. Results In total, 1,864 men met inclusion criteria. Nonsteroidal anti-inflammatory drug (NSAID; P = .03), statin (P = .01), and thiazide diuretic (P = .025) intake was inversely related to PSA levels. Five years of NSAID, statin, and thiazide diuretic use was associated with PSA levels lower by 6%, 13%, and 26%, respectively. The combination of statins and thiazide diuretics showed the greatest reduction in PSA levels: 36% after 5 years. Concurrent calcium channel blocker use minimizes or negates the inverse relationship of statin use and PSA level. Conclusion We found that men using NSAIDs, statins, and thiazide diuretics have reduced PSA levels by clinically relevant amounts. The impact of regularly consuming these common medications on prostate cancer screening is unknown.

PURPOSE Several studies have examined the association between diabetes mellitus (DM) and prostate cancer (PCa) risk and progression, however nearly all of these studies have compared diabetic versus non-diabetic men. We sought to investigate the role of glycemic control, as measured by HbA1c, on PCa aggressiveness and prognosis in men with DM and PCa from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. METHODS We identified 247 men in SEARCH with DM and a recorded HbA1c value within the 12 months prior to radical prostatectomy between 1988 and 2009. We divided these men into tertiles by HbA1c level. The associations between HbA1c tertiles and risk of adverse pathology and biochemical recurrence were tested using multivariate logistic regression and Cox proportional hazards models, respectively. RESULTS Median HbA1c level was 6.9. On multivariate analysis, HbA1c tertiles were predictive of pathological Gleason score (P-trend = 0.001). Relative to the first tertile, men in the second (OR 4.68, P = 0.003) and third tertile (OR 6.60, P or = 4 + 3. HbA1c tertiles were not associated with margin status, node status, extracapsular extension or seminal vesicle invasion (all P-trend > 0.2). In the multivariate Cox proportional hazards model, increasing HbA1c tertiles were not significantly related to risk of biochemical recurrence (P-trend = 0.56). CONCLUSION Men with higher HbA1c levels presented with more biologically aggressive prostate tumors at radical prostatectomy. Although risk of recurrence was unrelated to HbA1c levels, further studies are needed to better explore the importance of glycemic control on long-term outcomes in diabetic men with PCa.

Prostate growth is dependent on circulating androgens which can be influenced by hepatic function. Liver disease has been suggested to influence prostate cancer (CaP) incidence. However, the effect of hepatic function on CaP outcomes has not been investigated. A total of 1,181 patients who underwent radical prostatectomy (RP) between 1988 and 2008 at four Veterans Affairs hospitals that comprise the Shared Equal Access Regional Cancer Hospital (SEARCH) database and had available liver function test (LFT) data were included in the study. Independent associations of LFTs with unfavorable pathological features and biochemical recurrence were determined using logistic and Cox regression analyses. Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels were elevated in 8.2% and 4.4% of patients, respectively. After controlling for CaP features, logistic regression revealed a significant association between SGOT levels and pathological Gleason sum ≥7(4+3) cancer (odds ratio=2.12; 95% confidence interval=1.11-4.05; p=0.02). Mild hepatic dysfunction was significantly associated with adverse CaP grade but was not significantly associated with other adverse pathological features or biochemical recurrence in a cohort of men undergoing R. The effect of moderate to severe liver disease on disease outcomes in CaP patients managed non-surgically remains to be investigated.

561 Background: Testicular cancer is a rare disease; multidisciplinary management by experienced clinicians is recommended. Methods: Multidisciplinary specialized review of all new testicular cancer cases was established in a community setting by creating a twice monthly Testicular Cancer Review Panel, comprised of two subspecialized medical oncologists and two surgical urologic oncologists, at Kaiser Permanente in Northern California. An early ascertainment list of new testicular cancer diagnoses was obtained and review of the history, labs, pathology reports, and all relevant imaging was performed via a web-based conference. Urologic cancer fellowship trained pathologists and body fellowship trained radiologists were available for secondary review when requested. All recommendations were documented in patient charts. Results: From June 2016 to June 2017, 131 cases were reviewed. Review by the panel resulted in significant changes in care in 19 of 131 patients (14.5%). Pathology and radiology re-reviews were the most common sources of changes in treatment recommendations. Embryonal predominant T1 disease was referred for GU pathology review in 14 cases; in 8, lymphovascular invasion was identified, upstaging 6.1% of patients from 1A to 1B, changing treatment from observation to chemotherapy. Radiology re-review changed the stage and treatment in 11 patients (8.4%), identifying lymphadenopathy not previously noted in 7 patients and reassessing previously identified lymphadenopathy as a non-pathologic finding in 4 patients. The percentage of patients with stage I seminoma observed rather than undergoing adjuvant therapy increased from 11/15 (73.3%) over the first six months of the panel to 18/20 (90%) over the second six months. Convening the panel also resulted in dissemination of oncologic knowledge among treating physicians. Conclusions: Multidisciplinary specialized case review for a rare disease is feasible in the community setting and frequently alters care.

Study Type – Diagnosis (exploratory cohort) Level of Evidence 2b OBJECTIVE To clarify the relationship between estimated blood loss (EBL) and biochemical recurrence, assessed by prostate-specific antigen (PSA) level, as blood loss is a long-standing concern associated with radical prostatectomy (RP), and no studies to date have examined the association between blood loss and cancer control. PATIENTS AND METHODS In all, 1077 patients were identified in the Shared Equal-Access Regional Cancer Hospital database who underwent retropubic RP (between 1998 and 2008) and had EBL and follow-up data available. We examined the relationship between EBL and recurrence using multivariate Cox regression analyses. RESULTS Increased EBL was correlated with PSA recurrence in a multivariate-adjusted model (P = 0.01). When analysed by 500-mL EBL categories, those with an EBL of

Because guidelines for the early detection of prostate cancer were developed by the ACS in the early 1990s, many variants of the total PSA assay have been introduced in attempts to increase the sensitivity of screening programs (cancer detection) while maintaining their specificity (elimination of unnecessary biopsies). Again, it is important to note that the NCCN guidelines recommend a method by which individuals and their physicians can use these new methods rationally for the early detection of prostate cancer. These guidelines are not designed to provide an argument for the use of early detection programs for prostate cancer. Rather, they are meant to provide a vehicle by which early detection efforts can be practiced in an evidence-based, systematic fashion in patients who choose to participate in such programs. The NCCN guidelines incorporate many new validated findings in addition to the DRE and PSA test. These new factors include percent-free PSA, PSA velocity, PSA testing intervals, biopsy pathology, and TRUS-guided biopsy techniques. The panel will re-examine the clinical utility of these new modalities annually and the guidelines will be modified accordingly. In addition, future iterations of these guidelines may incorporate new serum markers currently undergoing clinical investigation. It is the hope of the NCCN and this guideline panel that these algorithms will achieve the goal of assisting patients and clinicians who are choosing a program of early detection for prostate cancer to make decisions regarding the need for prostate biopsy. Any clinician who uses these guidelines is expected to exercise independent medical judgment in the context of the individual clinical circumstances to determine the patient's need for prostate biopsy. These guidelines will continue to evolve as the field of prostate cancer advances.

Background: Diabetes is associated with lower prostate cancer risk. The association of diabetes with prostate cancer outcomes is less clear. We examined the association between diabetes and outcomes after radical prostatectomy and tested whether associations varied by race and/or obesity. Materials and Methods: This study is a retrospective analysis of 1,262 men treated with radical prostatectomy between 1988 and 2008 within the Shared Equal-Access Regional Cancer Hospital database. We examined the multivariate association between diabetes at surgery and adverse pathology, biochemical recurrence (BCR), and prostate-specific antigen doubling time at recurrence using logistic, proportional hazards, and linear regression, respectively. Data were examined as a whole and stratified by race and obesity. Results: Diabetes was more prevalent among black (22% versus 15%, P < 0.001) and more obese men (P < 0.001). Diabetes was associated with higher tumor grade (odds ratio, 1.73; P = 0.002), seminal vesicle invasion (odds ratio, 1.73; P = 0.04), but not BCR (P = 0.67) or PSADT at recurrence (P = 0.12). In the secondary analysis, among white obese men, diabetes was associated with 2.5-fold increased BCR risk (P = 0.002) and a trend toward shorter PSADT, whereas among all other men (nonobese white men and black men), diabetes was associated with 23% lower recurrence risk (P = 0.09) and longer PSADT (P = 0.04). Conclusion: In a radical prostatectomy cohort, diabetes was not associated with BCR. In the secondary analysis, diabetes was associated with more aggressive disease in obese white men and less aggressive disease for all other subsets. If externally validated, these findings suggest that among men with prostate cancer, the association between diabetes and prostate cancer aggressiveness may vary by race and obesity. Cancer Epidemiol Biomarkers Prev; 19(1); 9–17

OBJECTIVE To determine if prostate-specific antigen doubling time (PSADT), calculated from the first detectable PSA level after radical prostatectomy (RP) to the first PSA level of ≥0.2 ng/mL (early PSADT or ePSADT), correlated with ‘standard’ PSADT (henceforth PSADT) calculated using values ≥0.2 ng/mL, as a short PSADT following biochemical recurrence (BCR) after RP portends a poor prognosis and poor response to salvage treatment but this is based upon PSADT calculated using PSA values of ≥0.2 ng/mL. PATIENTS AND METHODS We used Spearman’s correlation to determine the correlation between ePSADT and PSADT among 157 men in the Shared Equal Access Regional Cancer Hospital database who underwent RP between 1988 and 2005 and had a calculable ePSADT and PSADT. We systematically examined ePSADT thresholds and their positive and negative predictive values (PPV and NPV, respectively), to predict aggressive recurrences (PSADT of

Study Type – Prognosis (case series) Level of Evidence 4 OBJECTIVE To re-calibrate the previously published Duke Prostate Center (DPC) nomogram for the prediction of biochemical recurrence (BCR) after radical prostatectomy (RP) to not only predict overall BCR but also the clinically more relevant endpoint of an aggressive recurrence (i.e. a BCR with a postoperative PSA doubling time (PSADT) of

Study Type – Prognosis (inception cohort) Level of Evidence 1b OBJECTIVES To define a level of persistently elevated prostate-specific antigen (PSA) after radical prostatectomy (RP) that equates with high-risk for disease progression, and to identify preoperative predictors of PSA persistence among men from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. PATIENTS AND METHODS A total of 901 men treated with RP between 2001 and 2008 were separated into groups based upon PSA nadir within 6 months after RP. We explored the association between nadir groups and time to biochemical recurrence (BCR) using multivariate Cox proportional hazards and determined the preoperative predictors of PSA persistence using logistic regression. RESULTS Relative to men with undetectable PSA levels, those with a PSA nadir of 0.03 (hazard ratio [HR] 3.88, P

Preoperative prostate specific antigen is widely used to predict unfavorable pathological features and biochemical relapse after radical prostatectomy. Recent reports that hemodilution may be responsible for lower prostate specific antigen in obese men led to concerns that prostate specific antigen may be less effective for prognosticating in men with increased body mass index. We determined whether the clinical usefulness of prostate specific antigen is negatively impacted by obesity by examining its operating characteristics and predictive accuracy as a function of body mass index.We performed a multicenter retrospective analysis of the records of 11,705 men who underwent radical prostatectomy from 1988 to 2007 from Veterans Affairs hospitals of the Shared Equal Access Regional Cancer Hospital Database, the Duke Prostate Center and Johns Hopkins Hospital. ROC curve analysis, the concordance index and the test for interaction were used to compare the ability of prostate specific antigen to predict unfavorable tumor characteristics and biochemical recurrence across body mass index categories.There were no significant differences in the area under ROC curves across increasing body mass index categories for prostate specific antigen to predict pathological Gleason sum (7 or greater, 7 [4 + 3] or greater, or 8 or greater), positive surgical margins, extracapsular extension or seminal vesicle invasion in all 3 cohorts. There was no significant difference in prostate specific antigen accuracy to predict biochemical failure across increasing body mass index categories.In 3 cohorts of men treated with radical prostatectomy the ability of preoperative prostate specific antigen to predict adverse pathological features and posttreatment biochemical recurrence is not significantly affected by obesity. However, adjusting for obesity related hemodilution may still be required to properly interpret prostate specific antigen results in men with increased body mass index.

Purpose: Although showing a 25% reduction in the biopsy prevalence of cancer compared with placebo in the Prostate Cancer Prevention Trial, finasteride was associated with a higher prevalence of high-grade disease. This observation was driven by “for-cause” biopsies. We sought to understand how volume-dependent changes in prostate-specific antigen test performance characteristics may have contributed. Experimental Design: A retrospective review was done on 1,304 men referred for initial biopsy with a prostate-specific antigen between 4 and 10 ng/mL or an abnormal digital rectal examination. Receiver-operator curves and positive predictive values were ascertained for prostate-specific antigen stratified by diagnosis and prostate volume. Results: The performance of prostate-specific antigen changed for any and high-grade (Gleason, ≥3 + 4) cancer in a volume-specific manner. For any cancer, the area under the curve (AUC) decreased from 0.758 to 0.629 to 0.520 as prostate volume increased (50 cm3, respectively). For high-grade cancer, a similar trend was shown (AUC, 0.712, 0.639, and 0.497, respectively). The positive predictive value of a prostate-specific antigen of ≥4 ng/mL was also affected by prostate volume. Trends for Gleason ≤ 6 decreased as prostate volume increased (positive predictive value for 50 cm3, 17.3%). A more significant trend was seen for high-grade cancer (positive predictive value for 50 cm3, 10.7%). Conclusion: Decreases in prostate volume over time and the resultant change in prostate-specific antigen performance characteristics may have contributed a bias toward the detection of high-grade disease in the finasteride arm of the Prostate Cancer Prevention Trial.

OBJECTIVE To compare the predictive accuracy (PA) of existing models in estimating risk of biochemical recurrence (BCR) vs aggressive recurrence (BCR with a prostate-specific antigen, PSA, doubling time, DT, of

OBJECTIVE To test the hypothesis that the association between prostate size and risk of Gleason grade upgrading varies as a function of sampling. PATIENTS AND METHODS We examined the association between pathological prostate weight, prostate biopsy scheme and Gleason upgrading (Gleason ≥7 at radical prostatectomy, RP) among 646 men with biopsy Gleason 2–6 disease treated with RP between 1995 and 2007 within the Shared Equal Access Regional Cancer Hospital Database using logistic regression. In all, 204 and 442 men had a sextant (six or seven cores) or extended-core biopsy (eight or more cores), respectively. Analyses were adjusted for centre, age, surgery, preoperative prostate-specific antigen level, clinical stage, body mass index, race, and percentage of cores positive for cancer. RESULTS In all, 281 men (44%) were upgraded; a smaller prostate was positively associated with the risk of upgrading in men who had an extended-core biopsy (P

The incidence of prostate cancer is known to vary as a function of race. To date few studies have evaluated the performance of the prostate specific antigen test and its indexes in unique racial populations. We examined the performance of prostate specific antigen, prostate specific antigen density and transition zone density in racial groups undergoing an extended prostate biopsy scheme.A retrospective review was performed of prospectively collected data on 1,115 white, 288 black and 161 Asian/Pacific Islander men referred for prostate needle biopsy. All participants had not undergone previous biopsy. ROC curves stratified by race were ascertained for prostate specific antigen, prostate specific antigen density and transition zone density for detecting cancer and high grade cancer (Gleason 3 + 4 or greater).Across all races prostate specific antigen density outperformed prostate specific antigen for detecting any prostate cancer and high grade cancer. Prostate specific antigen and prostate specific antigen density performed best for diagnosing high grade cancer and diagnosing cancer in men with an abnormal digital rectal examination. When comparing differing races, prostate specific antigen density performed the best in Asian/Pacific Islander men for high grade cancer detection. The performance of transition zone density was inferior to that of prostate specific antigen density.Racial variations exist in the performance of prostate specific antigen and prostate specific antigen density. In men of Asian/Pacific Islander descent prostate specific antigen and prostate specific antigen density perform better than in white men, especially for diagnosing clinically significant, high grade prostate cancer. In general prostate specific antigen and prostate specific antigen density perform equally well in white and black populations.

Prostate specific antigen doubling time following biochemical recurrence after radical prostatectomy is a powerful predictor of prostate cancer specific and overall death. To calculate prostate specific antigen doubling time requires multiple prostate specific antigen determinations that are unaltered by secondary therapy and separated by sufficient time. Physicians and patients may be unwilling to wait before starting secondary therapy, especially for high risk recurrences. Hence, those with calculable prostate specific antigen doubling time may represent a select lower risk group relative to all men with biochemical recurrence.We compared clinical and pathological features between patients with and without calculable prostate specific antigen doubling time. We assessed time trends in the proportion with calculable prostate specific antigen doubling time in 535 patients with biochemical recurrence after radical prostatectomy at 5 Veterans Affairs medical centers comprising the SEARCH (Shared Equal Access Regional Cancer Hospital) database between 1988 and 2003.Prostate specific antigen doubling time was not calculable in 187 patients (35%) due to secondary therapy in 155 (83%). With time the proportion of patients with calculable prostate specific antigen doubling time decreased significantly (p0.001). Adverse pathological features, more rapid time to recurrence, higher body mass index and differing surgical centers were associated with not having a calculable prostate specific antigen doubling time. Of all men with recurrence in the most recent year of analysis the adjusted probability of having a calculable prostate specific antigen doubling time was only 43%, that is 61% in patients with favorable pathological results but only 30% in those with seminal vesicle invasion.Those with calculable prostate specific antigen doubling time represented a select, lower risk cohort and the proportion of patients with calculable prostate specific antigen doubling time decreased with time. This highlights the need for alternative markers in men with recurrent prostate cancer because one of our best current markers, prostate specific antigen doubling time, is only available in a limited number of patients.

Purpose Identification of patients most likely to benefit from salvage radiotherapy (RT) using postoperative (postop) prostate-specific antigen (PSA) kinetics. Methods and Materials From 1984 to 2004, 81 patients who fit the following criteria formed the study population: undetectable PSA after radical prostatectomy (RP); pathologically negative nodes; biochemical relapse defined as a persistently detectable PSA; salvage RT; and two or more postop PSAs available before salvage RT. Salvage RT included the whole pelvic nodes in 55 patients and 4 months of total androgen suppression in 56 patients. The median follow-up was >5 years. All relapses were defined as a persistently detectable PSA. Kaplan-Meier and Cox proportional hazards multivariable analysis were performed for all clinical, pathological, and treatment factors predicting for biochemical relapse-free survival (bRFS). Results There were 37 biochemical relapses observed after salvage RT. The 5-year bRFS after salvage RT for patients with postop prostate-specific antigen velocity ≤1 vs. >1 ng/ml/yr was 59% vs. 29%, p = 0.002. In multivariate analysis, only postop PSAV ( p = 0.0036), pre-RT PSA level ≤1 ( p = 0.037) and interval-to-relapse >10 months ( p = 0.012) remained significant, whereas pelvic RT, hormone therapy, and RT dose showed a trend ( p = ∼0.06). PSAV, but not prostate-specific antigen doubling time, predicted successful salvage RT, suggesting an association of zero-order kinetics with locally recurrent disease. Conclusions Postoperative PSA velocity independently predicts for the failure of salvage RT and can be considered in addition to high-risk features when selecting patients in need of systemic therapy following biochemical failure after RP. For well-selected patients, salvage RT can achieve high cure rates.