Faculty Bibliography

This article describes markers used for prostate biopsy decisions, including prostrate-specific antigen (PSA), free PSA, the prostate health index, 4Kscore, PCA3, and ConfirmMDx. It also summarizes the use of nomograms combining multiple variables for prostate cancer detection.

Purpose The association between exposure to testosterone replacement therapy (TRT) and prostate cancer risk is controversial. The objective was to examine this association through nationwide, population-based registry data. Methods We performed a nested case-control study in the National Prostate Cancer Register of Sweden, which includes all 38,570 prostate cancer cases diagnosed from 2009 to 2012, and 192,838 age-matched men free of prostate cancer. Multivariable conditional logistic regression was used to examine associations between TRT and risk of prostate cancer (overall, favorable, and aggressive). Results Two hundred eighty-four patients with prostate cancer (1%) and 1,378 control cases (1%) filled prescriptions for TRT. In multivariable analysis, no association was found between TRT and overall prostate cancer risk (odds ratio [OR], 1.03; 95% CI, 0.90 to 1.17). However, patients who received TRT had more favorable-risk prostate cancer (OR, 1.35; 95% CI, 1.16 to 1.56) and a lower risk of aggressive prostate cancer (OR, 0.50; 95% CI, 0.37 to 0.67). The increase in favorable-risk prostate cancer was already observed within the first year of TRT (OR, 1.61; 95% CI, 1.10 to 2.34), whereas the lower risk of aggressive disease was observed after > 1 year of TRT (OR, 0.44; 95% CI, 0.32 to 0.61). After adjusting for previous biopsy findings as an indicator of diagnostic activity, TRT remained significantly associated with more favorable-risk prostate cancer and lower risk of aggressive prostate cancer. Conclusion The early increase in favorable-risk prostate cancer among patients who received TRT suggests a detection bias, whereas the decrease in risk of aggressive prostate cancer is a novel finding that warrants further investigation.

PURPOSE OF REVIEW/OBJECTIVE:This article intends to review biomarkers derived from blood, urine, and tissue that can aid in the diagnosis of prostate cancer (PCa). RECENT FINDINGS/RESULTS:PCa screening requires tools that complement prostate-specific antigen (PSA) with a higher specificity for clinically significant disease. Novel blood biomarkers, such as the Prostate Health Index (phi) and 4Kscore, utilize isoforms of PSA to more accurately predict high-grade PCa than traditional tools such as PSA and the percentage free-to-total PSA. Several gene products associated with PCa can be detected in the urine through commercially available assays. PCa antigen 3 (PCA3), though approved for repeat biopsy decisions, appears inferior to other biomarkers such as phi for identifying aggressive disease. However, combinations of PCA3 with other urine assays have shown promising results. One tissue-based hypermethylation test, named ConfirmMDx, can also be used to determine the need for repeat biopsy in men with a prior negative biopsy. SUMMARY/CONCLUSIONS:Several biomarkers have been developed to aid in the screening and diagnosis of PCa. Such tests are often indicated in men with moderately elevated PSA or history of a prior negative biopsy. Their use facilitates reduction of unnecessary biopsies without sacrificing the early diagnosis of clinically significant PCa.

BACKGROUND:An increasing proportion of prostate cancer is being managed conservatively. However, there are no randomized trials or consensus regarding the optimal follow-up strategy. OBJECTIVE:To compare life expectancy and quality of life between watchful waiting (WW) versus different strategies of active surveillance (AS). DESIGN, SETTING, AND PARTICIPANTS/METHODS:A Markov model was created for US men starting at age 50, diagnosed with localized prostate cancer who chose conservative management by WW or AS using different testing protocols (prostate-specific antigen every 3-6 mo, biopsy every 1-5 yr, or magnetic resonance imaging based). Transition probabilities and utilities were obtained from the literature. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS/UNASSIGNED:Primary outcomes were life years and quality-adjusted life years (QALYs). Secondary outcomes include radical treatment, metastasis, and prostate cancer death. RESULTS AND LIMITATIONS/CONCLUSIONS:All AS strategies yielded more life years compared with WW. Lifetime risks of prostate cancer death and metastasis were, respectively, 5.42% and 6.40% with AS versus 8.72% and 10.30% with WW. AS yielded more QALYs than WW except in cohorts age >65 yr at diagnosis, or when treatment-related complications were long term. The preferred follow-up strategy was also sensitive to whether people value short-term over long-term benefits (time preference). Depending on the AS protocol, 30-41% underwent radical treatment within 10 yr. Extending the surveillance biopsy interval from 1 to 5 yr reduced life years slightly, with a 0.26 difference in QALYs. CONCLUSIONS:AS extends life more than WW, particularly for men with higher-risk features, but this is partly offset by the decrement in quality of life since many men eventually receive treatment. PATIENT SUMMARY/UNASSIGNED:More intensive active surveillance protocols extend life more than watchful waiting, but this is partly offset by decrements in quality of life from subsequent treatment.

PURPOSE/OBJECTIVE:In this white paper update we identify and discuss the prevalence and prevention of common complications of prostate needle biopsy. MATERIALS AND METHODS/METHODS:A literature review was performed on prostate biopsy complications via queries of PubMed and EMBASE® databases for prostate biopsy complications from January 1, 2010 until June 1, 2015. We focused on infection, bleeding, urinary retention, needle tract seeding and erectile dysfunction. A total of 346 articles were identified for full text review and 119 are included in the final data synthesis. RESULTS:Infection is the most common complication of prostate biopsy with fluoroquinolone resistant Escherichia coli having a prominent role. Reported rates of infectious complications range from 0.1% to 7.0%, and sepsis rates range from 0.3% to 3.1% depending on antibiotic prophylaxis regimens. Mild, self-limiting and transient bleeding is also a common complication. Other complications are extremely rare. CONCLUSIONS:This white paper provides a concise reference document for the more common prostate biopsy complications and prevention strategies. Risk assessment should be performed for all patients to identify known risk factors for harboring fluoroquinolone resistance. If infection incidence increases check the local antibiogram, current equipment and cleaning practices, and consider alternate approaches to antibiotic prevention such as needle cleaning, risk basked augmentation, rectal culture with targeted prophylaxis and transperineal biopsy. If infection occurs, actively re-situate the patient and start empiric intravenous treatment with carbapenems, amikacin or second and third generation cephalosporins.

The US Food and Drug Administration recently announced the need to evaluate the association between PDE5is and melanoma. We performed a meta-analysis on the association between PDE5i and melanoma using random effects models and examined whether it met Hill's criteria for causality. A systematic search of Medline, EMBASE, and the Cochrane Library from 1998 to 2016 identified three case-control studies and two cohort studies, including a total of 866 049 men, of whom 41 874 were diagnosed with melanoma. We found a summary estimate indicating an increased risk of melanoma in PDE5i users (relative risk = 1.11, 95% confidence interval = 1.02 to 1.22). However, the association was only statistically significant among men with low PDE5i exposure (not high exposure) and with low-stage melanoma (not high stage), indicating a lack of dose response and biological gradient. PDE5i use was also associated with basal cell cancer, suggesting a lack of specificity and likely confounding by ultraviolet exposure. Thus, although this meta-analysis found a statistically significant association between PDE5i and melanoma, it did not satisfy Hill's criteria for causality.

Introduction: Many new markers are now available as an aid for decisions about prostate biopsy for men without prostate cancer, and/or to improve risk stratification for men with newly diagnosed prostate cancer. Methods: A literature review was performed on currently available markers for use in decisions about prostate biopsy and initial prostate cancer treatment. Results: Although total prostate-specific antigen cutoffs were traditionally used for biopsy decisions, PSA elevations are not specific. Repeating the PSA test, and adjusting for factors like age, prostate volume and changes over time can increase specificity for biopsy decisions. The Prostate Health Index (phi) and 4K Score are new PSA-based markers that can be offered as second-line tests to decide on initial or repeat prostate biopsy. The PCA3 urine test and ConfirmMDx tissue test are additional options for repeat biopsy decisions. For men with newly diagnosed prostate cancer, genomic tests are available to refine risk classification and may influence treatment decisions. Conclusions: Numerous secondary testing options are now available that can be offered to patients deciding whether to undergo prostate biopsy and those with newly diagnosed prostate cancer.

Importance: Active surveillance is an important option to reduce prostate cancer overtreatment, but it remains underutilized in many countries. Models from the United States show that greater use of active surveillance is important for prostate cancer screening to be cost-effective. Objectives: To perform an up-to-date, nationwide, population-based study on use of active surveillance for localized prostate cancer in Sweden. Design, Setting, and Participants: Cross-sectional study in the National Prostate Cancer Register (NPCR) of Sweden from 2009 through 2014. The NPCR has data on 98% of prostate cancers diagnosed in Sweden and has comprehensive linkages to other nationwide databases. Overall, 32518 men with a median age of 67 years were diagnosed with favorable-risk prostate cancer, including 4693, 15403, and 17115 men with very-low-risk (subset of the low-risk group) (clinical stage, T1c; Gleason score,