Christopher J. Welty

Extended Followup and Risk Factors for Disease Reclassification in a Large Active Surveillance Cohort for Localized Prostate Cancer

PURPOSE Active surveillance to manage prostate cancer provides an alternative to immediate treatment in men with low risk prostate cancer. We report updated outcomes from a long-standing active surveillance cohort and factors associated with reclassification. MATERIALS AND METHODS We retrospectively reviewed data on all men enrolled in the active surveillance cohort at our institution with at least 6 months of followup between 1990 and 2013. Surveillance consisted of quarterly prostate specific antigen testing, repeat imaging with transrectal ultrasound at provider discretion and periodic repeat prostate biopsies. Factors associated with repeat biopsy reclassification and local treatment were determined by multivariate Cox proportional hazards regression. We also analyzed the association of prostate specific antigen density and outcomes stratified by prostate size. RESULTS A total of 810 men who consented to participate in the research cohort were followed on active surveillance for a median of 60 months. Of these men 556 (69%) met strict criteria for active surveillance. Five-year overall survival was 98%, treatment-free survival was 60% and biopsy reclassification-free survival was 40%. There were no prostate cancer related deaths. On multivariate analysis prostate specific antigen density was positively associated with the risk of biopsy reclassification and treatment while the number of biopsies and time between biopsies were inversely associated with the 2 outcomes (each p <0.01). When stratified by prostate volume, prostate specific antigen density remained significantly associated with biopsy reclassification for all strata but prostate specific antigen density was only significantly associated with treatment in men with a smaller prostate. CONCLUSIONS Significant prostate cancer related morbidity and mortality remained rare at intermediate followup. Prostate specific antigen density was independently associated with biopsy reclassification and treatment while on active surveillance.

Diagnostic associations of gene expression signatures in prostate cancer tissue.

Purpose of review Over the past several years, multiple biomarkers designed to improve prostate cancer risk stratification have become commercially available, while others are still being developed. In this review, we focus on the evidence supporting recently reported biomarkers, with a focus on gene expression signatures. Recent findings Many recently developed biomarkers are able to improve upon traditional risk assessment at nearly all stages of disease. Prominent examples are reviewed in this article. ConfirmMDx uses gene methylation patterns to improve detection of clinically significant cancer following negative biopsy. Both the Prolaris and Oncotype DX Genomic Prostate Score tests can improve risk stratification following biopsy, especially among men who are eligible for active surveillance. Prolaris and the Decipher genomic classifier have been associated with risk of adverse outcome following prostatectomy, while Oncotype DX is being studied in this setting. Finally, recent reports of the association of androgen receptor-V7 in circulating tumor cells with resistance to enzalutamide and abiraterone raise the possibility of extending the use of genetic biomarkers to advanced disease. Summary With the development of multiple genetic expression panels in prostate cancer, careful study and validation of these tests and integration into clinical practice will be critical to realizing the potential of these tools.

Immediate Versus Delayed Radical Prostatectomy: Updated Outcomes Following Active Surveillance of Prostate Cancer

BACKGROUND Biopsy progression on active surveillance (AS) for prostate cancer (PCa) often reflects failure of the initial biopsy to detect cancer present at enrollment. The risks for delayed treatment among men who progress on AS are not well defined. OBJECTIVE To report outcomes for men who underwent surgery after AS compared to men who underwent immediate surgery and the influence of selection bias on this outcome. DESIGN, SETTING, AND PARTICIPANTS AS-eligible (ASE) men who underwent radical prostatectomy (RP) after a median of 20 mo of AS were compared to ASE men who underwent RP within 6 mo of diagnosis. A subset of men on AS who underwent RP after upgrade to Gleason 3+4 was compared to matched controls with similar pretreatment biopsy features who underwent immediate RP. OUTCOME MEASUREMENT AND STATISTICAL ANALYSIS Rates of adverse pathology (upstaging, positive surgical margin, or Gleason upgrading) were examined. Logistic regression was used to determine associations between treatment subgroup and adverse pathology. RESULTS AND LIMITATIONS Of 157 ASE men who underwent delayed RP after AS, 54 were upgraded to Gleason 3+4 before surgery. ASE men who underwent immediate RP had lower probability of adverse pathology than ASE men who underwent delayed RP (hazard ratio [HR] 0.34, 95% confidence interval [CI] 0.21-0.55). The rate of adverse pathology did not differ between immediate and delayed RP patients matched for pretreatment characteristics (HR 0.79, 95% CI 0.27-2.28). The observational design of this study is its main limitation. CONCLUSIONS When compared to men with similar pretreatment biopsy features, those who underwent delayed RP were not at higher risk of adverse pathology. PATIENT SUMMARY The oncologic safety of delayed treatment when indicated for men enrolled in active surveillance for prostate cancer is important. We found that men who underwent delayed surgery had similar outcomes to men who underwent immediate prostatectomy.

Untreated Gleason Grade Progression on Serial Biopsies during Prostate Cancer Active Surveillance: Clinical Course and Pathological Outcomes

PURPOSE We describe the outcomes of patients with low risk localized prostate cancer who were upgraded on a surveillance biopsy while on active surveillance and evaluated whether delayed treatment was associated with adverse outcome. MATERIALS AND METHODS We included men in the study with lower risk disease managed initially with active surveillance and upgraded to Gleason score 3+4 or greater. Patient demographics and disease characteristics were compared. Kaplan-Meier curve was used to estimate the treatment-free probability stratified by initial upgrade (3+4 vs 4+3 or greater), Cox regression analysis was used to examine factors associated with treatment and multivariate logistic regression analysis was used to evaluate the factors associated with adverse outcome at surgery. RESULTS The final cohort comprised 219 men, with 150 (68%) upgraded to 3+4 and 69 (32%) to 4+3 or greater. Median time to upgrade was 23 months (IQR 11-49). A total of 163 men (74%) sought treatment, the majority (69%) with radical prostatectomy. The treatment-free survival rate at 5 years was 22% for 3+4 and 10% for 4+3 or greater upgrade. Upgrade to 4+3 or greater, higher prostate specific antigen density at diagnosis and shorter time to initial upgrade were associated with treatment. At surgical pathology 34% of cancers were downgraded while 6% were upgraded. Cancer volume at initial upgrade was associated with adverse pathological outcome at surgery (OR 3.33, 95% CI 1.19-9.29, p=0.02). CONCLUSIONS After Gleason score upgrade most patients elected treatment with radical prostatectomy. Among men who deferred definitive intervention, few experienced additional upgrading. At radical prostatectomy only 6% of cases were upgraded further and only tumor volume at initial upgrade was significantly associated with adverse pathological outcome.

Age and Baseline Quality of Life at Radical Prostatectomy—Who Has the Most to Lose?

PURPOSE Although younger men have better health related quality of life scores after radical prostatectomy, many have higher baseline function with more to lose than older men. We examined the impact of age on sexual and urinary function and bother during the first 2 years after radical prostatectomy. MATERIALS AND METHODS Participants enrolled in CaPSURE™ reported sexual and urinary scores before and after radical prostatectomy using UCLA-PCI. Repeated measures mixed models were used to compare the change in health related quality of life with time between men who were younger (age 60 years or less) and older (age greater than 60 years). Logistic regression models were used to assess associations between age and clinically meaningful health related quality of life decreases (worsening). Models were adjusted for clinical characteristics. RESULTS Of 1,806 patients younger men reported higher sexual and urinary function scores at each time point and higher sexual function decrease rates at 1 year than older men (81% vs 75%, p<0.01). Younger men also had higher sexual bother decrease rates 1 year (74% vs 61%, p<0.01) and 2 years (62% vs 56%, p=0.02) after radical prostatectomy. On multivariate analysis age was associated with changes in sexual function and bother from baseline through 2 years (each p<0.01). Younger men had higher adjusted odds of sexual function decreases at 1 year (OR 1.15/5 years, 95% CI 1.01-1.30, p=0.03) but not at 2 years. Younger age was associated with lower odds of worsening sexual bother at 2 years (OR 0.79/5 years, 95% CI 0.67-0.94, p<0.01). Urinary function and bother decrease rates were similar by age. Secondary analyses of the age/health related quality of life interaction showed that men were at greater risk for health related quality of life decreases if baseline scores were above average regardless of age. CONCLUSIONS Younger men reported higher sexual and urinary function overall, and experienced greater decreases in sexual function immediately after radical prostatectomy than older men. While the 2 groups experienced similar relative sexual function decreases at 2 years, younger men had worse interim decreases at 1 year. Providers should consider these findings when discussing treatment timing, particularly with younger men diagnosed with early stage, low grade disease.

Meaningful end points and outcomes in men on active surveillance for early-stage prostate cancer

Purpose of review Active surveillance is a management strategy for early-stage prostate cancer designed to balance early detection of aggressive disease and overtreatment of indolent disease. We evaluate recently reported outcomes and discuss the potentially most important endpoints for such an approach. Recent findings The past 2 years have seen the publication of two trials of watchful waiting versus immediate treatment and updates of multiple active surveillance cohorts for men with early-stage prostate cancer. The watchful waiting trials demonstrated a small potential mortality benefit to immediate treatment when applied to all risk levels (6% absolute difference at 15 years), emphasizing the importance of a risk-adapted strategy. In reported active surveillance cohorts, prostate cancer death and metastasis remain rare events. Intermediate outcomes such as progression to treatment and upgrading/upstaging on final disease appear consistent among cohorts, but must be interpreted with caution when compared with historical controls of immediate treatment because of potential selection bias. Summary The safety of active surveillance has been reinforced by recent reports. Accumulation of additional data on men with intermediate risk cancer and development and validation of new biomarkers of risk will allow refined and, likely, expanded use of this approach.

National Prostate Cancer Registries: Contemporary Trends of Prostate Cancer in the United States

Introduction: Randomized clinical trials are considered the gold standard for evidence‐based practices but strict inclusion and exclusion criteria, costs to perform them and the time required to design and complete them may limit generalizability, followup and timeliness. Observational studies based on well designed, large volume patient registries may be more flexible in that scope. Such registries can be modified with time to incorporate new treatments as they emerge. Methods: We describe the design, objectives, funding mechanisms and results to date of the major prostate cancer registries in the United States, highlighting as examples PCOS, CaPSURE™, PROST‐QA, CEASAR, MUSIC and AQUA. Results: Registries and collaborations have provided valuable knowledge for prostate cancer regarding oncologic and health related quality of life outcomes among treatments, changes in disease prevalence, staging, national practice trends and health service utilization. Conclusions: While there are important limitations to observational data, registries will continue to have an important and growing role in advancing prostate cancer care as a complement to data from clinical trials and traditional cohort studies.

The Ongoing Need for Improved Risk Stratification and Monitoring for Those on Active Surveillance for Early Stage Prostate Cancer

With the recognition of the prevalence of clinically indolent prostate cancer (PCa), the goal of PCa care has shifted from detection and treatment of all men with PCa to identifying and treating only men with clinically significant disease, disease that would put them at risk if left undiagnosed. However, current risk stratification schemes are not perfect. The parameters traditionally used to stratify pretreatment PCa risk (e.g., prostate-specific antigen [PSA], Gleason score (GS), T stage, tumor volume) misclassify some patients [1,2]. As a result, current active surveillance (AS) protocols call for monitoring all patients, even those with very favorable disease characteristics, with serial PSAs, examination, selective use of imaging, and periodic prostate biopsy. However, such a strategy for all patients may neither be safe nor necessary. The potential morbidity and cost of repeat biopsy, as well as other repeated evaluations, is leading clinicians (and their patients) in search of new,more refinedmarkers of risk and the need for eventual treatment. In this month’s issue of European Urology, van den Bergh and colleagues provide an excellent summary of the studies to date examining novel markers in AS for PCa [3]. The authors identified 30 original articles for review assessing a variety of potential markers including magnetic resonance imaging, serum and urinary tests, histopathologic panels, and germline genetic markers. As the authors note, MRI has been the most commonly studied test to date and currently has the most utility in AS. The reported ability ofMRI to predict future biopsy results or surgical pathology results has varied depending on magnet strength, imaging technique, and cohort used. In several

The Cancer of the Bladder Risk Assessment (COBRA) score: Estimating mortality after radical cystectomy

Risk stratification of patients with urothelial carcinoma of the bladder (UCB) after cystectomy has important clinical and research implications. The authors assessed the relative effect of tumor stage and lymph node status on cancer‐specific survival (CSS) after cystectomy and developed a simplified risk‐assessment tool.

A Randomized Study of Intraoperative Autologous Retropubic Urethral Sling on Urinary Control after Robotic Assisted Radical Prostatectomy

Purpose: We evaluated whether placement of a retropubic urethral sling fashioned from autologous vas deferens during robotic assisted radical prostatectomy would improve recovery of continence. Materials and Methods: In a phase 2, single blind trial age stratified patients were randomized to undergo robotic assisted radical prostatectomy by multiple surgeons with or without sling placement. The outcomes were complete continence (0 urinary pads of any type) and near continence (0, an occasional or 1 pad per day) at 6 months, which was assessed by the Fisher exact test and logistic regression. The Kaplan‐Meier method and the log rank test were used to evaluate time to continence. EPIC‐UIN (Expanded Prostate Cancer Index Composite‐Urinary Inventory) and I‐PSS (International Prostate Symptom Score) 1, 3 and 6 months after catheter removal were evaluated by mixed models for repeated measures. Results: Of 203 patients who were recruited 95 and 100 were randomized to undergo sling and no sling placement, respectively, and completed postoperative interviews. Six months after surgery the proportions reporting complete and near continence (66% and 87%, respectively) and times to complete and near continence were similar in the groups. Younger age was associated with a higher likelihood of complete continence (OR 1.74 per decreasing 5‐year interval, 95% CI 1.23–2.48, p <0.01) and near continence (OR 2.18 per decreasing 5‐year interval, 95% CI 1.21–3.92, p <0.01) adjusting for clinical, urinary and surgical factors. Adjusted EPIC‐UIN and I‐PSS scores changed with time but did not differ between the groups. No serious adverse events were observed. Conclusions: This trial failed to demonstrate a benefit of autologous urethral sling placement at robotic assisted radical prostatectomy on early return of continence at 6 months. Continence was related to patient age in adjusted models.