Adam B. Weiner

National Trends in the Management of Low and Intermediate Risk Prostate Cancer in the United States

PURPOSE To our knowledge factors affecting the adoption of noncurative initial management in the United States for low risk prostate cancer on a population based level are unknown. We measured temporal trends in the proportion of patients with low and intermediate risk prostate cancer who elected noncurative initial treatment in the United States and analyzed the association of factors affecting management choice. MATERIALS AND METHODS We identified 465,591 and 237,257 men diagnosed with low or intermediate risk prostate cancer using NCDB and SEER (2004 to 2010), respectively. We measured the proportion of men who elected noncurative initial treatment and used multivariate logistic regression analysis to evaluate factors affecting the treatment choice. RESULTS During the study period noncurative initial management increased in patients at low risk from 21% to 32% in SEER and from 13% to 20% in NCDB (each p < 0.001). This increase was not reflected in our overall study population (SEER 20% to 22% and NCDB 11% to 13%) since the proportion of patients with Gleason score 6 or less decreased with time (61% to 49% and 61% to 45%, respectively). From 2004 to 2010 older age, lower prostate specific antigen, earlier clinical stage, increased comorbidity index and not being married were associated with a higher likelihood of noncurative initial management (each p < 0.05). CONCLUSIONS Two independently managed, population based data sets confirmed a temporal increase in noncurative initial management in patients with low risk PCa that did not translate into greater use overall in those at low and intermediate risk combined. These contrasting results are likely due to grade migration resulting in fewer men being classified as with low risk PCa based on Gleason score.

Increasing incidence of metastatic prostate cancer in the United States (2004–2013)

Background:Changes in prostate cancer screening practices in the United States have led to recent declines in overall incidence, but it is unknown whether relaxed screening has led to changes in the incidence of advanced and metastatic prostate cancer at diagnosis.Methods:We identified all men diagnosed with prostate cancer in the National Cancer Data Base (2004–2013) at 1089 different health-care facilities in the United States. Joinpoint regressions were used to model annual percentage changes (APCs) in the incidence of prostate cancer based on stage relative to that of 2004.Results:The annual incidence of metastatic prostate cancer increased from 2007 to 2013 (Joinpoint regression: APC: 7.1%, P<0.05) and in 2013 was 72% more than that of 2004. The incidence of low-risk prostate cancer decreased from years 2007 to 2013 (APC: −9.3%, P<0.05) to 37% less than that of 2004. The greatest increase in metastatic prostate cancer was seen in men aged 55–69 years (92% increase from 2004 to 2013).Conclusions:Beginning in 2007, the incidence of metastatic prostate cancer has increased especially among men in the age group thought most likely to benefit from definitive treatment for prostate cancer. These data highlight the continued need for nationwide refinements in prostate cancer screening and treatment.

Ongoing Gleason Grade Migration in Localized Prostate Cancer and Implications for Use of Active Surveillance

Active surveillance (AS), the ongoing reassessment of low-risk cancer with delayed treatment if clinically indicated, is a management strategy intended to minimize unnecessary treatment of localized prostate cancer (PCa) without compromising mortality rates [1]. Given increasing enthusiasm for AS, our objective was to analyze temporal trends in US men with localized PCa meeting standard low-risk criteria. All men diagnosed with nonmetastatic PCa and known information on prostate-specific antigen (PSA), clinical stage, and Gleason score were identified using data from Surveillance Epidemiology and End Results (SEER; 2004–2010, n = 310 875) and the National Cancer Data Base (NCDB; 2004–2011, n = 640 996) [2,3]. The proportion of patients with low-risk characteristics (PSA <10 ng/ml, stage cT1–cT2a disease, or Gleason ≤6) was measured, and multivariate logistic regression adjusting for age (continuous) and race (white vs black vs other) were used to compare these proportions by year of diagnosis. All statistical analyses were conducted using Stata v.12.0 (StataCorp, College Station, TX, USA), and p values <0.05 were considered significant. On multivariate analysis, SEER showed that the proportion of men with PSA <10 ng/ml increased from 73% to 77% (odds ratio [OR] 1.15; 95% confidence interval [CI], 1.11–1.18; p < 0.001), cT1-cT2a disease increased from 60% to 73% (OR: 1.71; 95% CI, 1.67–1.77; p < 0.001), and Gleason ≤6 decreased from 54% to 43% (OR: 0.62; 95% CI, 0.60–0.64; p < 0.001), and the proportion of men meeting all three low-risk criteria decreased from 29.0% to 28.9% (OR: 0.97; 95% CI, 0.94–0.99; p = 0.02) from 2004 to 2010 (Fig. 1). In the NCDB, the proportion of men with PSA <10 ng/ml increased from 76% to 79% (OR: 1.14; 95% CI, 1.11–1.17; p < 0.001), cT1-cT2a disease increased from 64% to 73% (OR: 1.47; 95% CI, 1.44–1.50; p < 0.001), and Gleason ≤6 decreased from 57% to 42% (OR: 0.51; 95% CI, 0.50–0.62; p < 0.001), and the proportion of men meeting all three low-risk criteria decreased from 32.7% to 28.8% (OR: 0.79; 95% CI, 0.77–0.80; p < 0.001) from 2004 to 2011. Fig. 1 Trends in prostate-specific antigen (PSA), clinical stage, and Gleason score for localized prostate cancer patients in the United States. Patient population is all males in the SEER (2004–2010) and NCDB (2004–2011) databases with localized ... This is the first large population-based study demonstrating an ongoing Gleason grade migration through 2011, as there was a substantial decrease in localized PCa patients with Gleason ≤6 and a slight to modest decrease in low-risk cancers. This cannot be easily explained by a change in screening or biopsy patterns because PSA and clinical stage at diagnosis decreased over our study period, suggesting that men should have been more likely to have low-grade cancers [4]. The implications of a Gleason grade migration are profound, particularly given its use as an eligibility criterion for AS. Grade migration may be attributable to a more restrictive definition of Gleason 6 proposed by the 2005 International Society of Urologic Pathology Consensus Conference [5]. The grading modification will likely improve the outcomes of AS by homogenizing Gleason 6 cancers, leading to a statistical artifact of spuriously improved outcomes due to stage migration, referred to as the Will Rogers phenomenon [5]. More important, with fewer Gleason 6 cancers diagnosed, fewer men will have the opportunity to utilize AS, limiting the potential for AS to minimize so-called overtreatment of PCa. To prevent further overtreatment due to grade migration, future investigations are needed to assess the safety of AS for selected intermediate-risk patients.

Bladder Cancer Mortality in the United States: A Geographic and Temporal Analysis of Socioeconomic and Environmental Factors.

PURPOSE We assessed the association of temporal, socioeconomic and environmental factors with bladder cancer mortality in the United States. Our hypothesis was that bladder cancer mortality is associated with distinct environmental and socioeconomic factors with effects varying by region, race and gender. MATERIALS AND METHODS NCI (National Cancer Institute) age adjusted, county level bladder cancer mortality data from 1950 to 2007 were analyzed to identify clusters of increased bladder cancer death using the Getis-Ord Gi* statistic. Socioeconomic, clinical and environmental data were assessed using geographically weighted spatial regression analysis adjusting for spatial autocorrelation. County level socioeconomic, clinical and environmental data were obtained from national databases, including the United States Census, CDC (Centers for Disease Control and Prevention), NCHS (National Center for Health Statistics) and County Health Rankings. RESULTS Bladder cancer mortality hot spots and risk factors for bladder cancer death differed significantly by gender, race and geographic region. From 1996 to 2007 smoking, unemployment, physically unhealthy days, air pollution ozone days, percent of houses with well water, employment in the mining industry and urban residences were associated with increased rates of bladder cancer mortality (p <0.05). Model fit was significantly improved in hot spots compared to all American counties (R(2) = 0.20 vs 0.05). CONCLUSIONS Environmental and socioeconomic factors affect bladder cancer mortality and effects appear to vary by gender and race. Additionally there were temporal trends of bladder cancer hot spots which, when persistent, should be the focus of individual level studies of occupational and environmental factors.

Intravesical therapy for bladder cancer

Introduction: Transurethral resection of bladder tumor (TURBT) is the gold standard initial diagnostic intervention for bladder cancer and provides diagnostic, therapeutic and prognostic benefit in non-muscle-invasive bladder cancer (NMIBC). However, TURBT alone is inadequate for optimal management of NMIBC, as patients will experience recurrence or progression depending on tumor characteristics. Adjuvant intravesical therapy with either immunotherapy or chemotherapy has been shown to reduce recurrence and/or progression in appropriately selected patients through immunostimulation or direct cell ablation. Areas covered: This review will discuss risk stratification of patients with NMIBC and role of intravesical therapies in reducing recurrence and progression of disease in these patients. A Medline search was performed to identify the best available evidence available from various systematic reviews, meta-analyses, and clinical trials on various immunotherapy and chemotherapy agents. In addition, the main aspects of drug pharmacology (mechanism of action, dosing and administration) and side effects will be reviewed. Expert opinion: The selection of the appropriate intravesical agent for NMIBC is complex and is dependent on risk stratification and intravesical agent toxicity. Intravesical induction and maintenance immunotherapy with Bacillus Calmette–Guerin (BCG) is the preferred and most effective agent for patients with high-risk NMIBC (carcinoma in situ and high-grade disease) and reduces both recurrence and progression.

Pathologic outcomes for low-risk prostate cancer after delayed radical prostatectomy in the United States.

OBJECTIVES To measure adverse pathologic outcomes following radical prostatectomy (RP) for men with low-risk prostate cancer in the United States based on time from diagnosis to surgery. METHODS We extracted data from the National Cancer Database in 2010 and 2011 on 17,943 low-risk patients (Gleason score = 3+3, prostate-specific antigen < 10 ng/ml, and cT1-T2) who underwent RP. We identified men who delayed RP by>6 months after diagnosis and measured the effect of delayed RP on pathologic upgrading, upstaging, nodal metastases, and positive surgical margins. RESULTS Overall, 16,818 underwent RP ≤ 6 months, 894 at 6 to 9 months, 169 at 9 to 12 months, and 62 at>12 months from diagnostic biopsy. Furthermore, upgrading occurred in 43%, upstaging in 9%, positive surgical margins in 16%, and nodal metastases in 0.3% of men. Upgrading, upstaging, or nodal metastases occurred in 45% of men. On multivariable analysis, higher prostate-specific antigen (4.1-9.9 ng/ml vs. 0.1-2.4 ng/ml; odds ratio [OR] = 1.87, 95% CI: 1.66-2.10),>2 positive biopsy cores (OR = 1.68, 95% CI: 1.57-1.81), ≥ 34% positive biopsy cores (OR = 1.28, 95% CI: 1.18-1.39), black race (OR = 1.16, 95% CI: 1.05-1.28), and time from biopsy to RP>12 months (vs. ≤ 6 mo: OR = 1.70, 95% CI: 1.01-2.84) each independently increased the composite risk of adverse pathology (all P< 0.05). CONCLUSION In the United States, nearly half of men with low-risk prostate cancer experience at least one adverse pathologic outcome at RP. Delaying RP up to 12 months did not change the risk of adverse pathology. Men may safely use the time following their initial biopsy to consider management options and obtain a restaging biopsy, if recommended.

Management trends for men with early stage nonseminomatous germ cell tumors of the testicle: An analysis of the National Cancer Database.

Surveillance has been recommended more frequently as a postorchiectomy management option for men with early stage nonseminomatous germ cell tumor (NSGCT) of the testicle. It is unknown how contemporary treatment patterns reflect these recommendations.

Metastatic small cell carcinoma of the prostate: Population-based analysis of patient characteristics and treatment paradigms

INTRODUCTION Small cell carcinoma of the prostate is a rare malignancy comprising<1% of prostate cancers. Little is known about population-based treatment patterns for metastatic small cell carcinoma of the prostate. We evaluated clinical characteristics, treatment patterns, and survival outcomes. METHODS Using the National Cancer Database, we identified patients between 1998 and 2011 diagnosed with pure small cell carcinoma of the prostate as their only malignancy who presented with nodal involvement or distant metastasis. RESULTS Treatment information was available for 379 patients. Of them, 122 (32.5%) underwent chemotherapy (CT) alone, 25 (6.7%) received hormonal therapy (androgen-deprivation therapy) alone, 10 (2.7%) underwent radiation therapy alone, 3 (1%) underwent radical prostatectomy, and 167 (44.4%) underwent combination therapy. The 1- and 3-year survival rates were 35.3% and 4.4%, respectively. Those receiving any CT as part of their treatment had a median survival of 9.3 vs. 3.2 months for those not receiving it (P<0.001). Those receiving CT, androgen-deprivation therapy, and radiation had a median survival of 15.1 vs. 7 months for those receiving CT alone (P<0.001). On multivariable analysis (controlling for age, Charlson comorbidity index, extent of metastasis, prostate-specific antigen level, and type of treatment), older age (hazard ratio [HR] = 3.87; 95% CI: 1.41-9.34; P = 0.007) and distant metastatic disease (HR = 7.17; 95% CI: 1.62-31.8; P = 0.010) increased risk of death, whereas receipt of CT (HR = 0.15; 95% CI: 0.05-0.44; P = 0.001) decreased risk of death. CONCLUSION Men presenting with metastatic small cell carcinoma of the prostate have poor overall survival. Older patients and those presenting with distant metastases have an increased risk of death. It appears that patients receiving CT experience a modest survival benefit. The role of hormonal therapy in this population remains unclear.

Risk of lymph node metastases in pathological gleason score≤6 prostate adenocarcinoma: Analysis of institutional and population-based databases

INTRODUCTION Several institutional studies have suggested that pathological Gleason score≤6 prostate cancer has little or no capacity for metastasis. MATERIALS AND METHODS Using the Surveillance, Epidemiology, and End Results database (SEER, 2004-2011, n = 19,594) and the National Cancer Database (NCDB, 2004-2013, n = 57,540), we identified patients with pathological Gleason score≤6 prostate cancer following radical prostatectomy and lymph node dissection. At the University of Chicago Medicine (UCM, 2003-2014), we considered men with Gleason score≤6 prostate cancer who did (n = 267) and did not receive (n = 770) a lymph node dissection at the time of radical prostatectomy. Temporal trends in lymph node dissection and lymph node metastases were determined, and multivariable logistic regressions were used to analyze factors associated with lymph node metastases. In the UCM cohort, we also evaluated secondary endpoints, including biochemical recurrence (BCR), metastatic disease on follow-up imaging, and response to salvage radiation therapy. RESULTS The incidence of lymph node dissection at the time of radical prostatectomy decreased from 60% to 37% in SEER (2004-2011) and from 62% to 45% in NCDB (2004-2013). Positive lymph node metastases were found in 0.2% of SEER and 0.18% of NCDB patients who received a lymph node dissection. Elevated PSA, higher clinical stage, and African American race were associated with lymph node positivity in one or both of these databases (P<0.05). Among UCM patients who received a lymph node dissection, no lymph node metastases were found, though a BCR occurred in 3 cases (1%). All 3 men responded favorably to salvage therapy, suggestive of local recurrence. A total of 21 patients (3%) from UCM who did not receive a lymph node dissection had a BCR and underwent salvage radiation therapy. Of these, 4 patients had persistently detectable PSA levels without evidence of local or distant disease at median follow-up of 65 months (range: 29-79) following salvage therapy. Surgical specimens were available for contemporary pathologic review in 3 of these cases, and all were upgraded to Gleason 7 disease. CONCLUSIONS Our population-based and institutional analyses suggest metastases in cases of Gleason score≤6 prostate cancer to be extremely rare.

Contemporary Population-Based Comparison of Localized Ductal Adenocarcinoma and High-Risk Acinar Adenocarcinoma of the Prostate

OBJECTIVE To compare pathological characteristics, treatment patterns, and survival in patients with ductal adenocarcinoma (DC) compared to those with acinar adenocarcinoma (AC). MATERIALS AND METHODS Using the National Cancer Database, we identified patients diagnosed with clinically localized (cN0, cM0) pure DC (n = 1328) and AC (n = 751,635) between 1998 and 2011. High-risk AC was defined as Gleason 8-10. Demographic, treatment, pathological, and survival characteristics of patients were compared. RESULTS Compared to patients with Gleason 8-10 AC, those with DC presented with lower mean prostate-specific antigen (10.3 vs 16.2 ng/mL, P <.001), had similar rates (11.7% vs 11.5%, P = .8) of clinical extra-capsular extension (stage ≥ cT3), and were more likely to undergo prostatectomy (54% vs 36%, P <.001). Compared to patients with Gleason 8-10 AC undergoing prostatectomy, those with DC had more favorable pathology: stage ≥ T3 (39% vs 52%, P <.001), fewer positive lymph nodes (4% vs 11%, P <.001), and fewer positive margins (25% vs 33%, P <.001). On Kaplan-Meier analysis, patients with DC had similar 5-year survival (75.0%, 95% confidence interval [CI] [71.7-78.9]) compared to those with Gleason 8-10 AC (77.1%, 95% CI [76.6%-77.6%], P = .2). On Cox multivariable analysis, patients with Gleason 8-10 AC had a similar risk of death compared to those with DC (hazards ratio = 0.92, 95% CI [0.69-1.23], P = 6). CONCLUSION In this large contemporary population-based series, patients with DC of the prostate presented with lower prostate-specific antigen, had more favorable pathological features, and similar overall survival compared to men with Gleason 8-10 AC.