Prostate cancer-specific mortality burden by risk group among men with localized disease: Implications for research and clinical trial priorities.

OBJECTIVE: To estimate contemporary population-based patterns of the relative burden of prostate cancer-specific mortality (PCSM) attributable to each N0M0 prostate cancer risk-group, that may guide prioritization in research, trial design, and clinical practice. METHODS: We categorized 2004-2015 Surveillance, Epidemiology, and End Results database patients by risk group (low, favorable intermediate, unfavorable intermediate, high, and very highrisk). Using the Fine-Gray method, we calculated the relative burden of 10-year PCSM attributable to each risk group. RESULTS: Among N = 337 162 men (6.8-year median follow-up; median age 65 years), the relative proportion of low-, favorable intermediate-, unfavorable intermediate-, high-, and very high-risk diagnoses were 29.9% (N = 100 969), 31.1% (N = 104 696), 17.9% (N = 60 360), 18.1% (N = 61 023), and 3.0% (N = 10 114). Within 10 years of diagnosis, among patients who died of prostate cancer (N = 15 064), 5.0% (N = 746) had low-risk, 13.7% (N = 2060) had favorable intermediate-risk, 16.1% (N = 2429) had unfavorable intermediate-risk, 47.8% (N = 7196) had high-risk, and 17.5% (N = 2633) had very high-risk disease at diagnosis. Patients aged 65 and older accounted for 51.9% of all diagnoses and 72.3% of 10-year PCSM. Although black patients accounted for 15.0% of low-risk diagnoses, they accounted for 20.6% of 10-year PCSM. White patients accounted for 80.3% of low-risk diagnoses and 75.7% of 10-year PCSM. CONCLUSION: Although high-risk and very high-risk disease account for one-fifth of diagnoses, they account for two-thirds of 10-year PCSM. Older patients and black patients with low-risk disease accounted for a disproportionately large proportion of deaths. These findings support targeting research toward high-risk disease and ensuring adequate representation of older and black men in clinical trials.

Impact of percent positive biopsy cores on cancer-specific mortality for patients with high-risk prostate cancer.

OBJECTIVE: A high percent positive biopsy cores (PBC), typically dichotomized at ≥50% is prognostic of worse cancer-specific outcomes for patients with low- and intermediate-risk prostate cancer (CaP). The clinical significance of ≥50% PBC for patients with high-risk disease is poorly understood. We examined the association between ≥50% PBC, compared to <50% PBC, and prostate cancer-specific mortality (PCSM) for patients with high-risk disease. MATERIALS AND METHODS: We identified 7,569 men from the Surveillance, Epidemiology, and End Results program who were diagnosed with high-risk CaP (Gleason score of 8-10, prostate-specific antigen >20 ng/mL, or cT3-T4 stage) in 2010-2011 and had 6 to 24 cores sampled at biopsy. Multivariable Fine and Gray competing risks regression was utilized to examine the association between ≥50% PBC and PCSM. RESULTS: Median follow-up was 3.8 years. 56.2% of patients (4,253) had ≥50% PBC. On competing risks regression, ≥50% PBC was associated with a significantly higher risk of PCSM compared to <50% PBC (adjusted hazard ratio [AHR] 2.00, 95% confidence interval [CI] 1.48-2.70, P < 0.001). On subgroup analyses, ≥50% PBC was associated with a significantly higher risk of PCSM only for cT1-T2 disease (AHR 2.23, 95% CI 1.62-3.07) but not cT3-T4 disease (AHR 0.83, 95% CI 0.39-1.76), with a significant interaction (Pinteraction = 0.016). No significant interactions by Gleason score, prostate-specific antigen level, use of definitive therapy, or number of biopsy cores sampled were observed. CONCLUSION: In this large cohort of patients with high-risk CaP, ≥50% PBC was independently associated with an approximately 2-fold increased risk of PCSM for patients with cT1-T2, but not cT3-T4, tumors. Percent PBC, which is a widely available clinical value, should be routinely used to risk stratify men with high-risk disease and identify patients whom may benefit from treatment intensification.

Risk of Upgrading and Upstaging Among 10 000 Patients with Gleason 3+4 Favorable Intermediate-risk Prostate Cancer.

BACKGROUND: It is unknown whether active surveillance can be safely offered to patients with Gleason 3+4 favorable intermediate-risk (FIR) prostate cancer. OBJECTIVE: To examine the incidence and predictors of upgrading and upstaging among patients with Gleason 3+4 FIR disease. DESIGN, SETTING, AND PARTICIPANTS: The study involved 10 089 patients in the National Cancer Database diagnosed from 2010 to 2012 with Gleason 3+4 disease, prostate-specific antigen (PSA) <10ng/ml, and cT1c-2a prostate cancer with <50% positive biopsy cores (PBCs) who underwent radical prostatectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Logistic regression was used to examine predictors of upgrading (pathologic Gleason ≥4+3 or tertiary Gleason 5 in a Gleason 7 tumor) or upstaging (pT3-4/N1). RESULTS AND LIMITATIONS: Some 30.3% of Gleason 3+4 FIR patients were upgraded or upstaged. On multivariable analysis, predictors included higher PSA, percentage PBC, age, and cT2a versus cT1c (all p<0.001), but not black race (p=0.895). When stratified into ordinal variables, PSA 8.1-9.9 versus ≤4.0ng/ml (adjusted odds ratio [AOR] 1.93, 38.3% vs 24.4%), PBC 37.5-49.9% versus <12.5% (AOR 1.79, 37.8% vs 25.1%); highest age quartile (≥67 yr) versus lowest (≤55 yr; AOR 1.46, 35.7% vs 24.7%); and cT2a versus cT1c (AOR 1.33, 34.3% vs 29.8%) were associated with a higher risk of upgrading or upstaging (all p<0.001). Men with PBC <12.5% and PSA ≤4.0ng/ml had a 21.7% risk of more advanced disease. This increased to 44.3% for PBC 37.5-49.9% and PSA 8.1-9.9ng/ml. A limitation of the study is its retrospective nature. CONCLUSIONS: Approximately one in three patients with Gleason 3+4 FIR harbored disease of higher grade or stage. Younger patients with low percentage PBC and PSA and cT1c disease have a lower risk and may be candidates for active surveillance. However, widely available clinical information is insufficient for predicting the risk of more advanced disease, and the development and incorporation of additional tools, including magnetic resonance imaging and genomic tests, are necessary. PATIENT SUMMARY: Nearly one-third of patients with Gleason 3+4 favorable intermediate-risk prostate cancer harbor disease of higher grade or higher stage than their biopsy and clinical examination suggest. These patients would therefore be poor candidates for active surveillance.

Pathologic Outcomes of Gleason 6 Favorable Intermediate-Risk Prostate Cancer Treated With Radical Prostatectomy: Implications for Active Surveillance.

BACKGROUND: The safety of active surveillance (AS) for Gleason 6 favorable intermediate-risk (FIR) prostate cancer is unknown. To provide guidance, we examined the incidence and predictors of upgrading or upstaging for Gleason 6 FIR patients treated with radical prostatectomy. PATIENTS AND METHODS: We identified 2807 men in the National Cancer Database diagnosed from 2010 to 2012 with Gleason 6 FIR disease (<50% positive biopsy cores [PBC] with either prostate-specific antigen [PSA] of 10-20 ng/mL or cT2b-T2c disease) treated with radical prostatectomy. Logistic regression was used to identify predictors of upgrading (Gleason 3+4 with tertiary Gleason 5 or Gleason ≥4+3) or upstaging (pT3-4/N1). RESULTS: Fifty-seven percent of the cohort had PSA of 10 to 20 ng/mL; 25.5% patients with PSA of 10 to 20 ng/mL and 12.4% with cT2b to T2c disease were upgraded or upstaged. In multivariable analysis, predictors of upgrading or upstaging included increasing age (P = .026), PSA (P = .001), and percent PBC (P < .001), and black race versus white (P = .035) for patients with PSA of 10 to 20 ng/mL and increasing PSA (P = .001) and percent PBC (P < .001) for patients with cT2b to T2c disease. Men with PSA of 15.0 to 20.0 ng/mL or 37.5% to 49.9% PBC with PSA of 10 to 20 ng/mL had >30% risk of upgrading or upstaging, whereas cT2b to T2c patients with <12.5% PBC or PSA <5.0 ng/mL had <10% risk. CONCLUSION: We found that Gleason 6 FIR patients with cT2b to T2c tumors had a low risk of harboring higher grade or stage disease and would be reasonable AS candidates, whereas patients with PSA of 10 to 20 ng/mL had a high risk and might generally be poor AS candidates.

Receipt of definitive therapy in elderly patients with unfavorable-risk prostate cancer.

BACKGROUND: Conservative management of aggressive prostate cancer in the elderly without definitive therapy has been associated with a 10-year prostate cancer-specific mortality of approximately 50%. The authors examined the prevalence of definitive therapy in elderly patients with intermediate-risk or high-risk disease. METHODS: 411,343 patients who were diagnosed from 2004 through 2012 with intermediate-risk or high-risk prostate cancer were identified in the National Cancer Database. Multivariable logistic regression adjusting for sociodemographic characteristics and comorbidity was used to examine the association between age and receipt of definitive therapy, defined as radical prostatectomy or radiotherapy, and of primary androgen deprivation therapy (ADT) among patients who did not receive definitive therapy. RESULTS: In total, 87.1% of high-risk patients and 91.9% of intermediate-risk patients received definitive therapy. When stratified by age, 93.7%, 92.1%, 90.8%, 87.6%, 80.9%, and 55.2% of high-risk patients and 96.1%, 94.7%, 93.4%, 89.7%, 82.7%, and 62.8% of intermediate-risk patients ages <60, 60 to 64, 65 to 69, 70 to 74, 75 to 79, and ≥80 years received definitive therapy, respectively. For both high-risk and intermediate-risk patients, increasing age was significantly associated with a decreased likelihood of receiving definitive therapy overall (both P < .001) and a greater likelihood of receiving primary ADT among those who did not receive definitive therapy (both P < .001). CONCLUSIONS: Older age was significantly associated with a decreased likelihood of receiving definitive therapy and an increased likelihood of receiving primary ADT in this national cohort of patients with intermediate-risk or high-risk prostate cancer. Notably, approximately 40% to 45% of patients aged ≥80 years did not receive definitive therapy. These findings are alarming given the dismal outcomes of conservatively managed unfavorable-risk prostate cancer. Cancer 2017;123:4832-40. © 2017 American Cancer Society.

Disparities in the Receipt of Local Treatment of Node-positive Prostate Cancer.

INTRODUCTION: We sought to determine whether any sociodemographic disparities are present in the receipt of local treatment for node-positive prostate cancer. PATIENTS AND METHODS: We identified 9771 patients with clinical N1M0 prostate cancer diagnosed from 1998 to 2012 using the National Cancer Database. We used multivariable logistic regression modeling to identify patient-specific factors that were associated with a reduced likelihood of receiving prostate or pelvic radiation or radical prostatectomy. We also used Cox regression modeling to estimate the differences in overall survival (OS) using these factors. RESULTS: The factors associated with a reduced likelihood of receiving local therapy included black race versus white race (43.6% vs. 49.4%; adjusted odds ratio [AOR], 0.76; P = .001), bottom income quartile versus top quartile (44.7% vs. 52.7%; AOR, 0.69; P = .001), age > 66 years versus ≤ 66 years (40.8% vs. 55.1%; AOR, 0.48; P < .001), diagnosis before 2005 versus after 2005 (30.5% vs. 61.7%; AOR, 0.66; P < .001), and Medicaid or no insurance versus private insurance (41.0% vs. 49.4%; AOR, 0.41; P < .001). Although patients had reduced 5-year OS if they were from lower income quartiles (adjusted hazard ratios [AHRs], 1.18-1.22; P < .05), were older (AHR, 1.82; P < .001), or had Medicaid or no insurance (AHR, 1.24; P = .032), these disparities were no longer present or were smaller in magnitude after adjustment for receipt of local treatment. CONCLUSION: Significant treatment disparities exist in the receipt of local therapy for node-positive prostate cancer. Given the accumulating evidence supporting this practice, the factors underlying these disparities should be studied and addressed.

National Trends and Predictors of Androgen Deprivation Therapy Use in Low-Risk Prostate Cancer.

PURPOSE: Androgen deprivation therapy (ADT) is not recommended for low-risk prostate cancer because of its lack of benefit and potential for harm. We evaluated the incidence and predictors of ADT use in low-risk disease. METHODS AND MATERIALS: Using the National Cancer Database, we identified 197,957 patients with low-risk prostate cancer (Gleason score of 3 + 3 = 6, prostate-specific antigen level <10 ng/mL, and cT1-T2a) diagnosed from 2004 to 2012 with complete demographic and treatment information. We used multiple logistic regression to evaluate predictors of ADT use and Cox regression to examine its association with all-cause mortality. RESULTS: Overall ADT use decreased from 17.6% in 2004 to 3.5% in 2012. In 2012, 11.5% of low-risk brachytherapy patients and 7.6% of external beam radiation therapy patients received ADT. Among 82,352 irradiation-managed patients, predictors of ADT use included treatment in a community versus academic cancer program (adjusted odds ratio [AOR], 1.60; 95% confidence interval [CI], 1.50-1.71; P<.001; incidence, 14.0% vs 6.0% in 2012); treatment in the South (AOR, 1.51), Midwest (AOR, 1.81), or Northeast (AOR, 1.90) versus West (P<.001); and brachytherapy use versus external beam radiation therapy (AOR, 1.32; 95% CI, 1.27-1.37; P<.001). Among 25,196 patients who did not receive local therapy, predictors of primary ADT use included a Charlson-Deyo comorbidity score of ≥2 versus 0 (AOR, 1.42; 95% CI, 1.06-1.91; P=.018); treatment in a community versus academic cancer program (AOR, 1.61; 95% CI, 1.37-1.90; P<.001); and treatment in the South (AOR, 1.26), Midwest (AOR, 1.52), or Northeast (AOR, 1.28) versus West (P≤.008). Primary ADT use was associated with increased all-cause mortality in patients who did not receive local therapy (adjusted hazard ratio, 1.28; 95% CI, 1.14-1.43; P<.001) after adjustment for age and comorbidity. CONCLUSIONS: ADT use in low-risk prostate cancer has declined nationally but may remain an issue of concern in certain populations and regions.

Low rates of androgen deprivation therapy use with salvage radiation therapy in patients with prostate cancer after radical prostatectomy.

OBJECTIVE: The RTOG 9601 and GETUG-AFU 16 randomized controlled trials demonstrated that the addition of androgen deprivation therapy (ADT) to salvage radiation therapy (SRT) improves progression-free and, for RTOG 9601, overall survival. We examined national trends in the use of ADT with SRT. MATERIALS AND METHODS: Of the 484,009 patients in the National Cancer Database from 2004 to 2012 with localized or locally advanced prostate cancer treated with radical prostatectomy (RP), 4,200 men received SRT (≥6mo after surgery). We used Pearson's chi-squared test to evaluate changes in ADT use, and multiple logistic regression to examine predictors of ADT use. RESULTS: Overall, 32.1% of SRT patients received ADT, which increased after initial results of RTOG 9601 showed an improvement in metastasis-free survival in 2010 (28.5% in 2008/2009 vs. 34.5% in 2011/2012, P = 0.006). Predictors of ADT use include presurgery prostate-specific antigen>20ng/ml vs.<10ng/ml (adjusted odds ratio [AOR] = 1.34, P = 0.002; 36.7% vs. 29.6%); positive vs. negative margins (AOR = 1.29, P = 0.001; 34.9% vs. 27.8%); Gleason 3+4 (AOR = 1.53; 21.3%), Gleason 4+3 (AOR = 2.40; 32.0%), or Gleason 8 to 10 (AOR = 4.49; 49.2%) vs. Gleason 2 to 6 (P≤0.005 for all; 13.2%); and pathologic T3a (AOR = 1.46; 30.9%), T3b (AOR = 2.50; 47.6%), or T4 (AOR = 4.14; 60.9%) vs. T2 (P<0.001 for all; 19.1%). Starting SRT 12 to 23.9 months (AOR = 0.69; 23.2%) or≥24 months (AOR = 0.25; 8.0%) after RP was associated with decreased odds of ADT use vs. starting SRT 6 to 8.9 months after RP (P≤0.002 for both; 35.0%). CONCLUSION: Although less than one-third of SRT patients from the study era received ADT, there is evidence that physicians and patients have begun slowly adopting this practice with the 2010 reporting of a decrease in the cumulative incidence of metastases with the addition of ADT to SRT. Given the newly reported survival benefit of RTOG 9601, additional work will be necessary to identify which patients benefit the most from the use of ADT with SRT to individualize treatment.

Association Between Travel Distance and Choice of Treatment for Prostate Cancer: Does Geography Reduce Patient Choice?

OBJECTIVE: To determine whether the distance between a prostate cancer patient's home and treatment facility was related to the choice of treatment received among those opting for surgery or radiation. METHODS AND MATERIALS: We identified 222,804 patients diagnosed with National Comprehensive Cancer Network low-, intermediate-, or high-risk N0M0 prostate cancer and treated with local therapy (surgery or radiation alone, with or without hormone therapy) using the National Cancer Database. We used multivariable logistic regression to determine whether the choice of radiation therapy vs radical prostatectomy varied by distance among patients living in rural and urban areas. Analyses were adjusted for geographic location within the United States, age, race, Charlson/Deyo comorbidity score, year of diagnosis, income quartile, education quartile, Gleason score, prostate-specific antigen level, and T stage. RESULTS: Patients living in urban or rural areas were less likely to receive radiation compared with surgery if they lived farther from the treatment facility. Among urban patients living ≤5 miles from the treatment facility, 53.3% received radiation, compared with 47.0%, 43.6%, and 33.8% of those living 5 to 10, 10 to 15, or >15 miles away, respectively (P<.001 in all cases). Similarly, rural patients were less likely to receive radiation the farther they lived from the treatment facility (≤25 miles: 62.3%; 25-50 miles: 55.5%; 50-75 miles: 38.4%; >75 miles: 23.8%; P<.05 in all cases). These trends were also present when each risk group was analyzed separately. CONCLUSION: Patients with prostate cancer in both urban and rural settings were less likely to receive radiation therapy rather than surgery the farther away they lived from a treatment center. These findings raise the possibility that the geographic availability of radiation treatment centers may be an important determinant of whether patients are able to choose radiation rather than surgery for localized prostate cancer.

Factors associated with the omission of androgen deprivation therapy in radiation-managed high-risk prostate cancer.

PURPOSE: Androgen deprivation therapy (ADT) has been shown to improve survival for men with unfavorable-risk prostate cancer (PCa). We investigated the utilization and factors associated with the omission of ADT in radiation-managed high-risk PCa. METHODS AND MATERIALS: We used the National Cancer Database to identify men with National Comprehensive Cancer Network high-risk PCa treated with external beam radiation therapy (EBRT) with or without brachytherapy boost from 2004 to 2012. Multivariable logistic regression adjusting for clinical and sociodemographic factors was used to identify independent predictors for ADT use. RESULTS: A total of 57,968 radiation-treated high-risk PCa men were included in our analysis. There were 49,363 patients (85.2%) treated with EBRT alone and 8605 patients (14.8%) treated with EBRT plus brachytherapy boost. Overall, 77% of men received ADT. In multivariable regression analysis, the use of brachytherapy boost was associated with a significantly lower utilization of ADT (70% vs. 78%; adjusted odds ratio [AOR]: 0.65; 95% CI: 0.62-0.69; p-Value <0.0001), as was treatment at an academic vs. nonacademic center (AOR: 0.90; 95% CI: 0.86-0.95; p-Value <0.0001) and treatment in 2010-2012 compared to 2004-2006 (AOR: 0.85; 95% CI: 0.81-0.90; p-Value <0.0001). Conversely, greater ADT use was seen with higher Gleason scores, PSA, and T-category (all p-Values <0.001). CONCLUSIONS: Approximately one in four men with radiation-managed high-risk PCa do not receive ADT, which may reflect concerns about its toxicity profile despite known improvements in overall survival. Practice patterns suggest that some providers believe dose escalation through brachytherapy boost may obviate the need for ADT in some high-risk patients, but this hypothesis requires further testing.

Variation in National Use of Long-Term ADT by Disease Aggressiveness Among Men With Unfavorable-Risk Prostate Cancer.

BACKGROUND: The current NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer recommend long-term androgen deprivation therapy (ADT) for all men with high-risk prostate cancer treated with external-beam radiation therapy (EBRT). We determined whether the use of long-term ADT varied by the recently defined subcategories of high-risk disease (favorable, other, and very high) versus unfavorable intermediate-risk disease. METHODS: We identified 5,524 patients with unfavorable-risk prostate cancer diagnosed from 2004 to 2007 and managed with EBRT using the SEER-Medicare linked database. Patients were stratified by risk group: unfavorable intermediate-risk, favorable high-risk (previously defined and validated as clinical stage T1c, Gleason score of 4 + 4 = 8, and prostate-specific antigen [PSA] level <10 ng/mL, or clinical stage T1c, Gleason score of 6, and PSA level >20 ng/mL), very-high-risk (clinical stage T3b-T4 or primary Gleason pattern 5), or other high risk (ie, neither favorable nor very high). We used multivariable competing risks regression to estimate the rates of long-term (≥2 years) ADT by group. RESULTS: Men with favorable high-risk prostate cancer were significantly less likely to receive long-term ADT than those with other high-risk disease (15.4% vs 24.6%, adjusted hazard ratio [AHR], 0.68; 95% CI, 0.60-0.76;P<.001), and similarly likely as those with unfavorable intermediate-risk disease (AHR, 1.10; 95% CI, 0.99-1.23;P=.087). Other high-risk disease was less likely to receive long-term ADT than very high-risk cancer (24.6% vs 30.8%; AHR, 0.83; 95% CI, 0.74-0.93;P=.002). CONCLUSIONS: Despite current guidelines, patients with EBRT-managed high-risk prostate cancer received significantly different rates of long-course ADT based on subclassification. Our results suggest that oncologists view these patients as a heterogeneous group with favorable high-risk cancer warranting less aggressive therapy than other high-risk or very high-risk disease.

Association of Androgen Deprivation Therapy With Depression in Localized Prostate Cancer.

PURPOSE: Androgen deprivation therapy (ADT) may contribute to depression, yet several studies have not demonstrated a link. We aimed to determine whether receipt of any ADT or longer duration of ADT for prostate cancer (PCa) is associated with an increased risk of depression. METHODS: We identified 78,552 men older than age 65 years with stage I to III PCa using the SEER-Medicare-linked database from 1992 to 2006, excluding patients with psychiatric diagnoses within the prior year. Our primary analysis was the association between pharmacologic ADT and the diagnosis of depression or receipt of inpatient or outpatient psychiatric treatment using Cox proportional hazards regression. Drug data for treatment of depression were not available. Our secondary analysis investigated the association between duration of ADT and each end point. RESULTS: Overall, 43% of patients (n = 33,882) who received ADT, compared with patients who did not receive ADT, had higher 3-year cumulative incidences of depression (7.1% v 5.2%, respectively), inpatient psychiatric treatment (2.8% v 1.9%, respectively), and outpatient psychiatric treatment (3.4% v 2.5%, respectively; all P < .001). Adjusted Cox analyses demonstrated that patients with ADT had a 23% increased risk of depression (adjusted hazard ratio [AHR], 1.23; 95% CI, 1.15 to 1.31), 29% increased risk of inpatient psychiatric treatment (AHR, 1.29; 95% CI, 1.17 to 1.41), and a nonsignificant 7% increased risk of outpatient psychiatric treatment (AHR, 1.07; 95% CI, 0.97 to 1.17) compared with patients without ADT. The risk of depression increased with duration of ADT, from 12% with ≤ 6 months of treatment, 26% with 7 to 11 months of treatment, to 37% with ≥ 12 months of treatment (P trend < .001). A similar duration effect was seen for inpatient (P trend < .001) and outpatient psychiatric treatment (P trend < .001). CONCLUSION: Pharmacologic ADT increased the risk of depression and inpatient psychiatric treatment in this large study of elderly men with localized PCa. This risk increased with longer duration of ADT. The possible psychiatric effects of ADT should be recognized by physicians and discussed with patients before initiating treatment.

Occult High-risk Disease in Clinically Low-risk Prostate Cancer with ≥50% Positive Biopsy Cores: Should National Guidelines Stop Calling Them Low Risk?

OBJECTIVE: To identify contemporary, clinically low-risk patients with ≥50% cores positive and compare the risk of upgrading at prostatectomy with other low- or intermediate-risk patients. MATERIALS AND METHODS: We studied 14,902 patients with prostate cancer in the Surveillance, Epidemiology, and End Results database in 2010-2011 treated with prostatectomy. Patients were categorized by National Comprehensive Cancer Network clinical risk groups, separating low-risk patients by percent positive biopsy cores (PBC). We measured incidence of pathologic high-risk disease, defined as pT3a-T4 or Gleason 8-10, and multivariable logistic regression was used to determine if patients with clinical low-risk disease and ≥50% PBC were similar to other low- or intermediate-risk patients. This analysis was repeated with favorable and unfavorable intermediate risk. RESULTS: At prostatectomy, 9.2% of clinically low-risk patients with <50% PBC, 18.6% of clinically low-risk patients with ≥50% PBC, and 27.6% of clinically intermediate-risk patients had occult, high-risk disease (P <.001). On multivariable logistic regression, low-risk patients with ≥50% PBC were more likely than low-risk patients with <50% PBC to have pathologic high-risk disease (adjusted odds ratio [AOR] 2.28, 95% confidence interval 1.90-2.73, P <.001), had similar risk to favorable intermediate patients overall (AOR 1.09, 0.91-1.31, P = .33), and had higher risk than favorable intermediate patients aged over 60 years (AOR 1.28, 1.00-1.64, P = .04). Low-risk patients with ≥50% PBC had a mean tumor size similar to unfavorable intermediate-risk patients (21.3 vs 21.0 mm, P = .82). CONCLUSION: Nearly 1 in 5 clinically low-risk prostate cancer patients with ≥50% PBC harbor occult pT3a-T4 or Gleason 8-10, suggesting that national guidelines should not classify low-risk patients with ≥50% cores positive as "low risk," and patients should be made aware of this excess risk if considering active surveillance.

Significant increase in prostatectomy and decrease in radiation for clinical T3 prostate cancer from 1998 to 2012.

PURPOSE: We aimed to describe changes in treatment patterns for clinical T3 prostate cancer (PCa) from 1998 to 2012, specifically investigating what factors influence receipt of prostatectomy or radiation. MATERIALS AND METHODS: Using the Surveillance, Epidemiology, and End Results database, we studied 11,604 men with clinical T3N0M0 PCa from 1998 to 2012, with treatment categorized as radiation, radical prostatectomy (RP), or no curative therapy. We calculated rate of treatment type by year of diagnosis to investigate trends in treatment patterns, further stratifying by clinical T3a, defined as unilateral and bilateral extracapsular extension (n = 3,842), vs. T3b (defined as extension to seminal vesicles (n = 3,665). Finally, a multivariable logistic regression analysis measured association of demographic and clinical variables with type of treatment received for years 2010 to 2011. RESULTS: Rates of prostatectomy increased significantly from 1998 to 2012 (12.5% vs. 44.4%), radiation decreased significantly (55.8% vs. 38.4%), and receipt of no treatment also decreased (31.7% vs. 17.2%, all P<0.001). These trends were similar for clinical T3a and T3b. Rates of prostatectomy surpassed radiation by 2008 in clinical T3a, reaching 49.8% vs. 37.1%, respectively, in 2012 (P = 0.002), and were statistically similar to radiation in 2012 for clinical T3b, reaching 41.6% vs. 42.1% (P = 0.92). Multivariable logistic regression analysis demonstrated that patients were less likely to receive prostatectomy than radiation if biopsy Gleason scores of 8 to 10 (adjusted odds ratio [AOR] = 0.41, 0.32-0.53), higher initial prostate-specific antigen (AOR = 0.97, 0.97-0.98), and older age (AOR = 0.92, 0.90-0.03, all P<0.01). The likelihood of RP was similar among cT3b vs. cT3a (AOR = 0.95, 0.71-1.26, P = 0.74). CONCLUSIONS: Since 1998, there has been a significant increase in the use of RP for clinical T3 PCa and a significant decrease in the use of radiation such that in 2012, the use of prostatectomy exceeded the use of radiation.

Risk of prostate cancer mortality in men with a history of prior cancer.

OBJECTIVES: To describe outcomes of patients with prostate cancer diagnosed after another malignancy and identify factors associated with prostate cancer death in this population, as little is known about the clinical significance of prostate cancer as a subsequent malignancy. PATIENTS AND METHODS: We studied 18 225 men diagnosed with prostate cancer after another malignancy from 1973 to 2006. We compared demographic and clinical variables, and the proportion of death from prostate cancer vs prior malignancy with t-test and chi-squared analyses. Fine and Gray's regression was used to consider the effect of treatment on prostate cancer death. We then studied a second cohort of 88 013 men with prostate cancer as a first or second malignancy to describe current diagnostic and treatment patterns. RESULTS: One in seven men died from prostate cancer in our first cohort. More died from prostate cancer following colorectal cancer (16.8% vs 13.7%), melanoma (13.4% vs 7.56%), and oral cancer (19.1% vs 4.04%), but fewer following bladder cancer, kidney cancer, lung cancer, leukaemia and non-Hodgkin's lymphoma (all P < 0.001). Prostate cancer treatment was associated with a nearly 50% lower risk of death when high-grade or high-stage (adjusted hazard ratio 0.55, 95% confidence interval [CI] 0.47-0.64). Patients who died from prostate cancer had higher grade and stage disease, and received less treatment than patients who died from prior malignancy. The second cohort showed subsequent prostate cancer had more high-risk disease (36.3% vs 22.2%, P < 0.001) and less prostate cancer treatment (adjusted odds ratio 0.872, 95% CI 0.818-0.930) than primary prostate cancer. CONCLUSIONS: Prostate cancer remains a significant cause of mortality when diagnosed as a subsequent cancer. These results suggest prostate cancer treatment should be seriously considered in patients with prior malignancies, especially those with high-grade or locally advanced prostate cancer.

Association between very small tumour size and increased cancer-specific mortality after radical prostatectomy in lymph node-positive prostate cancer.

OBJECTIVE: To determine whether very small prostate cancers present in patients who also have lymph node (LN) metastases represent a particularly aggressive disease variant compared with larger LN-positive tumours. PATIENTS AND METHODS: We identified 37 501 patients diagnosed with prostate cancer between 1988 and 2001 treated with radical prostatectomy within the Surveillance, Epidemiology, and End Results database. The primary study variables were tumour size by largest dimension (stratified into: (i) microscopic focus only or 1 mm; (ii) 2-15 mm; (iii) 16-30 mm; (iv) >30 mm), regional LN involvement, and the corresponding interaction term. We evaluated the risk of 10-year prostate cancer-specific mortality (PCSM) using the Fine and Gray model for competing risks after controlling for race, tumour grade, T stage, receipt of radiation, number of dissected LNs, number of positive LNs, year of diagnosis, and age at diagnosis. RESULTS: The median follow-up was 11.8 years. There was a significant interaction between tumour size and LN involvement (P-interaction <0.001). In the absence of LN involvement (36 561 patients), the risk of 10-year PCSM increased monotonically with increasing tumour size. Among patients with LN involvement (940), those with the smallest tumours had increased 10-year PCSM compared with patients with tumours sized 2-15 mm (24.7% vs 11.8%; adjusted hazard ratio [AHR] 2.84, 95% confidence interval [CI] 1.21-6.71; P = 0.017) or 16-30 mm (24.7% vs 15.5%; AHR 3.12, 95% CI 1.51-6.49; P = 0.002), and similar 10-year PCSM as those with tumours >30 mm (24.7% vs 24.9%; P = 0.156). CONCLUSION: In patients with prostate cancer with LN involvement, very small tumour size may predict for higher PCSM compared with some larger tumours, even after controlling for other prognostic variables. These tumours might be particularly aggressive, beyond what is captured by pathological assessment of tumour grade and stage.

Association Between Older Age and Increasing Gleason Score.

INTRODUCTION: In order to help inform the discussion about the risks versus benefits of prostate cancer screening among older men, we determined whether advanced age is associated with a higher probability of harboring high-grade or high-risk disease. PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 383,039 men diagnosed with prostate cancer in 2004-2011. The percentage of patients diagnosed with low-, intermediate-, or high-risk disease or a Gleason score of 6, 7, or 8 to 10 was calculated by age range. As a secondary analysis, we examined whether this relationship was different in 2010-2011 versus 2007-2008 (before and after the 2009 publication of screening trials). RESULTS: The probability of Gleason score 8 to 10 or high-risk disease increased significantly with increasing age. The percentage of Gleason score 8 to 10 disease among men ages 50 to 54, 70 to 74, and 80 to 84 years was 8.9%, 16.2%, and 28.5%, respectively, and the percentage of high-risk disease was 14.3%, 22.4%, and 38.7% (P < .001). There were similar relationships among men with stage T1c disease. In addition, older men experienced a significant increase in the relative probability of high-risk or high-grade disease from 2007-2008 to 2010-2011. CONCLUSION: In this large US-based cohort, older men had a much higher probability of high-grade or high-risk prostate cancer. Physicians and patients should take into account the higher risk of more aggressive or advanced disease in older men when discussing the risks and benefits of prostate-specific antigen screening with healthy older men with a substantial life expectancy.

Differential post-prostatectomy cancer-specific survival of occult T3 vs. clinical T3 prostate cancer: Implications for managing patients upstaged on prostate magnetic resonance imaging.

PURPOSE/OBJECTIVE: Long-term androgen deprivation therapy (ADT) was proven in randomized trials to be superior to short-term ADT for radiation-managed patients who have clinical T3 (cT3) disease, but it is unknown whether patients with T3 disease seen only on magnetic resonance imaging require similarly aggressive treatment. We attempted to study this issue by analogy by comparing the long-term post-prostatectomy survival of patients with cT3 disease versus cT1/T2 disease upstaged to pathologic T3 disease. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 60,165 men diagnosed with prostate adenocarcinoma between 1995 and 2002 who underwent prostatectomy. Prostate cancer-specific mortality (PCSM) was evaluated by stage after adjusting for grade, marital status, race, sex, year of diagnosis, and age. RESULTS: The median follow-up was 10.5 years. Patients with cT1/T2 but pathologic T3a disease had significantly better 10-year PCSM than men with cT3 disease had (3.0% vs. 9.9%, adjusted hazard ratio [AHR] = 0.420, P<0.001), but they had worse PCSM than men with pathologic T2 disease had (3.0% vs. 0.91%, AHR = 2.53, P<0.001). Of patients with occult T3a disease, those with low-grade/intermediate-grade disease (Gleason score 7 or less) had a slightly higher 10-year PCSM when compared with those with pathologic T2 disease (1.34% vs. 0.91%, AHR = 1.69, P<0.001). Patients with cT1/T2 and pathologic T3b disease had similar PCSM as men presenting with cT3 disease (11.0% vs. 9.86%, AHR = 1.14 [0.862, 1.52], P = 0.353). CONCLUSIONS: Patients with occult T3a disease had less than half the risk of PCSM as those with cT3 disease, and a subset of those men had similar risk as patients with pathologic T2 disease. Therefore, it is possible that radiation-managed patients with low-grade/intermediate-grade T3a disease by magnetic resonance imaging only might not require long-term ADT. However, patients with occult T3b or high-grade occult T3a disease have similar PCSM as that of those presenting with cT3 disease, so they should be treated as aggressively, including long-course ADT when managed by radiation.

Shifting brachytherapy monotherapy case mix toward intermediate-risk prostate cancer.

PURPOSE: The relative use of brachytherapy (BT) for prostate cancer has declined in recent years. In this setting, we sought to determine whether the case mix of BT monotherapy-treated men has changed over time in terms of risk group composition. METHODS AND MATERIALS: The Surveillance, Epidemiology, and End Results database was used to identify 30,939 patients diagnosed with prostate adenocarcinoma between 2004 and 2011 who received BT monotherapy. The case mix of BT monotherapy patients was calculated by patient risk group and year of diagnosis. RESULTS: Between 2004 and 2011, the use of BT monotherapy declined overall. The relative percentage of men undergoing BT with low-risk disease declined by 4.5%, whereas the relative percentage of patients with intermediate-risk disease increased by 4.7%. Non-white patients and those from poorer counties did not show shifts in the risk group makeup of BT monotherapy patients, whereas white patients and those from wealthier counties did. CONCLUSIONS: Although fewer patients with prostate cancer are undergoing BT monotherapy, men with intermediate-risk disease comprised a significantly larger portion of the BT case mix in 2011 compared with 2004. Future research efforts by brachytherapists should be directed toward improving BT technique, optimizing radiation doses, and obtaining long-term followup data for patients with intermediate-risk prostate cancer.

Incidence and Predictors of Upgrading and Up Staging among 10,000 Contemporary Patients with Low Risk Prostate Cancer.

PURPOSE: We determined the incidence of pathological upgrading and up staging for contemporary, clinically low risk patients, and identified predictors of having occult, advanced disease to inform the selection of patients for active surveillance. MATERIALS AND METHODS: We studied 10,273 patients in the SEER database diagnosed with clinically low risk disease (cT1c/T2a, prostate specific antigen less than 10 ng/ml, Gleason 3 + 3 = 6) in 2010 to 2011 and treated with prostatectomy. The primary outcome was the incidence of upgrading to pathological Gleason score 7-10 or up staging to pathological T3-T4/N1 disease. Multivariable logistic regression of cases with complete biopsy data (5,581) identified significant predictors of upgrading or up staging, which were then used to create a risk stratification table. RESULTS: At prostatectomy 44% of cases were upgraded and 9.7% were up staged. Multivariable analysis of 5,581 patients showed age, prostate specific antigen and percent positive cores (all p < 0.001) but not race were associated with occult, advanced disease. With these variables dichotomized at the median, age older than 60 years (AOR 1.39), prostate specific antigen greater than 5.0 ng/ml (AOR 1.28) and more than 25% positive cores (AOR 1.76) were significantly associated with upgrading (all p < 0.001). Similarly, age older than 60 years (AOR 1.42), prostate specific antigen greater than 5.0 ng/ml (AOR 1.44) and more than 25% positive cores (AOR 2.26) were associated with up staging (all p < 0.001). Overall 60% of 5,581 low risk cases with prostate specific antigen 7.5 to 9.9 ng/ml and more than 25% positive cores were upgraded. This study is limited by possible bias introduced by only using patients selected for prostatectomy. CONCLUSIONS: Nearly half of clinically low risk patients harbor Gleason 7 or greater, or pT3 or greater disease, and should be risk stratified by prostate specific antigen and percent positive cores for consideration of further testing before deciding on active surveillance.