An Exploration of Risk Stratification for Active Surveillance and Androgen Deprivation Therapy Side Effects for Prostate Cancer Utilizing Data From the Surveillance, Epidemiology, and End Results Database

Abstract

Part 1: Occult high-risk disease in clinically low-risk prostate cancer patients: Incidence and clinical predictors from SEER data Objective: First, to determine the incidence of pathologic upgrading and upstaging for contemporary, clinically low-risk patients and identify predictors of having occult, advanced disease to inform selection of patients for active surveillance. We will further consider the differing risk of upgrading at prostatectomy between clinically low-risk patients with ≥50% biopsy cores positive and other prostate cancer patients. Methods: For the first portion of the study, we identified 10,273 patients in the Surveillance, Epidemiology, and End Results (SEER) database diagnosed with clinically low-risk disease (cT1c/T2a, Prostate specific antigen (PSA)<10ng/mL, Gleason 3+3=6) in 2010-2011 who received a prostatectomy. The primary outcome was the incidence of upgrading to pathologic Gleason score 7-10 or upstaging to pathologic T3-T4/N1 disease. Multivariable logistic regression (MVA) of men with complete biopsy data (n=5,581) identified significant predictors of upgrading or upstaging. As a second analysis, we identified 14,902 patients with prostate cancer of any risk-group diagnosed 2010-2011 with prostatectomy who also had percent positive biopsy cores (PBC) available. Patients were categorized by NCCN clinical risk-groups, separating low-risk patients by percent PBC. We measured incidence of pathologic high-risk disease, defined as pT3a-T4 or Gleason 8-10, and used MVA to consider differing risk of advanced disease in patients with clinical low-risk disease and ≥50% PBC. Results: Of the first cohort, 44% of patients were upgraded and 9.7% were upstaged at prostatectomy. MVA showed age, PSA, and percent positive cores (all p<0.001), but not race, were associated with occult, more aggressive disease. With these variables dichotomized at the median, age >60 (Adjusted Odds Ratio [AOR] 1.39), PSA>5.0 (AOR 1.28), and >25% positive cores (AOR 1.76) were significantly associated with upgrading (all p<0.001). Similarly, age>60 (AOR 1.42), PSA>5.0 (AOR 1.44), and >25% positive cores (AOR 2.26) were associated with upstaging (all p<0.001). In the second cohort, 9.2% of clinically low-risk and <50%PBC, 18.6% of clinically low-risk and ≥50%PBC, and 27.6% of clinically intermediate-risk patients had occult, high-risk disease at prostatectomy (p<0.001). On MVA, low-risk with ≥50%PBC were more likely than low-risk with <50%PBC to have pathologic high-risk disease (AOR 2.28, 95%CI 1.90-2.73, p<0.001), had similar risk to favorable-intermediate disease overall (AOR 1.09, 0.91-1.31, p=0.33), and had higher risk than favorable-intermediate among men over 60 (AOR 1.28, 1.00-1.64, p=0.04). Conclusion: Nearly half of clinically low-risk patients harbor Gleason ≥7 or ≥pT3 disease. Percent PBC demonstrates utility for identifying a subset of NCCN low-risk patients who should have further testing before deciding on active surveillance as nearly one in five clinically low-risk prostate cancer patients with ≥50% positive biopsy cores harbored occult pT3a-T4 or Gleason 8-10. This suggests that such patients should not be classified by national guidelines as “low-risk” and these patients should be made aware of this excess risk if considering active surveillance. Part 2: Association of Androgen Deprivation Therapy with Depression in Localized Prostate Cancer Using SEER-Medicare Objective: Androgen deprivation therapy (ADT) may contribute to depression, yet several studies have not demonstrated a link. We aimed to determine if receipt of any ADT or longer duration of ADT for prostate cancer is associated with increasing risk of depression. Methods: We identified 78,552 men over 65 with stage I-III prostate cancer using the Surveillance, Epidemiology, and End Results-Medicare linked database from 1992-2006, excluding patients with psychiatric diagnoses within the prior year. Our primary analysis was the association of pharmacologic ADT with the diagnosis of depression, or receipt of inpatient- or outpatient-psychiatric treatment, using Cox-proportional hazard regression. Drug-data for treatment of depression was not available. Our secondary analysis was association of duration of ADT with each endpoint. Results: Overall, 43% (33,882) of patients received ADT and had higher 3-year cumulative incidence of depression (7.1% vs. 5.2%), inpatient- (2.8% vs. 1.9%), and outpatient-psychiatric treatment (3.4% vs. 2.5%) than patients without ADT (all p<0.001). Adjusted cox-analyses demonstrated patients with ADT had a 23% increased risk of depression (adjusted hazard ratio [AHR]=1.23,95%CI=[1.15-1.31]), 29% increased risk of inpatient-psychiatric treatment (AHR=1.29,95%CI=[1.17-1.41]), and a non-significant 7% increased risk of outpatient-psychiatric treatment (AHR=1.07,95%CI=[0.97-1.17]) compared to patients without ADT. The risk of depression increased with duration of ADT, from 12% with ≤6, 26% with 7-11, to 37% with ≥12 months (p-trend<0.0001). Similar duration-effect was seen for inpatient- (p-trend<0.0001) and outpatient-psychiatric treatment (p-trend<0.0001). Conclusion: Pharmacologic ADT increased the risk of depression and inpatient-psychiatric treatment in this large study of elderly men with localized prostate cancer. This risk increased with longer duration of ADT. The possible psychiatric effects of ADT should be recognized by physicians and discussed with patients prior to initiating treatment.