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.

Changes in cancer volume in serial biopsies of men on active surveillance for early stage prostate cancer.

PURPOSE: We described changes in tumor volume on serial biopsies during an extended period in men on active surveillance. MATERIALS AND METHODS: The study cohort included men diagnosed with prostate cancer between 1998 and 2010 enrolled in active surveillance with 6 or more months of followup. Change in volume over time was assessed as change in percent cores positive, percent cancer in 1 biopsy core and the doubling of total cancer volume (mm). Logistic regression was used to determine the association between grade and volume progression. RESULTS: A total of 399 men met the study inclusion criteria. Mean patient age was 61.8 years old and 313 (78%) had low risk disease. Overall 231 (58%) men had stable disease on repeat biopsies. There were 39 (10%) men with a volume increase, defined by an increase to more than 33% cores involved or an increase in maximum single core positive to more than 50%, and there were 44 (11%) with an increase in volume and grade. Approximately 10% of men experienced a decrease in cancer volume. On multivariate analysis there was a significant association between grade and volume progression on any biopsy (OR 3.07), and a doubling of tumor length (mm) at 5 years (OR 6.30). CONCLUSIONS: Prostate cancer volume increases and decreases at a similar rate of 10% per biopsy. An increase in tumor volume is associated with an increase in cancer grade on early repeat biopsies. However, there is a large degree of variation in cancer volume over time.

The relationship between prostate specific antigen change and biopsy progression in patients on active surveillance for prostate cancer.

PURPOSE: We assessed whether an association exists between a change in prostate specific antigen and biopsy progression in men on active surveillance. MATERIALS AND METHODS: A cohort of patients undergoing active surveillance for prostate cancer was identified from the urological oncology database at our institution. Multivariate logistic regression was performed to determine whether prostate specific antigen velocity, defined as the change in ln(prostate specific antigen) per year, is associated with biopsy progression, defined as a Gleason upgrade or volume progression on repeat biopsy within 24 months of diagnosis. RESULTS: A total of 241 men with a mean ± SD age of 61 ± 7 years and mean prostate specific antigen 4.9 ± 2.2 ng/ml met study inclusion criteria. Median time to repeat biopsy was 10 months (IQR 6-13). Biopsy progression developed in 55 men (23%), including a Gleason score upgrade in 46 (19%), greater than 33% positive cores in 11 (5%) and greater than 50% maximum single core positive in 12 (5%). The median prostate specific antigen ratio per year was 1.0 (IQR 0.95-1.03), although 1 man had a ratio of greater than 1.26 (doubled over 3 years) and 7 had a ratio of less than 1/1.26 (halved over 3 years). On multivariate analysis prostate specific antigen doubling within 3 years was associated with a 1.4-fold increase in the odds of biopsy progression (OR 1.4, 95% CI 0.6-3.4, p = 0.46). CONCLUSIONS: There is little change in prostate specific antigen during the first 24 months of surveillance in men with well staged, low risk prostate cancer. We believe that these findings highlight the importance of repeat biopsy during surveillance.

Surgical management after active surveillance for low-risk prostate cancer: pathological outcomes compared with men undergoing immediate treatment.

UNLABELLED: Study Type--Therapy (case control) Level of Evidence 3b. What's known on the subject? and What does the study add? The risks of delayed radical prostatectomy for men who progress on active surveillance are largely unknown. Two series have reported that prostatectomy after active surveillance has similar results to immediate therapy. Our data add to this growing body of evidence that appropriately selected men with prostate cancer can undergo active surveillance with delayed prostatectomy without added risk of missing an opportunity for cure as the majority of tumours remain organ confined. OBJECTIVE: • To compare the pathological outcomes of men undergoing radical prostatectomy (RP) after a period of active surveillance (AS) with those of a similar risk group undergoing immediate surgery. PATIENTS AND METHODS: • We identified men through our institutional database who underwent RP within 6 months of diagnosis or after a period of AS. The primary outcome of the present study was Gleason upgrade to ≥7 after prostatectomy. • Pathological stage and positive surgical margin rate were assessed as secondary outcomes. Binomial logistic regression models were used to determine associations of treatment subgroups with pathological upgrade, upstage and positive margins. RESULTS: • Thirty-three men with initially low-risk cancer features underwent RP after a median (range) of 18 (7-76) months of AS. A total of 278 men with low-risk disease features underwent immediate RP within 6 months of diagnosis. Rates of Gleason upgrading to ≥7, pathological category pT3 and positive surgical margins did not differ significantly from the immediate RP group. • On multivariate analysis of low-risk patients, adjusting for baseline pathological features, treatment group (AS followed by prostatectomy vs immediate prostatectomy) was not associated with Gleason upgrading (odds ratio, OR, 0.35; 95% CI, 0.12-1.04), non-organ-confined disease (OR, 1.67; 95% CI, 0.32-8.65) or positive surgical margins at prostatectomy (OR, 0.95; 95% CI, 0.16-5.76). CONCLUSION: • The present analysis did not show an association between RP after a period of AS and adverse pathological features for men with low-risk disease.

Active Surveillance in Younger Men With Prostate Cancer.

Purpose The suitability of younger patients with prostate cancer (PCa) for initial active surveillance (AS) has been questioned on the basis of eventual treatment necessity and concerns of safety; however, the role of age on surveillance outcomes has not been well defined. Patients and Methods We identified men managed with AS at our institution with a minimum follow-up of 6 months. The primary study objective was to examine the association of age with risk of biopsy-based Gleason score upgrade during AS. We also examined the association of age with related end points, including overall biopsy-determined progression, definitive treatment, and pathologic and biochemical outcomes after delayed radical prostatectomy (RP), using descriptive statistics, the Kaplan-Meier method, and multivariable Cox proportional hazards regression. Results A total of 1,433 patients were followed for a median of 49 months; 74% underwent initial biopsy at a referring institution. Median age at diagnosis was 63 years, including 599 patients (42%) ≤ 60 years old and 834 (58%) > 60 years old. The 3- and 5-year biopsy-based Gleason score upgrade-free rates were 73% and 55%, respectively, for men ≤ 60 years old compared with 64% and 48%, respectively, for men older than 60 years ( P < .01). On Cox regression analysis, younger age was independently associated with lower risk of biopsy-based Gleason score upgrade (hazard ratio per 1-year decrease, 0.969 [95% CI, 0.956 to 0.983]; P < .01), and persisted upon restriction to men meeting strict AS inclusion criteria. There was no significant association between younger age and risk of definitive treatment or risk of biochemical recurrence after delayed RP. Conclusion Younger patient age was associated with decreased risk of biopsy-based Gleason score upgrade during AS but not with risk of definitive treatment in the intermediate term. AS represents a strategy to mitigate overtreatment in young patients with low-risk PCa in the early term.

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.

Predictors of pathologic progression on biopsy among men on active surveillance for localized prostate cancer: the value of the pattern of surveillance biopsies.

BACKGROUND: A better understanding of the independent predictors of disease progression for prostate cancer (PCa) patients is needed to improve the selection of ideal candidates for active surveillance (AS) and refine the surveillance regimen. OBJECTIVE: To examine the association of clinical and pathologic characteristics, as well as patterns of surveillance biopsy results, with the risk of progression in men on AS. DESIGN, SETTING, AND PARTICIPANTS: The retrospective study consisted of men with PCa who were on AS in the prospectively maintained University of California, San Francisco, institutional database from 1996 to 2011. Strict criteria for AS were prostate-specific antigen (PSA) ≤10 ng/ml, clinical stage T1 or T2, biopsy Gleason grade 6, <33% positive cores, and <50% tumor in any single core. Men were then categorized based on results of their confirmatory surveillance biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Disease progression was defined as an increase in Gleason grade and/or biopsy volume beyond prespecified cut points. Serial biopsy patterns over the course of surveillance were stratified by confirmatory biopsy findings: negative, positive without progression, and positive with progression. Multivariable logistic regression models were used to evaluate predictors of progression during AS. RESULTS AND LIMITATIONS: A total of 465 men met inclusion criteria (median follow-up: 51 mo). Of these men, 23% had negative confirmatory biopsies. Only 3% of the men (1 of 30) progressed by the fourth surveillance biopsy following a biopsy pattern of negative confirmatory and negative third biopsy findings. Negative confirmatory biopsy and lower PSA density (both p<0.01) were independently associated with decreased odds of biopsy progression at 3 yr. The main limitation of this study is its observational nature. CONCLUSIONS: The patterns of surveillance biopsy results yield additional important information in AS. Negative confirmatory biopsy and PSA density are important independent predictors of progression on AS and may be used to better counsel men opting for AS.

Changes in prostate cancer grade on serial biopsy in men undergoing active surveillance.

PURPOSE: Active surveillance is now considered a viable treatment option for men with low-risk prostate cancer. However, little is known regarding changes in Gleason grade on serial biopsies over an extended period of time. PATIENTS AND METHODS: Men diagnosed with prostate cancer between 1998 and 2009 who elected active surveillance as initial treatment, with 6 or more months of follow-up and a minimum of six cores at biopsy, were included in analysis. Upgrading and downgrading were defined as an increase or decrease in primary or secondary Gleason score. Means and frequency tables were used to describe patient characteristics, and treatment-free survival rates were determined by life-table product limit estimates. RESULTS: Three hundred seventy-seven men met inclusion criteria. Mean age at diagnosis was 61.9 years. Fifty-three percent of men had prostate-specific antigen of 6 ng/mL or less, and 94% had Gleason score of 6 or less. A majority of men were cT1 (62%), had less than 33% of biopsy cores involved (80%), and were low risk (77%) at diagnosis. Median number of cores taken at diagnostic biopsy was 13, mean time to follow-up was 18.5 months, and 29% of men had three or more repeat biopsies. Overall, 34% (129 men) were found to have an increase in Gleason grade. The majority of men who experienced an upgrade (81%) did so by their second repeat biopsy. CONCLUSION: A proportion of men experience an upgrade in Gleason score while undergoing active surveillance. Men who experience early upgrading likely represent initial sampling error, whereas later upgrading may reflect tumor dedifferentiation.