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2.  Active Surveillance for Prostate Cancer: An Underutilized Opportunity for Reducing Harm 
The management of localized prostate cancer is controversial, and in the absence of comparative trials to inform best practice, choices are driven by personal beliefs with wide variation in practice patterns. Men with localized disease diagnosed today often undergo treatments that will not improve overall health outcomes, and active surveillance has emerged as one approach to reducing this overtreatment of prostate cancer. The selection of appropriate candidates for active surveillance should balance the risk of harm from prostate cancer without treatment, and a patient’s personal preferences for living with a cancer and the potential side effects of curative treatments. Although limitations exist in assessing the potential for a given prostate cancer to cause harm, the most common metrics used today consider cancer stage, prostate biopsy features, and prostate-specific antigen level together with the risk of death from nonprostate causes based on age and overall state of health.
PMCID: PMC3540867  PMID: 23271770
3.  Delayed Versus Immediate Surgical Intervention and Prostate Cancer Outcome 
For prostate cancer patients with small, lower-grade tumors, expectant management with delayed surgical intervention (active surveillance) is a rarely used therapeutic option because the opportunity for cure may be lost. We compared outcomes of 38 patients with small, lower-grade prostate cancer in an expectant management program who underwent delayed surgical intervention at a median of 26.5 months (95% confidence interval [CI] = 17 to 32 months; range = 12.0–73.0 months) after diagnosis with 150 similar patients who underwent immediate surgical intervention at a median of 3.0 months (95% CI = 2 to 4 months; range = 1.0–9.0 months) after diagnosis. Noncurable cancer was defined as adverse pathology associated with a less than 75% chance of remaining disease-free for 10 years after surgery. Noncurable cancer was diagnosed in nine (23%) of the 38 patients in the delayed intervention cohort and in 24 (16%) of the 150 men in the immediate intervention group. After adjusting for age and prostate-specific antigen (PSA) density (i.e., PSA value divided by prostate volume) in a Mantel–Haenszel analysis, the risks of noncurable cancer associated with delayed and immediate intervention did not differ statistically significantly (relative risk = 1.08, 95% CI = 0.55 to 2.12; P = .819, two-sided Cochran–Mantel–Haenszel statistic). Age, PSA, and PSA density were all statistically significantly associated with the risk of noncurable cancer (P = .030, .013, and .008, respectively; two-sided chi-square test). Thus, delayed prostate cancer surgery for patients with small, lower-grade prostate cancers does not appear to compromise curability.
PMCID: PMC3477641  PMID: 16507832
4.  Prostate-Specific Antigen Velocity Risk Count Assessment: A New Concept for Detection of Life-Threatening Prostate Cancer During Window of Curability 
Urology  2007;70(4):685-690.
To determine whether the number of times the prostate-specific antigen (PSA) velocity (PSAV) exceeds a threshold (PSAV risk count) is predictive of high-risk prostate cancer.
The PSAV was determined in 717 men (606 without prostate cancer; 32 with high-risk prostate cancer defined as death from cancer, PSA level of 20 ng/mL or more, or a Gleason score of 8 or more; and 79 with prostate cancer who were alive or dead of another cause). Multiple PSAVs determined from three repeated measures from each subject during 10 to 20 years were used to determine the risk count by summing the number of times a subject exceeded a PSAV threshold. Cox proportional hazards regression analysis was used to evaluate the associations between the risk count and the probability of high-risk disease. The statistical tests were two-sided.
The probability of high-risk disease increased directly with the risk count. After adjusting for age, PSA level, PSAV, and date of diagnosis, the PSAV risk count was significantly associated with the development of high-risk prostate cancer (relative risk 1.41, 95% confidence interval 1.25 to 1.59 for a PSAV cutpoint 0.2 ng/mL/yr; relative risk 1.49, 95% confidence interval 1.29 to 1.71 for a PSAV cutpoint of 0.4 ng/mL/yr; P <0.001).
The PSAV risk count could be a useful method of interpreting a PSA history to help identify those men who will benefit from a diagnosis of prostate cancer at PSA levels associated with curable disease.
PMCID: PMC2645699  PMID: 17991538
5.  Detection of Life-Threatening Prostate Cancer With Prostate-Specific Antigen Velocity During a Window of Curability 
Prostate-specific antigen (PSA) level is typically used as a dichotomous test for prostate cancer, resulting in overdiagnosis for a substantial number of men. The rate at which serum PSA levels change (PSA velocity) may be an important indicator of the presence of life-threatening disease.
PSA velocity was determined in 980 men (856 without prostate cancer, 104 with prostate cancer who were alive or died of another cause, and 20 who died of prostate cancer) who were participants in the Baltimore Longitudinal Study of Aging for up to 39 years. The relative risks (RRs) of prostate cancer death and prostate cancer–specific survival stratified by PSA velocity were evaluated in the three groups of men by Cox regression and Kaplan–Meier analyses. Statistical tests were two-sided.
PSA velocity measured 10–15 years before diagnosis (when most men had PSA levels below 4.0 ng/mL) was associated with cancer-specific survival 25 years later; survival was 92% (95% confidence interval [CI] = 84% to 96%) among men with PSA velocity of 0.35 ng/mL per year or less and 54% (95% CI = 15% to 82%) among men with PSA velocity above 0.35 ng/mL per year (P<.001). Furthermore, men with PSA velocity above 0.35 ng/mL per year had a higher relative risk of prostate cancer death than men with PSA velocity of 0.35 ng/mL per year or less (RR = 4.7, 95% CI = 1.3 to 16.5; P = .02); the rates per 100 000 person-years were 1240 for men with a PSA velocity above 0.35 ng/mL per year and 140 for men with a PSA velocity of 0.35 ng/mL per year or less.
PSA velocity may help identify men with life-threatening prostate cancer during a period when their PSA levels are associated with the presence of curable disease.
PMCID: PMC2645644  PMID: 17077354
6.  Serum prostate-specific antigen (PSA) concentration is positively associated with rate of disease reclassification on subsequent active surveillance prostate biopsy in men with low PSA density 
BJU international  2013;113(4):561-567.
To investigate the association between serum prostate-specific antigen (PSA) concentration at active surveillance (AS) entry and disease reclassification on subsequent AS biopsy (‘biopsy reclassification’) in men with low PSA density (PSAD).
To investigate whether a clinically meaningful PSA threshold for AS eligibility/ineligibility for men with low PSAD can be identified based on risk of subsequent biopsy reclassification.
Patients and Methods
We included men enrolled in the Johns Hopkins AS Study (JHAS) who had a PSAD of <0.15 ng/mL/g (640 men).
We estimated the incidence rates (IRs; per 100 person years) and hazard ratios (HR) of biopsy reclassification (Gleason score ≥ 7, any Gleason pattern 4 or 5, ≥3 positive cores, or ≥50% cancer involvement/biopsy core) for categories of serum PSA concentration at the time of entry into AS.
We generated predicted IRs using Poisson regression to adjust for age and prostate volume, mean percentage free PSA (ratio of free to total PSA) and maximum percentage biopsy core involvement with cancer.
The unadjusted IRs (per 100 person years) of biopsy reclassification across serum PSA concentration at entry into JHAS showed, in general, an increase; however, the pattern was not linear with higher IRs in the group ≥ 4 to <6 ng/mL (14.2, 95% confidence interval [CI] 11.8–17.2%) when compared with ≥ 6 to <8 ng/mL (8.4, 95% CI 5.7–12.3%) but almost similar IRs when compared with the group ≥ 8 to <10 ng/mL (14.8, 95% CI 8.4–26.1%).
The adjusted predicted IRs of reclassification showed a similar non-linear increase in IRs, whereby the rates around 4 ng/mL were similar to the rates around 10 ng/mL.
Risk for biopsy reclassification increased non-linearly across PSA concentration in men with low PSAD, whereby no obvious clinically meaningful threshold could be identified. This information could be incorporated into decision-making for AS. However, longer follow-up times are needed to warrant final conclusions.
PMCID: PMC3978167  PMID: 23746233
active surveillance; PSA; patient selection
7.  Pathological Outcomes in Men with Low Risk and Very Low Risk Prostate Cancer: Implications on the Practice of Active Surveillance 
The Journal of urology  2013;190(4):1218-1222.
We assessed oncologic outcomes at surgery in men with low risk and very low risk prostate cancer who were candidates for active surveillance.
Materials and Methods
In a prospectively collected institutional database, we identified 7,486 subjects eligible for active surveillance who underwent radical retropubic prostatectomy. Candidates were designated as being at low risk (stage T1c/T2a, prostate specific antigen 10 ng/ml or less, and Gleason score 6 or less) or very low risk (stage T1c, prostate specific antigen density 0.15 or less, Gleason score 6 or less, 2 or fewer positive biopsy cores, 50% or less cancer involvement per core) based on preoperative data. Adverse findings were Gleason score upgrade (score 7 or greater) and nonorgan confined cancer on surgical pathology. The relative risk of adverse findings in men at low risk with very low risk disease was evaluated in a multivariate model using Poisson regression.
A total of 7,333 subjects met the criteria for low risk disease and 153 had very low risk disease. The proportion of subjects at low risk found to have Gleason score upgrade or nonorgan confined cancer on final pathology was 21.8% and 23.1%, respectively. Corresponding values in those at very low risk were 13.1% and 8.5%, respectively. After adjusting for age, race, year of surgery, body mass index, and prostate specific antigen at diagnosis, the relative risk of Gleason score upgrade in men with low risk vs very low risk disease was 1.89 (95% CI 1.21–2.95). The relative risk of nonorgan confined cancer was 2.06 (95% CI 1.19–3.57).
Men with very low risk prostate cancer were at significantly lower risk for adverse findings at surgery compared to those with low risk disease. These data support the stratification of low risk cancer when selecting and counseling men who may be appropriate for active surveillance.
PMCID: PMC3978170  PMID: 23643603
prostate; prostatic neoplasms; risk; disease progression; treatment outcome
8.  Multiparametric magnetic resonance imaging findings in men with low-risk prostate cancer followed using active surveillance 
BJU international  2013;111(7):1037-1045.
To assess the performance of multiparametric magnetic resonance imaging (MRI) in identifying pathological-index (path-index) lesions, defined as cancer present in the same prostate sextant in two separate surveillance biopsies, in men followed within an active surveillance (AS) programme for low-risk prostate cancer (CaP) with extended follow-up.
Materials and Methods
A total of 50 men, representing >215 person-years of follow-up in an AS programme, who were referred for prostate MRI were randomly chosen to have their images reviewed by a radiologist with expertise in prostate MRI, who was blinded to biopsy results.
Index lesions on MRI were defined as a single suspicious lesion ≥10 mm or >2 lesions in a given prostate sextant. Lesions on MRI were considered suspicious if ≥2 abnormal parameters co-registered anatomically. Path-index lesions were defined as cancer present in a given prostate sextant on two separate biopsy sessions.
Sensitivity and specificity were calculated to test the performance of MRI for identifying path-index lesions.
Clinical and pathological features were compared between men with and without a MRI-index lesion.
A total of 31 path-index and 13 MRI-index lesions were detected in 22 and 10 patients, respectively.
Multiparametric MRI demonstrated excellent specificity and negative predictive value (0.974 and 0.897, respectively) for the detection of path-index lesions. Sensitivity (0.19) and positive predictive value (0.46) were considerably lower.
Patients with an index lesion on MRI were younger and less likely to have met the ‘Epstein’ criteria for very low-risk CaP.
Compared with men without an MRI lesion, a significant increase in biopsy reclassification was noted for men with a MRI lesion (40 vs 12.5%, P = 0.04).
A non-suspicious MRI was highly correlated with a lack of path-index lesions in an AS population.
Multiparametric MRI may be useful in both the selection and monitoring of patients undergoing AS.
PMCID: PMC3978179  PMID: 23464904
prostate cancer; surveillance; magnetic resonance imaging; sensitivity and specificity
9.  Association of [-2]proPSA with Biopsy Reclassification During Active Surveillance for Prostate Cancer 
The Journal of urology  2012;188(4):1131-1136.
Previous studies have suggested an association between [-2]proPSA expression and prostate cancer detection. Less is known about the utility of this marker in following prostate cancer patients on active surveillance. Thus, our objective was to examine the relationship between [-2]proPSA and biopsy results in men enrolled in an active surveillance program.
Materials and Methods
In 167 men from our institutional active surveillance program, we used Cox proportional hazards models to examine the relationship between [-2]proPSA and annual surveillance biopsy results. The outcome of interest was biopsy reclassification (Gleason score ≥7, or >2 positive biopsy cores, or >50% involvement of any core with cancer). We also examined the association of biopsy results with total PSA, %fPSA, [-2]proPSA/%fPSA, and the Beckman Coulter Prostate Health Index [phi=([-2]proPSA/fPSA) x (tPSA)½].
While on active surveillance (median time from diagnosis 4.3 years), 63 (37.7%) men demonstrated biopsy reclassification based on the above criteria, including 28 (16.7%) of whom had reclassification based on Gleason score upgrading (Gleason score≥7). Baseline and longitudinal %fPSA, %[-2]proPSA, [-2]proPSA/%fPSA, and phi measurements were significantly associated with biopsy reclassification, and %[-2]proPSA and phi provided the greatest predictive accuracy for high-grade cancer.
In men on active surveillance, measures based on [-2]proPSA such as phi, appear to provide improved prediction of biopsy reclassification during follow-up. Additional validation is warranted to determine whether clinically useful thresholds can be defined, and to better characterize the role of %[-2]proPSA and phi in conjunction with other markers in monitoring patients enrolled in active surveillance.
PMCID: PMC3976250  PMID: 22901577
proPSA; PSA; prostate cancer; biopsy; active surveillance
10.  Active Surveillance Versus Surgery for Low Risk Prostate Cancer: A Clinical Decision Analysis 
The Journal of urology  2012;187(4):1241-1246.
We assessed the effect of age, health status and patient preferences on outcomes of surgery vs active surveillance for low risk prostate cancer.
Materials and Methods
We used Monte Carlo simulation of Markov models of the life courses of 200,000 men diagnosed with low risk prostate cancer and treated with surveillance or radical prostatectomy to calculate quality adjusted life expectancy, life expectancy, prostate cancer specific mortality and years of treatment side effects, with model parameters derived from the literature. We simulated outcomes for men 50 to 75 years old with poor, average or excellent health status (50%, 100% and 150% of average life expectancy, respectively). Sensitivity of outcomes to uncertainties in model parameters was tested.
For 65-year-old men in average health, surgery resulted in 0.3 additional years of life expectancy, 1.6 additional years of impotence or incontinence and a 4.9% decrease in prostate cancer specific mortality compared to surveillance, for a net difference of 0.05 fewer quality adjusted life years. Increased age and poorer baseline health status favored surveillance. With greater than 95% probability, surveillance resulted in net benefits compared to surgery for age older than 74, 67 and 54 years for men in excellent, average and poor health, respectively. Patient preferences toward life under surveillance, biochemical recurrence of disease, treatment side effects and future discount rate affected optimal management choice.
Older men and men in poor health are likely to have better quality adjusted life expectancy with active surveillance. However, specific individual preferences impact optimal choices and should be a primary consideration in shared decision making.
PMCID: PMC3952430  PMID: 22335873
prostatic neoplasms; quality-adjusted life years; prostatectomy; watchful waiting; decision support techniques
11.  Geometric Evaluation of Systematic Transrectal Ultrasound Guided Prostate Biopsy 
The Journal of urology  2012;188(6):10.1016/j.juro.2012.07.107.
Transrectal ultrasound guided prostate biopsy results rely on physician ability to target the gland according to the biopsy schema. However, to our knowledge it is unknown how accurately the freehand, transrectal ultrasound guided biopsy cores are placed in the prostate and how the geometric distribution of biopsy cores may affect the prostate cancer detection rate.
Materials and Methods
To determine the geometric distribution of cores, we developed a biopsy simulation system with pelvic mock-ups and an optical tracking system. Mock-ups were biopsied in a freehand manner by 5 urologists and by our transrectal ultrasound robot, which can support and move the transrectal ultrasound probe. We compared 1) targeting errors, 2) the accuracy and precision of repeat biopsies, and 3) the estimated significant prostate cancer (0.5 cm3 or greater) detection rate using a probability based model.
Urologists biopsied cores in clustered patterns and under sampled a significant portion of the prostate. The robot closely followed the predefined biopsy schema. The mean targeting error of the urologists and the robot was 9.0 and 1.0 mm, respectively. Robotic assistance significantly decreased repeat biopsy errors with improved accuracy and precision. The mean significant prostate cancer detection rate of the urologists and the robot was 36% and 43%, respectively (p <0.0001).
Systematic biopsy with freehand transrectal ultrasound guidance does not closely follow the sextant schema and may result in suboptimal sampling and cancer detection. Repeat freehand biopsy of the same target is challenging. Robotic assistance with optimized biopsy schemas can potentially improve targeting, precision and accuracy. A clinical trial is needed to confirm the additional benefits of robotic assistance.
PMCID: PMC3876458  PMID: 23088974
prostate; prostatic neoplasms; biopsy; ultrasonography; robotics
12.  Primary care providers’ perspectives on discontinuing prostate cancer screening 
Cancer  2012;118(22):5518-5524.
Clinical guidelines recommend against routine prostate specific antigen (PSA) screening in older men and those with lower life expectancies. We examined providers’ decision-making regarding discontinuing PSA screening.
We administered a survey of primary providers from a large, university-affiliated primary care practice. Providers were asked about their current screening practices, factors that influence their decision to discontinue screening, and barriers to discontinuing screening. Bivariate and multivariable logistic regression analyses were used to examine whether taking age and/or life expectancy into account and barriers to discontinuing were associated with clinician characteristics and practice styles.
88.7% of providers participated in the survey (125 out of 141). Over half (59.3%) took both age and life expectancy into account whereas 12.2% did not consider either in their decisions to discontinue PSA screening. Providers varied with the age they typically stop screening and majority (66.4%) report difficulty in assessing life expectancy. Taking patient age and life expectancy into account was not associated with provider characteristics or practice styles. The most frequently cited barriers to discontinuing PSA screening were patient expectation (74.4%) and time constraints (66.4%). Black providers were significantly less likely than non-black providers to endorse barriers related to time constraints and clinical uncertainty, though these results are limited by the small sample size of black providers.
Though age and life expectancy often figure prominently in decisions to employ screening, providers face multiple barriers to discontinue PSA routine screening,
PMCID: PMC3427393  PMID: 22517310
13.  Prostate cancer mortality following active surveillance versus immediate radical prostatectomy 
Active surveillance (AS) has been endorsed for low-risk prostate cancer, but information about long-term outcomes and comparative effectiveness of AS is lacking. The purpose of this study is to project prostate cancer mortality under AS followed by radical prostatectomy (RP) versus under immediate RP.
Experimental Design
A simulation model was developed to combine information on time from diagnosis to treatment under AS and associated disease progression from a Johns Hopkins AS cohort (n=769), time from RP to recurrence from cases in the CaPSURE database with T-stage ≤ T2a (n=3,470), and time from recurrence to prostate cancer death from a T-stage ≤ T2a Johns Hopkins cohort of patients whose disease recurred after RP (n=963). Results were projected for a hypothetical cohort aged 40–90 years with low-risk prostate cancer (T-stage ≤ T2a, Gleason score ≤ 6, and PSA level ≤ 10 ng/mL).
The model projected that 2.8% of men on AS and 1.6% of men with immediate RP would die of their disease in 20 years. Corresponding lifetime estimates were 3.4% for AS and 2.0% for immediate RP. The average projected increase in life expectancy associated with immediate RP was 1.8 months. On average, the model projected that men on AS would remain free of treatment for an additional 6.4 years relative to men treated immediately.
AS is likely to produce a very modest decline in prostate-cancer-specific survival among men diagnosed with low-risk prostate cancer but could lead to significant benefits in terms of quality of life.
PMCID: PMC3604990  PMID: 23008476
Active surveillance; radical prostatectomy; prostaticneoplasms; Gleason score
14.  Low Prostate-specific Antigen and No Gleason Score Upgrade Despite More Extensive Cancer During Active Surveillance Predicts Insignificant Prostate Cancer at Radical Prostatectomy 
Urology  2012;80(4):883-888.
To identify parameters that predict insignificant prostate cancer in 67 radical prostatectomies after biopsy reclassification to worse disease on active surveillance.
Parameters evaluated at diagnosis and at biopsy reclassification included serum prostate-specific antigen, prostate-specific antigen density, number of positive cores, maximum percent involvement of cancer per core, and any interval negative biopsies. Gleason upgrading at biopsy reclassification was also assessed to predict insignificant cancer.
Mean time between diagnosis and radical prostatectomies was 30.3 months with a median of 3 biopsies (range 2–9). Nineteen of 67 (28.4%) had clinically insignificant cancer at radical prostatectomy. In the entire group, there were no variables significantly associated with insignificant cancer at radical prostatectomy. In a subgroup analysis of 37 patients without Gleason pattern 4/5 at biopsy reclassification, 16/37 (43.2%) showed insignificant cancer at radical prostatectomy. In this subgroup, prostate-specific antigen at diagnosis was significantly lower in men with insignificant cancer (3.7 ng/mL) vs significant cancer (5.4 ng/mL) (P = .0005). With prostate-specific antigen <4 ng/mL at diagnosis or at biopsy reclassification, 12/13 (92.3%) men showed insignificant cancer, whereas only 4/24 (16.7%) men with prostate-specific antigen >4 ng/mL both at diagnosis and at biopsy reclassification showed insignificant cancer.
Most men with biopsy reclassification while on active surveillance have significant disease at radical prostatectomy, justifying their treatment. Low prostate-specific antigen at diagnosis or at biopsy reclassification can predict a high probability of insignificant cancer in the absence of Gleason pattern 4/5 on biopsy. These men may be candidates for continuing active surveillance.
PMCID: PMC3715088  PMID: 22921697
16.  Prostate-Specific Antigen Testing of Older Men 
Elevated serum prostate-specific antigen (PSA) levels are predictive of a future diagnosis of prostate cancer. To test the hypothesis that older men with low PSA levels may require less intensive PSA testing because of a reduced prostate cancer detection rate, we evaluated the association between age, baseline PSA level, and prostate cancer detection.
We conducted a prospective cohort study among participants in a study of aging who had serial PSA measurements taken from age 60 or 65 years until they either were diagnosed with prostate cancer (cancer case subjects) or reached the age of 75 years (subjects without prostate cancer). The time of cancer detection among cancer case subjects was defined as the measurement date on which a PSA level above 4.0 ng/mL was detected (i.e., PSA conversion). Cancer case subjects and subjects without prostate cancer were analyzed according to baseline PSA level and age.
All cancer case subjects in the 60-year-old cohort had baseline PSA levels above 0.5 ng/mL, and 14 of 15 cancer cases that would have been detected by a PSA conversion among the 65-year-old cohort were associated with baseline PSA levels of 1.1 ng/mL or more. If PSA testing were discontinued in men aged 65 years with PSA levels of 0.5 ng/mL or less, 100% (95% confidence interval [CI] = 78%–100%) of the cancers would still be detected by age 75 years; if PSA testing were discontinued in men aged 65 years who had PSA levels of 1.0 ng/mL or less, 94% (95% CI = 70%–100%) of the cancers would still be detected by age 75 years.
These data suggest that a decrease in the intensity of screening among older men with low PSA values may not lead to an increase in undetected prostate cancer.
PMCID: PMC3474977  PMID: 10528023
17.  Prostate Cancers in Men with Low PSA Levels — Must We Find Them? 
The New England journal of medicine  2004;350(22):2292-2294.
PMCID: PMC3474980  PMID: 15163780
18.  Risk Stratification of Men Choosing Surveillance for Low Risk Prostate Cancer 
The Journal of urology  2010;183(5):1779-1785.
We sought to predict biopsy progression in men on prostate cancer surveillance.
Materials and Methods
A total of 376 men with a median age of 65.5 years (range 45.8 to 79.5) with low risk prostate cancer on surveillance underwent at least 1 followup biopsy after diagnosis. Progression was defined at surveillance biopsy as Gleason pattern 4 or 5, greater than 2 biopsy cores with cancer or greater than 50% involvement of any core with cancer. Proportional hazards analysis was used to evaluate the association between covariates and progression at surveillance biopsy. The Kaplan-Meier method was used to estimate the probability of disease progression.
Of the 376 men 123 (32.7%) had progression a median of 5.6 years (range 0.3 to 8.5) after diagnosis. Percent free PSA and maximum percent core involvement at diagnosis were associated with progression, allowing stratification of the progression risk at initial surveillance biopsy. Cancer presence and PSA density at initial surveillance biopsy were associated with subsequent progression, allowing stratification of the cumulative incidence of progression 3 years after initial surveillance biopsy (cumulative incidence 11.1%, 95% CI 4.7 to 25.2 for negative biopsy and PSAD less than 0.08 ng/ml/cm3 vs 53.6%, 95% CI 38.6 to 70.0 for positive biopsy and PSAD 0.08 ng/ml/cm3 or greater, log rank test p < 0.0001).
Clinical variables at diagnosis and at first surveillance biopsy during followup in an active surveillance program can be used to inform men about the likelihood of an unfavorable prostate biopsy. This information could improve patient and physician acceptance of active surveillance in carefully selected men.
PMCID: PMC3474981  PMID: 20304433
prostate; prostatic neoplasms; biopsy; prostate specific antigen; disease progression
The Journal of urology  1997;157(6):2206-2209.
The pathological characteristics of stage Tlc cancers in the era of widespread prostate specific antigen (PSA) testing were determined, and the ability of pretreatment parameters to predict tumor significance in men with stage Tlc disease was evaluated.
Materials and Methods
Of 336 men with stage Tlc prostate cancer seen between 1994 and 1996, 240 (71.4%) were treated with radical prostatectomy, 20 (6%) with radiation therapy and 76 (22.6%) expectantly. Recommendations for treatment were based on previously determined criteria predictive of a significant stage Tlc cancer (more than 0.2 cm.3: 1) PSA density 0.15 ng./ml./gm. or more, 2) Gleason score 7 or greater, 3) 3 or more cores involved with cancer, or 4) 50% or more involvement of any core with cancer. Pathological evaluation of prostatectomy specimens allowed classification of tumors as insignificant (confined tumor smaller than 0.2 cm.3 with a Gleason score of less than 7), minimal (confined tumor 0.2 to less than 0.5 cm.3 with a Gleason score of less than 7), moderate (0.5 cm.3 or larger disease, or capsular penetration with a Gleason score of less than 7) and advanced (capsular penetration with a Gleason score of 7 or more, or positive margins, seminal vesicles or lymph nodes). Pathological characteristics of tumors in this series were compared to a previous series of 157 men with stage Tlc cancers who underwent radical prostatectomy between 1988 and 1992.
Of 240 men who underwent radical prostatectomy tumors were insignificant in 40 (17%), minimal in 29 (12%), moderate in 124 (52%) and advanced in 47 (19%). An increase in organ confined cancers (51 to 72%) and a decrease in positive margins (17 to 8%) were noted when comparing stage Tlc series (1988 to 1992 versus 1994 to 1996) but the percentage of insignificant tumors remained stable (16 versus 17%) between series. Ultrasound and sextant biopsies were available for review in 72 cases (current series). If the pretreatment criteria used to recommend therapy suggested significant tumor (64 cases) then insignificant tumor was present in only 10 (16%). If pretreatment criteria suggested insignificant tumor (8 cases), insignificant or minimal tumor was present in 6 (75%) and moderate organ confined disease was present in 2 (25%). The absence of a lesion on ultrasound and measurement of total length of cancer within the biopsy specimen were not predictive of an insignificant tumor.
In a nonscreened population stage Tlc cancers are being discovered earlier with widespread PSA testing. Even with the detection of earlier cancers we demonstrated that it is possible to minimize the number of patients with small tumors who will undergo radical prostatectomy using pretreatment criteria to counsel men regarding appropriate management options.
PMCID: PMC3461836  PMID: 9146616
adenocarcinoma; prostatic neoplasms; pathology
20.  Longitudinal Evaluation of Prostate-Specific Antigen Levels in Men With and Without Prostate Disease 
To evaluate longitudinal changes in prostate-specific antigen (PSA) levels in men with and without prostate disease.
Case-control study of men with and without prostate disease who were participants in a prospective aging study.
Gerontology Research Center of the National Institute on Aging; the Baltimore (Md) Longitudinal Study of Aging.
Sixteen men with no prostate disease (control group), 20 men with a histologic diagnosis of benign prostatic hyperplasia (BPH), and 18 men with a histologic diagnosis of prostate cancer.
Outcome Measures
Multiple PSA and androgen determinations on serum samples obtained from 7 to 25 years prior to histologic diagnosis or exclusion of prostate disease.
Changesin androgen levels with age did not differ between groups. Control subjects did not show a significant change in PSA levels with age. There was a significant difference in the age-adjusted rate of change in PSA levels between groups (prostate cancer>BPH>control; P<.01). At 5 years before diagnosis when PSA levels did not differ between subjects with BPH and prostate cancer, rate of change in PSA levels (0.75 μg/L per year) was significantly greater in subjects with prostate cancer compared with control subjects and subjects with BPH. Also, rate of change in PSA levels distinguished subjects with prostate cancer from subjects with BPH and control subjects with a specificity of 90% and 100%, respectively.
The most significant factor affecting serum PSA levels with age is the development of prostate disease. Rate of change in PSA levels may be a sensitive and specific early clinical marker for the development of prostate cancer.
PMCID: PMC3461837  PMID: 1372942
21.  Using Nuclear Morphometry to Predict the Need for Treatment Among Men With Low Grade, Low Stage Prostate Cancer Enrolled in a Program of Expectant Management With Curative Intent 
The Prostate  2008;68(2):183-189.
We assessed the use of quantitative clinical and pathologic information to predict which patients would eventually require treatment for prostate cancer (CaP) in an expectant management (EM) cohort.
We identified 75 men having prostate cancer with favorable initial biopsy characteristics; 30 developed an unfavorable biopsy (Gleason grade >6, >2 cores with cancer, >50% of a core with cancer, or a palpable nodule) requiring treatment and 45 maintained favorable biopsies throughout a median follow-up of 2.7years. Demographic, clinical data and quantitative tissue histomorphometry determined by digital image analysis were analyzed.
Logistic regression (LR) modeling generated a quantitative nuclear grade (QNG) signature based on the enrollment biopsy for differentiation of Favorable and Unfavorable groups using a variable LR selection criteria of Pz < 0.05. The QNG signature utilized 12 nuclear morphometric descriptors (NMDs) and had an area under the receiver operator characteristic curve (ROC-AUC) of 87% with a sensitivity of 82%, specificity of 70% and accuracy of 75%. A multivariable LR model combining QNG signature with clinical and pathological variables yielded an AUC-ROC of 88% and a sensitivity of 81%, specificity of 78% and accuracy of 79%. A LR model using prostate volume, PSA density, and number of pre-diagnosis biopsies resulted in an AUC-ROC of 68% and a sensitivity of 85%, specificity of 37% and accuracy of 56%.
QNG using EM prostate biopsies improves the predictive accuracy of LR models based on traditional clinicopathologic variables in determining which patients will ultimately develop an unfavorable biopsy. Our QNG-based model must be rigorously, prospectively validated prior to use in the clinical arena.
PMCID: PMC3354531  PMID: 18085616
prostate cancer; expectant management; quantitative nuclear grade; prostate biopsy; low grade and low stage cancer
22.  What Is the True Number Needed to Screen and Treat to Save a Life With Prostate-Specific Antigen Testing? 
Journal of Clinical Oncology  2010;29(4):464-467.
The European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 20% mortality reduction with prostate-specific antigen (PSA) screening. However, they estimated a number needed to screen (NNS) of 1,410 and a number needed to treat (NNT) of 48 to prevent one prostate cancer death at 9 years. Although NNS and NNT are useful statistics to assess the benefits and harms of an intervention, in a survival study setting such as the ERSPC, NNS and NNT are time specific, and reporting values at one time point may lead to misinterpretation of results. Our objective was to re-examine the effect of varying follow-up times on NNS and NNT using data extrapolated from the ERSPC report.
Materials and Methods
On the basis of published ERSPC data, we modeled the cumulative hazard function using a piecewise exponential model, assuming a constant hazard of 0.0002 for the screening and control groups for years 1 to 7 of the trial and different constant rates of 0.00062 and 0.00102 for the screening and control groups, respectively, for years 8 to 12. Annualized cancer detection and drop-out rates were also approximated based on the observed number of individuals at risk in published ERSPC data.
According to our model, the NNS and NNT at 9 years were 1,254 and 43, respectively. Subsequently, NNS decreased from 837 at year 10 to 503 at year 12, and NNT decreased from 29 to 18.
Despite the seemingly simplistic nature of estimating NNT, there is widespread misunderstanding of its pitfalls. With additional follow-up in the ERSPC, if the mortality difference continues to grow, the NNT to save a life with PSA screening will decrease.
PMCID: PMC3058289  PMID: 21189374
23.  Interpretation of the prostate-specific antigen history in assessing life-threatening prostate cancer 
BJU international  2010;106(9):1284-1292.
To present an effective approach to the early detection of lethal prostate cancer using longitudinal data on prostate-specific antigen (PSA) and its rate of change, i.e. PSA velocity (PSAV). This longitudinal approach might also be extendible to other biomarkers.
Subjects and methods
PSAV was calculated using five techniques for 634 subjects with at least three PSA measurements in a longitudinal ageing study, censoring PSA levels of > 10 ng/mL. The efficacy for predicting death from prostate cancer was assessed with concordance indices and by using net reclassification improvement (NRI), which indicated the net increase in sensitivity and specificity when adding a biomarker to a base Cox proportional hazards model. The PSAV techniques were compared for the 5–10 years before the clinical diagnosis of prostate cancer. The most effective technique was then applied at the transition point when each man's PSA history curve transformed from linear to exponentially increasing, and its predictive value was compared to that of concurrent PSA level.
A PSA transition point was found in 522 (82%) of the 634 men, including all 11 who died from prostate cancer. At the transition point, the mean PSA level was 1.4 ng/mL, and PSAV but not PSA level was significantly higher among men who died from prostate cancer than among men who did not (P = 0.021 vs P = 0.112; Wilcoxon two-sample test). At the transition point, adding PSAV to a base model consisting of age and date of diagnosis improved the concordance index by 0.05, and significantly improved the overall sensitivity and specificity (NRI, P = 0.028), while adding PSA level to the same base model resulted in little improvement (concordance index increase < 0.01 and NRI P = 0.275).
When the shape of a man's PSA history curve changes from linear to exponential, PSAV might help in the early identification of life-threatening prostate cancer at a time when PSA values are still low in most men.
PMCID: PMC2928882  PMID: 20477823
PSA; prostate cancer; kinetics; velocity
24.  Should prostate-specific antigen velocity be abandoned? 
Asian Journal of Andrology  2011;13(3):359-360.
PMCID: PMC3739355  PMID: 21499277
25.  Serum testosterone is associated with aggressive prostate cancer in older men: results from the Baltimore Longitudinal Study of Aging 
BJU international  2009;105(6):824-829.
To evaluate the relationship between testosterone levels and the development of high-risk prostate cancer, by prospectively examining serum androgen concentrations in a well-studied cohort, as the role of testosterone in prostate cancer progression is debated.
The study comprised 781 men in the Baltimore Longitudinal Study of Aging who had sex steroid measurements before a diagnosis of prostate cancer, or at their last visit for those without cancer (no cancer, 636; cancer, not high risk, 109; cancer, high risk, 36). High-risk cancer was defined as death from prostate cancer, a prostate specific antigen (PSA) level of ≥20 ng/mL at diagnosis, or a Gleason score of ≥8. The hazard ratio (HR) of high-risk disease was determined using a Cox proportional hazards regression model with simple updating, and risk rates were stratified by age and tercile for androgens of interest based on the proportional hazards analyses.
The likelihood of high-risk prostate cancer doubled per unit (0.1) increase in the free testosterone index (FTI) for patients aged >65 years (HR 2.07, 95% confidence interval, CI, 1.01–4.23; P = 0.047); the likelihood for men aged ≤65 years was inversely related to the FTI (HR 0.96, 95% CI 0.35–2.6; P = 0.9). The risk rate per person-years increased from lowest to highest tercile of FTI for the oldest men (age >70 years) but this trend was not apparent among younger men.
Higher levels of serum free testosterone are associated with an increased risk of aggressive prostate cancer among older men. These data highlight the importance of prospective trials to insure the safety of testosterone-replacement therapy.
PMCID: PMC2848292  PMID: 19751256
prostate cancer; testosterone; high-risk

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