Jeffrey J. Tosoian

Active surveillance program for prostate cancer: An update of the Johns Hopkins experience

PURPOSE We assessed outcomes of men with prostate cancer enrolled in active surveillance. PATIENTS AND METHODS Since 1995, a total of 769 men diagnosed with prostate cancer have been followed prospectively (median follow-up, 2.7 years; range, 0.01 to 15.0 years) on active surveillance. Enrollment criteria were for very-low-risk cancers, defined by clinical stage (T1c), prostate-specific antigen density < 0.15 ng/mL, and prostate biopsy findings (Gleason score ≤ 6, two or fewer cores with cancer, and ≤ 50% cancer involvement of any core). Curative intervention was recommended on disease reclassification on the basis of biopsy criteria. The primary outcome was survival free of intervention, and secondary outcomes were rates of disease reclassification and exit from the program. Outcomes were compared between men who did and did not meet very-low-risk criteria. RESULTS The median survival free of intervention was 6.5 years (range, 0.0 to 15.0 years) after diagnosis, and the proportions of men remaining free of intervention after 2, 5, and 10 years of follow-up were 81%, 59%, and 41%, respectively. Overall, 255 men (33.2%) underwent intervention at a median of 2.2 years (range, 0.6 to 10.2 years) after diagnosis; 188 men (73.7%) underwent intervention on the basis of disease reclassification on biopsy. The proportions of men who underwent curative intervention (P = .026) or had biopsy reclassification (P < .001) were significantly lower in men who met enrollment criteria than in those who did not. There were no prostate cancer deaths. CONCLUSION For carefully selected men, active surveillance with curative intent appears to be a safe alternative to immediate intervention. Limiting surveillance to very-low-risk patients may reduce the frequency of adverse outcomes.

Intermediate and Longer-Term Outcomes From a Prospective Active-Surveillance Program for Favorable-Risk Prostate Cancer

PURPOSE To assess long-term outcomes of men with favorable-risk prostate cancer in a prospective, active-surveillance program. METHODS Curative intervention was recommended for disease reclassification to higher cancer grade or volume on prostate biopsy. Primary outcomes were overall, cancer-specific, and metastasis-free survival. Secondary outcomes were the cumulative incidence of reclassification and curative intervention. Factors associated with grade reclassification and curative intervention were evaluated in a Cox proportional hazards model. RESULTS A total of 1,298 men (median age, 66 years) with a median follow-up of 5 years (range, 0.01 to 18.00 years) contributed 6,766 person-years of follow-up since 1995. Overall, cancer-specific, and metastasis-free survival rates were 93%, 99.9%, and 99.4%, respectively, at 10 years and 69%, 99.9%, and 99.4%, respectively, at 15 years. The cumulative incidence of grade reclassification was 26% at 10 years and was 31% at 15 years; cumulative incidence of curative intervention was 50% at 10 years and was 57% at 15 years. The median treatment-free survival was 8.5 years (range, 0.01 to 18 years). Factors associated with grade reclassification were older age (hazard ratio [HR], 1.03 for each additional year; 95% CI, 1.01 to 1.06), prostate-specific antigen density (HR, 1.21 per 0.1 unit increase; 95% CI, 1.12 to 1.46), and greater number of positive biopsy cores (HR, 1.47 for each additional positive core; 95% CI, 1.26 to 1.69). Factors associated with intervention were prostate-specific antigen density (HR, 1.38 per 0.1 unit increase; 95% CI, 1.22 to 1.56) and a greater number of positive biopsy cores (HR, 1.35 for one additional positive core; 95% CI, 1.19 to 1.53). CONCLUSION Men with favorable-risk prostate cancer should be informed of the low likelihood of harm from their diagnosis and should be encouraged to consider surveillance rather than curative intervention.

Accuracy of PCA3 Measurement in Predicting Short-Term Biopsy Progression in an Active Surveillance Program

PURPOSE PCA3 is a prostate specific noncoding mRNA that is significantly over expressed in prostate cancer tissue. Urinary PCA3 levels have been associated with prostate cancer grade and extent, suggesting a possible role in monitoring patients on active surveillance. We assessed the relationship between PCA3 and prostate biopsy results in men in a surveillance program. MATERIALS AND METHODS Urine specimens were obtained from 294 men with prostate cancer enrolled in the Johns Hopkins surveillance program. The followup protocol included semiannual free and total prostate specific antigen measurements, digital rectal examination and annual surveillance prostate biopsy. Cox proportional hazards regression was used to evaluate the association between PCA3 results and progression on surveillance biopsy (defined as Gleason pattern 4 or 5, more than 2 positive biopsy cores or more than 50% involvement of any core with cancer). RESULTS Patients with progression on biopsy (12.9%) had a mean PCA3 score similar to that of those without progression (60.0 vs 50.8, p = 0.131). ROC analysis suggested that PCA3 alone could not be used to identify men with progression on biopsy (AUC 0.589, 95% CI 0.496-0.683, p = 0.076). After adjustment for age and date of diagnosis PCA3 was not significantly associated with progression on biopsy (p = 0.15). CONCLUSIONS In men with low risk prostate cancer who were carefully selected for surveillance the PCA3 score was not significantly associated with short-term biopsy progression. Further analysis is necessary to assess the usefulness of PCA3 in combination with other biomarkers or in selected subsets of patients undergoing surveillance.

Active surveillance for prostate cancer: current evidence and contemporary state of practice

Prostate cancer remains one of the most commonly diagnosed malignancies worldwide. Early diagnosis and curative treatment seem to improve survival in men with unfavourable-risk cancers, but significant concerns exist regarding the overdiagnosis and overtreatment of men with lower-risk cancers. To this end, active surveillance (AS) has emerged as a primary management strategy in men with favourable-risk disease, and contemporary data suggest that use of AS has increased worldwide. Although published surveillance cohorts differ by protocol, reported rates of metastatic disease and prostate-cancer-specific mortality are exceedingly low in the intermediate term (5–10 years). Such outcomes seem to be closely associated with programme-specific criteria for selection, monitoring, and intervention, suggesting that AS — like other management strategies — could be individualized based on the level of risk acceptable to patients in light of their personal preferences. Additional data are needed to better establish the risks associated with AS and to identify patient-specific characteristics that could modify prognosis.

Association of [−2]proPSA with Biopsy Reclassification During Active Surveillance for Prostate Cancer

PURPOSE Previous studies have suggested an association between [-2]proPSA expression and prostate cancer detection. Less is known about the usefulness of this marker in following patients with prostate cancer on active surveillance. Thus, we examined 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 greater, more than 2 positive biopsy cores or more than 50% involvement of any core with cancer). We also examined the association of biopsy results with total prostate specific antigen, %fPSA, [-2]proPSA/%fPSA and the Beckman Coulter Prostate Health Index phi ([-2]proPSA/free prostate specific antigen) × (total prostate specific antigen)(½)). RESULTS While on active surveillance (median time from diagnosis 4.3 years), 63 (37.7%) men demonstrated biopsy reclassification based on the previously mentioned criteria, including 28 (16.7%) of whom had reclassification based on Gleason score upgrading (Gleason score 7 or greater). 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. CONCLUSIONS In men on active surveillance, measures based on [-2]proPSA such as phi appear to provide improved prediction of biopsy reclassification during followup. 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.

Pathological Outcomes in Men with Low Risk and Very Low Risk Prostate Cancer: Implications on the Practice of Active Surveillance

PURPOSE 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. RESULTS 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). CONCLUSIONS 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.

PSA and beyond: the past, present, and future of investigative biomarkers for prostate cancer.

The discovery of prostate-specific antigen (PSA) as a biomarker represented a major discovery in the early diagnosis and monitoring of prostate cancer. However, the use of PSA is limited by the lack of specificity and an inability to differentiate indolent from life-threatening disease reliably at the time of diagnosis. A multitude of studies have aimed to improve the performance of PSA as well as identify additional biomarkers. The purpose of this study is to review available data on prostate cancer biomarkers for prostate cancer screening and prognostication, including prostatic acid phosphatase, PSA, PSA derivatives (PSA density, free PSA, pro PSA, and PSA kinetics), PCA3, GSTP1, AMACR, and other newly emerging molecular and genetic markers.

Oligometastatic prostate cancer: definitions, clinical outcomes, and treatment considerations

The oligometastatic state has been proposed as an intermediate stage of cancer spread between localized disease and widespread metastases. With improvements in diagnostic modalities such as functional imaging, oligometastatic prostate cancer is being diagnosed with greater frequency than ever before. Furthermore, the paradigm for treatment of advanced prostate cancers is shifting toward a more aggressive approach. Many questions surround the understanding of the process and consequences of oligometastasis, meaning that the contemporary literature offers a wide variety of definitions of oligometastatic prostate cancer. Until genomic data exist to provide a biological component to the definition of oligometastatic disease, a clinical diagnosis made on the basis of up to five extrapelvic lesions is reasonable for use. Retrospective studies suggest that interventions such as radical prostatectomy and local or metastasis-directed radiotherapy can be performed in the metastatic setting with minimal risk of toxic effects. These therapies seem to decrease the need for subsequent palliative interventions, but insufficient data are available to draw reliable conclusions regarding their effect on survival. Thus, a protocol for clinicians to manage the patient presenting with oligometastatic prostate cancer would be a useful clinical tool.

The Role of Multiparametric Magnetic Resonance Imaging/Ultrasound Fusion Biopsy in Active Surveillance

BACKGROUND Multiparametric magnetic resonance imaging (mpMRI)/ultrasound fusion biopsy (targeted biopsy or TB) may improve detection of high-grade cancers when compared to systematic biopsy (SB). OBJECTIVE To assess TB in active surveillance (AS). DESIGN, SETTING, AND PARTICIPANTS We retrospectively evaluated SB (12-core sector) and TB among 103 AS men undergoing surveillance biopsy, 54 men undergoing confirmatory biopsy (CB), and 73 men referred for diagnostic biopsy (DB; comparison group). Regions of interest (ROIs) on mpMRI were assigned a PI-RADS score and targeted if the score was ≥3. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Detection of Gleason score (GS) ≥7 by TB and SB was the outcome of interest, except in a multivariable model, for which any cancer was the outcome. RESULTS AND LIMITATIONS GS ≥7was detected by either biopsy method in 25 men (24.3%) in the AS group, 12 men (22.2%) in the CB group, and 55 men (75.3%) in the DB group.GS ≥7 was found in 24.3% by SB + TB versus 20.4% by SB in the AS group (p=0.13); in 22.2% by SB + TB versus 16.7% by SB in the CB group (p=0.25); and in 75.3% by SB + TB versus 58.9% by SB in the DB group (p=0.002). The sensitivity for GS ≥7 detection was lower for TB than for SB (p=0.006) in the AS cohort (relative sensitivity ratio 0.33, 95% confidence interval 0.16-0.71). Higher PI-RADS score (4 vs 3, odds ratio [OR] 2.00, p=0.04; 5 vs 3, OR 4.74, p=0.02), lower MRI-estimated prostate volume (OR 1.20 per 10-cm3 lower volume, p=0.01), larger ROI (OR 1.04 per mm, p=0.02), and right-sided ROI (OR 2.27, p=0.01) were associated with finding cancer on TB. A potential limitation is that not all men who presented for biopsy underwent TB and the urologist was not blinded to MRI results before SB. CONCLUSIONS Owing to the low relative sensitivity of mpMRI for detection of GS ≥7 disease, SB still needs to be performed for men on AS. PATIENT SUMMARY This study suggests that image-guided prostate biopsy alone may not be informative for men enrolled in an active surveillance program for prostate cancer.

Pathologic Outcomes in Favorable-risk Prostate Cancer: Comparative Analysis of Men Electing Active Surveillance and Immediate Surgery

BACKGROUND It remains unclear whether men selecting active surveillance (AS) are at increased risk of unfavorable longer term outcomes as compared with men who undergo immediate treatment. OBJECTIVE To compare adverse pathologic outcomes in men with favorable-risk prostate cancer who underwent delayed prostatectomy after surveillance (DPAS) to those who elected immediate prostatectomy (IRP). DESIGN, SETTING, AND PARTICIPANTS We conducted a retrospective analysis of a prospective AS registry from 2004 to 2014. From the Johns Hopkins AS program (n = 1298), we identified a subset of men who underwent DPAS (n = 89) and was representative of the entire cohort, not just those that were reclassified to higher risk. These men were compared with men who underwent IRP (n = 3788). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We measured adverse pathologic features (primary Gleason pattern ≥ 4, seminal vesicle invasion [SVI], or lymph node [LN] positivity). Multivariable models were adjusted for age, prostate-specific antigen density, and baseline risk classification. RESULTS AND LIMITATIONS Delayed prostatectomy occurred at a median of 2.0 yr (range: 0.6-9.0) after diagnosis. The DPAS and IRP cohorts demonstrated similar proportions of men with primary Gleason pattern ≥ 4 (17% vs 20%; p = 0.11), SVI (3.3% vs 3.2%; p = 0.53), LN positivity (2.3% vs 1.2%; p = 0.37), and overall adverse pathologic features (21.3% vs 17.0%; p = 0.32). The adjusted odds ratio of adverse pathology was 1.33 (95% confidence interval, 0.82-2.79; p = 0.13) for DPAS as compared with IRP. Limitations include a modest cohort size and a limited number of events. CONCLUSIONS In men with favorable-risk cancer, the decision to undergo AS is not independently associated with adverse pathologic outcomes. PATIENT SUMMARY This report compares men with favorable-risk prostate cancer who elected active surveillance with those who underwent immediate surgery accounting for evidence that approximately one-third of men who choose surveillance will eventually undergo treatment. Our findings suggest that men who are closely followed with surveillance may have similar outcomes to men who elect immediate surgery, but additional research is needed.