Role of Surveillance Biopsy with No Cancer as a Prognostic Marker for Reclassification: Results from the Canary Prostate Active Surveillance Study

Background

Many patients who are on active surveillance (AS) for prostate cancer will have surveillance prostate needle biopsies (PNBs) without any cancer evident.

A Negative Confirmatory Biopsy Among Men on Active Surveillance for Prostate Cancer Does Not Protect Them from Histologic Grade Progression

Background

Many men (21–52%) are reported to have no cancer on the second, also known as the confirmatory, biopsy (B2) for prostate cancer active surveillance (AS). If these men had a reduced risk of pathologic progression, particularly grade related, the intensity of their follow-up could be decreased.

Objective

To investigate if men with no cancer on B2 are less likely to undergo subsequent pathologic progression.

Design, setting, and participants

Men were identified from our tertiary care center AS prostate cancer database (1995–2012). Eligibility criteria were prostate-specific antigen (PSA) ≤10, cT2 or lower, no Gleason grade 4 or 5, three or fewer positive cores, and no core >50% involved. Only patients with three or more biopsies were selected and then dichotomized on cancer status (yes or no) at B2.

Intervention

AS.

Outcome measurements and statistical analysis

Pathologic progression was defined as grade (advancement in Gleason score) and/or volume (more than three positive cores, >50% core involved). Progression-free survival was compared. Predictors of progression were investigated using a Cox proportional hazards model.

Results and limitations

Of the 286 patients remaining on AS after B2, 149 (52%) had no cancer and 137 (48%) had cancer. The median follow-up after B2 was 41 mo (interquartile range [IQR]: 26.5–61.9). Progression-free survival at 5 yr was 85.2% versus 67.3% for negative B2 versus cancer on B2, respectively (p = 0.002). Men with no cancer at B2 had a 53% reduction in risk of subsequent progression (hazard ratio [HR]: 0.47; 95% confidence interval [CI], 0.29–0.77; p = 0.003). Subanalysis showed prognostic indicators of volume-related progression were absence of cancer (HR: 0.36; 95% CI, 0.20–0.62; p = 0.0006) and PSA density (HR: 1.79; 95% CI, 1.12–2.89; p = 0.01). The only predictor of grade-related progression was age (HR: 1.05; 95% CI, 1.00–1.10; p = 0.04). Retrospective analysis was the major limitation of the study.

Conclusions

Absence of cancer on B2 is associated with a significantly decreased risk of volume-related but not grade-related progression. This must be considered when counseling men on AS.     

Medium-term Outcomes of Active Surveillance for Localised Prostate Cancer

Background

Active surveillance (AS) aims to allow men with favourable-risk, localised prostate cancer to avoid unnecessary treatment.

Objective

To describe the clinical outcomes of a prospective study of AS.

Design, setting, and participants

A single-centre, prospective cohort study. Eligibility criteria included histologically proven prostate adenocarcinoma, age 50–80 yr, stage T1/T2, prostate-specific antigen level (PSA) <15 ng/ml, Gleason score (GS) ≤3 + 3 (GS ≤3 + 4 if aged >65 yr), and percent positive biopsy cores (PPC) ≤50%.

Intervention

Patients were assessed by serum PSA level, and digital rectal examination at 3-mo intervals in year 1, 4-mo intervals in year 2, and at 6-mo intervals thereafter. Transrectal ultrasound-guided prostate biopsy was performed after 18–24 mo and every 2 yr thereafter. Treatment was recommended for PSA velocity (PSAV) >1 ng/ml per year or adverse histology, defined as GS ≥4 + 3 or PPC >50%.

Outcome measurements and statistical analysis

Outcomes described, using Kaplan-Meier methods, were rate of adverse histology on repeat biopsy, freedom from treatment, biochemical control after deferred treatment, and overall survival. Analyses using Cox regression were performed to determine predictors of deferred treatment and adverse histology.

Results and limitations

The study enrolled 471 eligible patients from 2002 to 2011. Median age was 66 yr and median initial PSA value was 6.4 ng/ml. Eighty-eight percent of patients had T1 disease and 93% had GS ≤3 + 3. At median follow-up of 5.7 yr, the 5-yr rate of adverse histology and treatment-free probability was 22% (95% confidence interval [CI], 16–29%) and 70% (95% CI, 65–75%), respectively. There were two deaths from prostate cancer. Predictors of time to adverse histology were GS 7, PSAV >1 ng/ml per year, low ratio of free PSA to total PSA, and PPC >25%. Longer follow-up is needed to confirm the safety of this strategy.

Conclusions

This study demonstrates satisfactory medium-term outcomes for AS in selected men with localised prostate cancer.     

A Study of Diffusion-Weighted Magnetic Resonance Imaging in Men with Untreated Localised Prostate Cancer on Active Surveillance

Background

Markers that predict the behaviour of localised prostate cancer are needed to identify patients that require treatment.

Objective

We have analysed the apparent diffusion coefficient (ADC) generated from diffusion-weighted magnetic resonance imaging (DW-MRI) with respect to repeat biopsy findings and time to radical treatment in patients in a prospective study of active surveillance.

Design, setting, and participants

Some 86 men recruited between 2002 and 2006 were followed for a median of 29 mo. Patients had clinical stage T1/T2a N0/Nx M0/Mx adenocarcinoma of the prostate, prostate-specific antigen (PSA) level <15 ng/ml, Gleason score ≤7, primary Gleason grade ≤3, and positive biopsy cores (pbc) ≤50%.

Measurements

All patients had DW-MRI in addition to standard MRI sequences. Tumour regions of interest (ROIs) were identified using T2-weighted fast-spin echo images as focal areas of restricted diffusion. Univariate analyses including all clinical variables and tumour ADC data were performed with respect to repeat biopsy findings and time to radical treatment. Receiver operating curves (ROC) compared predictive variables.

Results and limitations

Patients in the study had a median age of 66 yr and a median initial PSA level of 6.7 ng/ml. Some 39 patients (45%) received deferred radical treatment, and 34 patients (40%) had adverse histology on repeat biopsy. According to univariate analysis, tumour ADC was a significant predictor of both adverse repeat biopsy findings (p < 0.0001; hazard ratio [HR]: 1.3; 95% confidence interval [CI]: 1.1–1.6), and time to radical treatment (p < 0.0001; HR: 1.5; 95% CI: 1.2–1.8). ROC curves for ADC showed an area under the curve (AUC) of 0.7 for prediction of adverse repeat biopsy findings and an AUC of 0.83 for prediction of radical treatment.

Conclusions

In patients with low-risk, localised disease, tumour ADC on DW-MRI may be a useful marker of prostate cancer progression and may help to identify patients who stand to benefit from radical treatment. This possibility warrants further study.     

Outcome Following Active Surveillance of Men with Screen-detected Prostate Cancer. Results from the Göteborg Randomised Population-based Prostate Cancer Screening Trial

Background

Active surveillance (AS) has emerged as a treatment strategy for reducing overtreatment of screen-detected, low-risk prostate cancer (PCa).

Objective

To assess outcomes following AS of men with screen-detected PCa.

Design, setting, and participants

Of the 968 men who were diagnosed with screen-detected PCa between 1995 and 2010 in the Göteborg randomised, population-based PCa screening trial, 439 were managed with AS and were included in this study. Median age at diagnosis was 65.4 yr of age, and median follow-up was 6.0 yr from diagnosis.

Intervention

The study participants were followed at intervals of 3–12 mo and were recommended to switch to deferred active treatment in case of a progression in prostate-specific antigen, grade, or stage.

Outcome measurements and statistical analysis

The end points—overall survival (OS), treatment-free survival, failure-free (no relapse after radical treatment) survival, and cancer-specific survival—were calculated for various risk groups (very low, low, intermediate, and high) with Kaplan-Meier estimates. A Cox proportional hazards model as well as a competing risk analysis were used to assess whether risk group or age at diagnosis was associated with failure after AS.

Results and limitations

Forty-five per cent of all screen-detected PCa were managed with AS, and very low-risk and low-risk PCa constituted 60% of all screen-detected PCa. Thirty-seven per cent (162 of 439) switched from surveillance to deferred active treatment, and 39 men failed AS. The 10-yr OS, treatment-free survival, and failure-free survival were 81.1%, 45.4%, and 86.4%, respectively (Kaplan-Meier estimates). Men with low-, intermediate-, and high-risk tumours had a hazard ratio for failure of 2.1 (p = 0.09), 3.6 (p = 0.002), and 4.6 (p = 0.15), respectively, compared to very low-risk tumours (Cox regression). Only one PCa death occurred, and one patient developed metastasis (both in the intermediate-risk group). The main limitation of this study is the relatively short follow-up.

Conclusions

A large proportion of men with screen-detected PCa can be managed with AS. AS appears safe for men with low-risk PCa.     

Active Surveillance of Grade Group 1 Prostate Cancer: Long-term Outcomes from a Large Prospective Cohort

BackgroundActive surveillance (AS) is the preferred management option for most men with grade group (GG) 1 prostate cancer (PCa). Questions persist regarding long-term outcomes and the optimal approach to AS.ObjectiveTo determine survival and metastatic outcomes in AS patients. Secondary objectives were to measure the cumulative incidence and association of patient-level factors on biopsy grade reclassification.Design, setting, and participantsA prospective, active, open-enrollment cohort study was conducted from 1995 through July 2018 at a tertiary-care academic institution. Patients with very-low-risk or low-risk PCa were enrolled.InterventionAS with semiannual prostate-specific antigen (PSA) and digital rectal examination, serial prostate biopsy, and multiparametric magnetic resonance imaging (mpMRI).Outcome measurements and statistical analysisThe 10- and 15-yr cumulative incidences of primary and secondary outcomes were determined.Results and limitationsOverall, 1818 men were monitored on AS for a median of 5.0 yr (interquartile range 2.0–9.0). There were 88 non-PCa deaths, four PCa deaths, and one additional case of metastasis. The cumulative incidence of PCa-specific mortality or metastasis was 0.1% (95% confidence interval, 0.04–0.6%) at both 10 and 15 yr. The 5-, 10-, and 15-yr cumulative incidences of biopsy grade reclassification were 21%, 30%, and 32%, respectively. On multivariable analysis, biopsy grade reclassification was associated with older age, African-American race, PSA density, and increased cancer volume on biopsy, and men who underwent mpMRI prior to enrollment were less likely to undergo grade reclassification. Our selection and monitoring are more stringent than many other contemporary AS programs.ConclusionsIn a large, single-institution, prospective AS cohort, the risk of cancer death or metastasis was <1% over long-term follow-up. Consistent with clinical guidelines, these data support the use of AS for the management of most men diagnosed with GG1 PCa.Patient summaryThis study investigated long-term outcomes in patients with grade group 1 prostate cancer managed with active surveillance (AS). Ten years after enrolling in AS, the risk of metastasis or death from prostate cancer was <1%, while 48% of men switched to treatment. Patients who underwent multiparametric magnetic resonance imaging (mpMRI)/ultrasound-fusion targeted biopsy prior to enrollment were less likely to experience biopsy grade reclassification during follow-up, suggesting a role for mpMRI as part of a comprehensive risk assessment to confirm AS eligibility. These findings support the safety of AS in most men with grade group 1 prostate cancer, but specific outcomes may differ in programs with less intensive monitoring.     

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.     

Role of Changes in Magnetic Resonance Imaging or Clinical Stage in Evaluation of Disease Progression for Men with Prostate Cancer on Active Surveillance

BackgroundActive surveillance (AS) protocols rely on rectal examination, prostate-specific antigen, imaging, and biopsy to identify disease progression.ObjectiveTo evaluate whether an AS regimen based on magnetic resonance imaging (MRI) or clinical stage changes can detect reclassification to grade group (GG) ≥2 disease compared with scheduled systematic biopsies.Design, setting, and participantsWe identified a cohort of men initiated on AS between January 2013 and April 2016 at a single tertiary-care center. Patients completed confirmatory testing and prostate MRI prior to enrollment, then underwent laboratory and physical evaluation every 6 mo, MRI every 18 mo, and biopsy every 3 yr.Outcome measurements and statistical analysisMRI results were evaluated using composite Likert/Prostate Imaging Reporting and Data System v2 scoring. MRI and clinical changes were assessed for association with disease progression. Univariable and multivariable regression models were used to predict upgrading on 3-yr biopsy.Results and limitationsAt 3 yr, of 207 men, 66 (32%) had ≥ GG2 at biopsy: 55 (83%) with GG2, 10 (15%) with GG3, and one (1.5%) with GG4. Among patients with a 3-yr MRI score of ≥3, 41% had ≥ GG2 disease, compared with 15% with an MRI score of <3 (p = 0.0002). The MRI score increased in 48 men (23%), decreased in 27 (13%), and was unchanged in 132 (64%) men. Increases in MRI score were not associated with reclassification after adjusting for the 3-yr MRI score (p = 0.9). Biopsying only for an increased MRI score or clinical stage would avoid 681 biopsies per 1000 men, at the cost of missing ≥GG2 disease in 169 patients.ConclusionsAn AS strategy that uses MRI or clinical changes to trigger prostate biopsy avoids many biopsies but misses an unacceptable amount of clinically significant disease. Prostate biopsy for men on AS should be performed at scheduled intervals, regardless of stable imaging or examination findings.Patient summaryAn active surveillance strategy for biopsy based only on increases in magnetic resonance imaging score or clinical stage will avoid many biopsies; however, it will miss many patients with clinically significant prostate cancer.     

ERG Protein Expression in Diagnostic Specimens Is Associated with Increased Risk of Progression During Active Surveillance for Prostate Cancer

Background

Compelling biomarkers identifying prostate cancer patients with a high risk of progression during active surveillance (AS) are needed.

Objective

To examine the association between ERG expression at diagnosis and the risk of progression during AS.

Design, setting, and participants

This study included 265 patients followed on AS with prostate-specific antigen (PSA) measurements, clinical examinations, and 10–12 core rebiopsies from 2002 to 2012 in a prospectively maintained database. ERG immunohistochemical staining was performed on diagnostic paraffin-embedded formalin-fixed sections with a ready-to-use kit (anti-ERG, EPR3864). Men were characterised as ERG positive if a minimum of one tumour focus demonstrated ERG expression.

Outcome measurements and statistical analysis

Overall AS progression was defined as clinical progression: increased clinical tumour category ≥cT2b by digital rectal examination and ultrasound, and/or histopathologic progression: upgrade of Gleason score, more than three positive cores or bilateral positive cores, and/or PSA progression: PSA doubling time <3 yr. Risk of progression was analysed using multiple cause-specific Cox regression and stratified cumulative incidences (Aalen-Johansen method). Curatively intended treatment, watchful waiting, and death without progression were treated as competing events.

Results and limitations

A total of 121 of 142 ERG-negative and 96 of 123 ERG-positive patients had complete diagnostic information. In competing risk models, the ERG-positive group showed significantly higher incidences of overall AS progression (p < 0.0001) and of the subgroups PSA progression (p < 0.0001) and histopathologic progression (p < 0.0001). The 2-yr cumulative incidence of overall AS progression was 21.7% (95% confidence interval [CI], 14.3–29.1) in the ERG-negative group compared with 58.6% (95% CI, 48.7–68.5) in the ERG-positive group. ERG positivity was a significant predictor of overall AS progression in multiple Cox regression (hazard ratio: 2.45; 95% CI, 1.62–3.72; p < 0.0001). The main limitation of this study is its observational nature.

Conclusions

In our study, ERG positivity at diagnosis can be used to estimate the risk of progression during AS. If confirmed, ERG status can be used to individualise AS programmes.

Patient summary

The tissue biomarker ERG identifies active surveillance patients with an increased risk of disease progression.     

A Systematic Approach to Discussing Active Surveillance with Patients with Low-risk Prostate Cancer

Background

Physicians report difficulty convincing patients with prostate cancer about the merits of active surveillance (AS); as a result, a majority of patients unnecessarily choose to undergo radical treatment.

Active Surveillance for Low-Risk Prostate Cancer Worldwide: The PRIAS Study

Background

Overdiagnosis and subsequent overtreatment are important side effects of screening for, and early detection of, prostate cancer (PCa). Active surveillance (AS) is of growing interest as an alternative to radical treatment of low-risk PCa.

Objective

To update our experience in the largest worldwide prospective AS cohort.

Design, setting, and participants

Eligible patients had clinical stage T1/T2 PCa, prostate-specific antigen (PSA) ≤10 ng/ml, PSA density <0.2 ng/ml per milliliter, one or two positive biopsy cores, and Gleason score ≤6. PSA was measured every 3–6 mo, and volume-based repeat biopsies were scheduled after 1, 4, and 7 yr. Reclassification was defined as more than two positive cores or Gleason >6 at repeat biopsy. Recommendation for treatment was triggered in case of PSA doubling time <3 yr or reclassification.

Outcome measurements and statistical analysis

Multivariate regression analysis was used to evaluate predictors for reclassification at repeat biopsy. Active therapy–free survival (ATFS) was assessed with a Kaplan-Meier analysis, and Cox regression was used to evaluate the association of clinical characteristics with active therapy over time.

Results and limitations

In total, 2494 patients were included and followed for a median of 1.6 yr. One or more repeat biopsies were performed in 1480 men, of whom 415 men (28%) showed reclassification. Compliance with the first repeat biopsy was estimated to be 81%. During follow-up, 527 patients (21.1%) underwent active therapy. ATFS at 2 yr was 77.3%. The strongest predictors for reclassification and switching to deferred treatment were the number of positive cores (two cores compared with one core) and PSA density. The disease-specific survival rate was 100%. Follow-up was too short to draw definitive conclusions about the safety of AS.

Conclusions

Our short-term data support AS as a feasible strategy to reduce overtreatment. Clinical characteristics and PSA kinetics during follow-up can be used for risk stratification. Strict monitoring is even more essential in men with high-risk features to enable timely recognition of potentially aggressive disease and offer curative intervention. Limitations of using surrogate end points and markers in AS should be recognized.

Trial registration

The current program is registered at the Dutch Trial Register with ID NTR1718 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1718).     

Careful Selection and Close Monitoring of Low-Risk Prostate Cancer Patients on Active Surveillance Minimizes the Need for Treatment

Background

With the advent of prostate-specific antigen (PSA) screening and the increase in the number of transrectal ultrasound–guided biopsy cores, there has been a dramatic rise in the incidence of low-risk prostate cancer (LRPC). Because >97% of men with LRPC are likely to die of something other than prostate cancer, it is critical that patients give thought to whether early curative treatment is the only option at diagnosis.

Objective

To identify a group of men with LRPC who may not require initial treatment and monitor them on our active surveillance (AS) protocol, to determine the percentage treated and the outcome and to analyze the quality-of-life data.

Design, setting, and participants

We defined patients eligible for AS as Gleason ≤6, PSA ≤10, and two or fewer biopsy cores with ≤20% tumor in each core.

Measurements

Kaplan Meier analysis was used to predict the 5-year treatment free survival. Logistic regression determined the predictors of treatment. Data on sexual function, continence, and outcome were obtained and analyzed.

Results and limitations

The AS cohort consisted of 230 patients with a mean age of 63.4 yr; 86% remained on AS for a mean follow-up of 44 mo. Thirty-two of the 230 patients (14%) were treated for a mean follow-up of 33 mo. Twelve had a total prostatectomy (TP). The pathologic stage of these patients was similar to initially treated TP patients with LRPC. Fourteen underwent radiation therapy, and six underwent androgen-deprivation therapy. Fifty percent of patients had no tumor on the first rebiopsy, and only 5% of these patients were subsequently treated. PSA doubling time and clinical stage were not predictors of treatment. No patient progressed after treatment. Among the AS patients, 30% had incontinence, yet <15% were bothered by it. As measured by the Sexual Health Inventory for Men, 49% of patients had, at a minimum, moderate (≤16) erectile dysfunction.

Conclusions

If guidelines for AS are narrowly defined to include only patients with Gleason 6, tumor volume ≤20% in one or two biopsy cores, and PSA levels ≤10, few patients are likely to require treatment. Progression-free survival of those treated is likely to be equivalent to patients with similar clinical findings treated at diagnosis.     

Active Surveillance: Pathologic and Clinical Variables Associated with Outcome

Over the past 10 years, active surveillance has emerged as a primary management option for men diagnosed with low-risk prostate cancer. Given the morbidity associated with curative treatment, active surveillance maintains quality of life for men whose disease may never become symptomatic. In order to confidently and safely offer this approach to as many patients as possible, improved metrics are needed to fully assess risk. While pathologic and clinical variables currently help determine whether active surveillance is a reasonable approach, emerging biomarkers and imaging technologies demonstrate promise for more precise identification of ideal candidates.     

Predictors of Health-related Quality of Life and Adjustment to Prostate Cancer During Active Surveillance

Background

Active surveillance (AS) is emerging as an alternative approach to limit the risk of overtreatment and impairment of quality of life (QoL) in patients with low-risk localised prostate cancer. Although most patients report high levels of QoL, some men may be distressed by the idea of living with untreated cancer.

Objective

To identify factors associated with poor QoL during AS.

Design, setting, and participants

Between September 2007 and March 2012, 103 patients participated in the Prostate Cancer Research International Active Surveillance (PRIAS) QoL study. Mental health (Symptom Checklist-90), demographic, clinical, and decisional data were assessed at entrance in AS. Health-related QoL (HRQoL) Functional Assessment of Cancer Therapy-Prostate version and Mini-Mental Adjustment to Cancer outcomes were assessed after 10 mo of AS.

Outcome measurements and statistical analysis

Multivariate logistic regression models were used to identify predictors of low (<25th percentile) HRQoL, adjustment to cancer, and a global QoL index at 10 mo after enrolment.

Results and limitations

The mean age of the study patients was 67 yr (standard deviation: ±7 yr). Lack of partner (odds ratio [OR]: 0.08; p = 0.009) and impaired mental health (OR: 1.2, p = 0.1) were associated with low HRQoL (p = 0.006; area under the curve [AUC]: 0.72). The maladaptive adjustment to cancer (p = 0.047; AUC: 0.60) could be predicted by recent diagnosis (OR: 3.3; p = 0.072). Poor global QoL (overall p = 0.02; AUC: 0.85) was predicted by impaired mental health (OR: 1.16; p = 0.070) and time from diagnosis to enrolment in AS <5 mo (OR: 5.52; p = 0.009). Influence of different physicians on the choice of AS (OR: 0.17; p = 0.044), presence of a partner (OR: 0.22; p = 0.065), and diagnostic biopsy with >18 core specimens (OR: 0.89; p = 0.029) were predictors of better QoL. Limitations of this study were the small sample size and the lack of a control group.

Conclusions

Factors predicting poor QoL were lack of a partner, impaired mental health, recent diagnosis, influence of clinicians and lower number of core samples taken at diagnostic biopsy. Educational support from physicians and emotional/social support should be promoted in some cases to prevent poor QoL.