Table 1.
Clinico-pathologic variables and biomarkers for risk stratification
| Authors and references | ‘Significant’ predictors/findings | ‘Not significant’ predictors | Outcome | Analysis | |
|---|---|---|---|---|---|
| Tseng et al (5) |
|
Age, PSA, PSAD (outcome: progression at initial biopsy) Age, PSA, percent fPSA (outcome: progression at second or subsequent biopsy) |
Biopsy progression (defined at surveillance biopsy as Gleason pattern 4 or 5, >2 biopsy cores with cancer or >50% involvement of any core with cancer) upon 1) initial surveillance biopsy and 2) second or subsequent surveillance biopsy |
Multivariate | |
| Abern et al (8) | Black race, PSA, household income | Age, insurance, number of biopsy cores at diagnosis | Discontinuation of AS for treatment (all cause and due to progression excluding preference) |
Multivariate | 3 models adjusting for socio economic and clinical parameters at the time of PC diagnosis |
| Iremashvili et al (9) | African American race, prostate volume, PSA density at diagnosis, 2 positive biopsy cores (vs. 1) | Age at diagnosis, Hispanic, metabolic syndrome components, family history, negative prostate biopsies before diagnosis, clinical stage, PSA | High grade cancer, more than 2 positive cores or greater than 20% involvement of any core on surveillance biopsy. | Multivariate | |
| Sundi et al (10) | AA race independent predictor of reclassification by grade | PSA, prostate size, BMI. AA race was not associated with reclassification by volume. | Reclassification on serial biopsy (by grade or volume, by grade only, and by volume only) |
Multivariate | |
| Cohn et al (11) | Model 1:PNI, BMI, race/ethnicity (African-American), PSA density. Model 2: PNI, Number of positive cores at diagnostic biopsy |
Maximum single core involvement, total tumor length | AS failure at confirmation biopsy (Gleason ≥7, >3 cores positive, single core with >50% involvement, and/or tumour volume >5% of total biopsy volume) | Multivariate | Model 1: PNI and non-biopsy variables significant p<0.2 in univariate. Model 2: Biopsy variables |
| Cullen et al (12) | Younger age, black race, comorbidity, higher T stage, higher Gleason (shorter time to secondary treatment Age, PSADT (mortality) |
Time to secondary treatments, all-cause mortality | Multivariate | ||
| Fleshner et al (13) | Higher age, family history, dutasteride administration, baseline PSA, baseline prostate volume | Race, PSA velocity, baseline DHT/T | Disease progression (any indication of prostate cancer treatment or pathological progression) | Multivariate | |
| Smith et al (14) | Initial cancer core length, PSAV (trend) |
Baseline PSA, baseline grade, stage, age, race | Positive second biopsy | Univariate | |
| Dall’ Era et al (15) | PSA density ≥0.15 at diagnosis, increase in GS on repeat biopsy | Age at diagnosis, race, relationship status, clinical risk group, PSA velocity >0.75 ng/ml/year | Active treatment | Multivariate | |
| Patel et al (16) | PSA velocity risk count of 2 increased reclassification risk in next year | Age at diagnosis, race, PSAD at diagnosis, overall PSAV during follow-up and cancer on first surveillance biopsy | Biopsy reclassification (>2 positive cores, >50% core involvement, or GS >6)) |
Multivariate | (Adjusted for age at diagnosis, race, PSAD at diagnosis, overall PSAV during followup and cancer on first surveillance biopsy.) |
| Shappley et al (17) | Outcome 1: age. clinical stage. Outcome 2: clinical stage. PSA, Gleason |
Outcome 1: Race, height, BMI, PSA at diagnosis, Gleason. Outcome 2: Age, deferred treatment at >12 months |
Outcome 1: Time to initiation of active treatment. Outcome 2: time to metastasis or death as a result of PCa. | Multivariate | |
| Lin et al (18) | Log PSA, abnormal DRE | PCA3, TMPRSS2:ER G, family history, race, age (N.B. subset analysis of men with negative DRE had similar results) |
Gleason ≥7 | Multivariate | |
| Bul et al (19) | Baseline variables: number of positive cores (2 vs 1 core), PSA density, age, baseline PSA value. Also PSA-DT at the time of repeat biopsy | Clinical T stage, number of biopsy cores | Reclassification (defined as >2 positive cores or Gleason >6 at repeat biopsy) |
Multivariate | Model 1: 1st repeat biopsy. Model 2: All repeat biopsies |
| Klotz et al (20) | Outcome 1: clinical stage >T2, GS >6 at baseline (predict definitive treatment). Outcome 2: PSADT <3 years (higher likelihood of BCR). Outcome 3: Age (higher risk of non-prostate cancer mortality than prostate cancer mortality) |
Outcome 1: PSA >10 at baseline. | Outcomes 1: Time to treatment, Outcome 2: PSA failure after radical treatment, Outcome 3: Mortality |
Univariate | |
| Sternberg et al (21) | Nomogram including Age. clinical stage. PSA, # positive cores at diagnosis. % positive cores at diagnosis, # negative and positive biopsies to date | Progression (defined as failure to meet the inclusion criteria during follow up) |
Multivariate | ||
| Whitson et al (22) | Lower prostate volume, older age (increased odds of progression) |
PSADT, time to repeat biopsy, stage (T2 vs T1c), biopsy source (UCSF vs other), Johns Hopkins criteria eligibility | Biopsy progression on repeat biopsy within 24 months of diagnosis (GS ≥7, >33% of cores positive or >50% of the maximum core positive) | Multivariate | Adjusted for age, prostate volume, clinical stage, biopsy source, whether the case met Johns Hopkins AS protocol criteria and time from diagnostic to repeat biopsy |
| Zhang et al (23) | High risk: Baseline PSA, time Low risk: Baseline PSA, age, GS, time Patients at high risk for progression had much shorter PSADT on average than patients at low risk. |
Average predicted evolution of serial PSA measurements over time estimated from a general linear mixed model of the natural log of PSA, by risk group, with high risk defined as an increase in Gleason grade to at least 7 (4+3) on repeat biopsy and low risk if not. | General linear mixed model | ||
| Berg et al (24) | Percentage of positive biopsies (PPB), ERG positivity (outcome 2) ERG positivity (outcome 4) |
Clinical T stage, diagnostic GS, age, PSA density, maximum tumour involvement (outcome 2) Clinical T stage, diagnostic GS, age, percentage of positive biopsies (PPB), PSA density, maximum tumour involvement (outcome 4) |
|
Multivariate | |
| Bul et al (25) | Model 1: PSA density and number of initial positive cores (two vs one). Model 2: PSA density and number of initial positive cores (two vs one), PSADT <3 yr | Age, PSA, clinical stage, and total number of biopsy cores | Reclassification at repeat biopsy (>2 positive cores or Gleason >6). | Multivariate | Models with (1) baseline characteristic s and (2) also with PSADT at repeat biopsy |
| Cary et al (26) | Negative confirmatory biopsy and lower PSA density predicted decreased risk of progression at 3 and 4 years. At 4 years, having negative confirmatory and year 3 biopsy | Age, clinical stage, percentage of diagnostic positive biopsy cores (3 & 4 years) Age, clinical tumor stage, percentage of diagnostic positive biopsy cores (4 yr) |
Upgrading to GS ≥4+3, >33% positive cores, and/or>50% of a single core at 3 year and 4 year timepoints | Multivariate | |
| Eggener et al (27) | Cancer on 2nd biopsy and higher # of cancerous cores on the 2 biopsies combined | Age, PSA, clinical stage, prostate volume, total number of biopsy cores sampled | Remaining on active surveillance | Univariate | |
| Hirama et al (28) |
|
Age, percentage of positive cores, maximum cancer involvement and %free PSA (base model). Prostate volume in model adjusted for %p2PSA and phi. |
Pathological reclassification (GS ≥7, >2 positive biopsy cores or more than 50 % cancer involvement of any biopsy core) upon the 1 year prostate biopsy |
Multivariate | |
| Klotz et al (29) | Decrease PSA free-to-total ratio correlated with a rapid PSADT. Short PSADT → more aggressive phenotype at radical prostatectomy (A short PSADT was also a criterion for active treatment) |
Grade, stage, baseline PSA and patient age (outcome 1) |
|
Univariate | |
| Makarov et al (30) | Serum marker: [−2]proPSA/% fPSA Tissue markers: [−5/−7]proPSA % area and [−5/−7]proPSA stain intensity in benign adjacent areas |
Age; tPSA; fPSA; %fPSA; [−2]proPSA (pg/mL); PSA density; prostate volume; number of positive cores; maximum % core involvement with cancer; cancer [−5/−7]proPSA % area, and stain intensity in tumor areas | Unfavorable biopsy conversion on annual surveillance biopsy (GS ≥7, ≥3 cores positive for cancer, >50% of any core involved with cancer) |
Univariate | |
| Soloway et al (31) | PSADT, clinical stage | Age, PSA level and Gleason score at diagnosis | “Progression to treatment” = treatment received yes/no (based on PSADT, GS ≥7, increased tumor volume, stage progression or patient preference) | Multivariate | |
| Venkitaraman et al (32) | PSA density and maximum tumor involvement of any core | PSA velocity (p=0.069), age, clinical T stage, GS score, initial PSA | Histological disease progression on repeat biopsy (defined as primary GS ≥4, >50% positive cores or a GS increase from 6 or less to 7 or greater) |
Multivariate | |
| Cornu et al (33) | PSA density, PCA3, TMPRSS2:ERG | Genotypes for rsl447295 and rs6983267 (both on 8q24), testosterone, age, positive family history | Gleason 4 | Multivariate | Model including both AS and men with elevated PSA |
| Isharwal et al (34) | Serum markers: −2proPSA, Prostate Health Index phi. Tissue markers: DNA content in benign adjacent and cancer tissue areas | Age, PSA, free PSA, %free PSA, PSAD, # cores with cancer, max percent core involved with cancer | Unfavourable biopsy conversion (GS≥7, Gleason pattern 4/5, ≥3 cores positive for cancer, >50% of any core involved with cancer) |
Multivariate | |
| van den Bergh (35) | # positive cores at initial biopsy | Age, clinical stage, PSA, PSADT, prostate volume, time to rebiopsy, # biopsy cores taken at diagnosis or rebiopsy, difference in # of biopsy cores, ratio between initial and repeat # of cores. No baseline factor associated with adverse pathology at delayed prostatectomy | Unfavorable repeat biopsy findings, delayed prostatectomy pathology | Univariate | |
| San Francisco et al (36) | Analysis 1: PSA density >0.08 ng/ml/cc, combination of PSAD and family history of PCa as risk score. Analysis 2: PSAV: PSA density, family history and risk score with all 3. Analysis 3: validated the PSAD cutoff of + 0.08 ng/ml/cc at first rebiopsy. |
Progression (defined as ≥3 positive cores, increased grade (Gleason ≥7) and/or >50% of any core involved with cancer) |
Multivariate | Analysis 1: clinical and pathologic variables at diagnosis biopsy Analysis 2: Considering changes between diagnosis biopsy and 1st rebiopsy. Analysis 3: For men with ≥2 repeat biopsies |
|
| Valeri et al (37) | Men in 40s with family history less likely to have insignificant prostate cancer vs general population | Insigificant PCa | Descriptive | ||
| Burton et al (38) | Smoking status (outcome 1). exercise, height (outcome 1,2) (N.B.: correlation PSA baseline and PSA growth) GS>7 (outcome 1,2) compared to <6 (outcome 1 and 2) |
Weight; BMI; waist circumference; hip circumference; inside leg length; alcohol; family history; occupational class | 1) PSA at age 50 and 2) PSA growth (yearly increase in log PSA) | Multivariate | Adjusted for age and GS (not in analysis that includes GS) |
| Goh et al (39) | Family history (FH) of PCa and single nucleotide polymorphisms (SNPs) not associated with adverse histology or time to treatment | +Recommendation for treatment due to PSAV >l +ng/ml/year or adverse histology (>50% of cores involved/any increase in +primary GS/increase in composite GS of +>=8) |
Univariate | ||
| Mukerji et al (40) | Number of positive cores, presence of high grade PIN, and Gleason score 4 | Failure of AS, switching to active treatment | Univariate | ||
| Van den Bergh et al (41) | Gleason 7 who met all other AS criteria better treatment free survival than those who did not. Gleason score 3+4 better than 4+3 | Treatment-free survival | Univariate | ||
| Venkitarama n et al (42) | PSA density | Clinical T stage, GS, initial PSA level, maximum percentage involvement of any core | PSA velocity before treatment (as an important predictor of prostate cancer mortality) |
Multivariate | |
| Jhavar et al (43) | Ki-67 (max Ki-67 labelling index). Gleason score. PSA density | Initial PSA | Time to radical treatment (recommended for PSAV >1 ng/ml/year, GS ≥4+3, or >50% cores involved) |
Multivariate | |
| Van As et al (44) | Free/total PSA ratio, clinical stage T2a (vs Tl) | Initial PSA level, Gleason score, PSA density, prostate volume, % positive cores, number of positive cores, and maximum involvement of any core | Time to radical treatment based on PSA velocity > 1 ng/ml/yr or histological progression (GS ≥4+3, or > 50% positive biopsy cores) | Multivariate | |
| Iremashvili et al (45) | Significant predictors combined into a nomogram: Number of positive cores on diagnostic and first surveillance biopsy, race, PSAD | Mean and max percent core involvement | Histologic progression during successive surveillance biopsies | Multivariate | |
| Iremashvili et al (46) | Number of positive cores (on diagnostic or 1st surveillance biopsy) and mean %core involvement (diagnostic biopsy). HGPIN significant for combination of the 2 biopsies | Number of cores taken | Biopsy progression (presence of Gleason 4/5 cancer, > two positive cores or >20% involvement of any core) | +Multivariate | Using data from diagnostic biopsy, first surveillance biopsy or both |
| Ng et al (47) | PSAD, PSAV, PSADT, max percentage of any core | Adverse histology on repeat biopsy defined as any of: primary Gleason grade ≥4,>50% cores positive, or initial Gleason score 3+3 upgraded to ≥3+4 | Multivariate | Adjusted for age, T stage, Gleason score, percentage of cores positive, baseline PSA level, maximum percentage of any core involved, prostate volume, PSA density, and free-total PSA ratio). | |
| Adamy et al (48) | Positive confirmatory biopsy (modified criteria without PSA) |
|
Progression defined as no longer meeting eligibility criteria
|
Multivariate | Adjusted for age, PSA, PSA density, prostate volume, number of positive cores, result of confirmatory biopsy (+/−) and initial biopsy extent (< 10 versus ≥ 10 cores) |
| Yee et al (49) | Initial biopsy extent (< 10 cores vs >10 cores) | Initial biopsy extent in relation to no longer meeting inclusion criteria on rebiopsy | Univariate | ||
| Fromont et al (50) | 1/3 no longer eligible on confirmatory bioposy | Concordance initial biopsy and confirmation biopsy (≥16 cores at ≤3 months after initiation to determine if patients still met the eligibility criteria) | Descriptive | ||
| Soloway et al (51) | Any tumor in the lst re-Bx | PSA doubling time, clinical stage | Treatment free survival (treatment indications: GS>3, increased tumor volume or # positive cores on rebiopsy, or preference) |
Univariate | |
| Umbehr et al (52) | PSA concentration at entry (but nonlinear pattern-unable to identify specific cutpoint) | Biopsy reclassification (GS ≥7, any Gleason pattern 4 or 5, ≥3 positive cores, or ≥50% cancer involvement/biopsy core) |
Multivariate | Adjusting for age, prostate volume, mean %f PSA and maximum percentage biopsy core involvement | |
| Barayan et al (53)’ | PSA density >0.15 | Disease progression, defined as the presence of >1 of the following criteria on repeat biopsies: >50% of cancer in any involved core, GS >4+3, and >3 positive biopsy cores | Multivariate | Adjusted for patients’ age, number of positive cores, maximum cancer percentage in any core, total number of cores and GS | |
| Welty et al (54) | PSA density, total number of biopsies, later year of diagnosis | Biopsy progression (upgrade GS ≥7 or increase in volume >33% cores) | Multivariate | ||
| Tosoian et al (55) | Baseline and longitudinal measures of %fPSA, %[−2]proPSA; [−2]proPSA/%fPSA, Prostate health index phi (both outcomes) | Baseline and longitudinal total PSA | 1) Risk of biopsy reclassification (Gleason score ≥7, >2 positive biopsy cores or>50% involvement of any core with cancer); 2) Upgrading only (GS ≥7) | Multivariate | Adjusted for age, date of diagnosis and PSA density |
| Komisarenk o et al (56) | Volume progression (>4 cores or>50% core involved) | Relation of increased volume of Gleason 6 PCa (4 cores or 50% of core involved) with the risk of later grade progression (>= 7) |
Univariate | ||
| Loblaw et al (57) | 13–86% of patients would have trigger for intervention based on PSA kinetics | Proportion of patients who had a trigger for treatment based on the various prostate specific antigen triggers: PSADT, PSAV, PSA threshold | Descriptive | ||
| Kakehi et al (58) | Only descriptives pathological findings, no formal analysis | No association between PSADT and aggressive findings on rebiopsy |
|
Descriptive | |
| Ross et al (59) | PSAV (calculated as PSA multiplied by the slope of a linear regression of log(PSA) | PSADT | Biopsy progression (Gleason score ≥7, or >2 positive cores, or >50% core involvement) | Univariate | |
| Khatami et al (60) | PSADT (Caveat: PSA predicting PSA & PSADT not known at time zero) |
PSA, ratio of free PSA and amount of cancer in biopsy | PSA relapse | Multivariate | |
| Iremashvili et al (61) | PSAV in men with at least 3 PSA’s over 18 months, and those with 4th and later biopsy | PSADT (calculated using the log-slope method) |
Biopsy progression (Gleason 4/5 cancer, more than two positive cores, or more than 20% involvement of any core) |
Univariate | |
| Krakowsky et al (62) | 2 men who died on AS initially met Epstein criteria. All 5 patients had a PSADT ≤1.6 years triggering radical therapy | Description of 5 PCa deaths in Toronto series | Descriptive | ||
| Pujara et al (63) | Median PSA doubling time higher in AS patients than in the control group Median PSA velocity lower in AS patients than in the control group |
AS patients compared to control group with at least 2 negative biopsies | Descriptive | ||
| Tosoian et al (66) | PCA3 | Progression on surveillance biopsy (defined as Gleason pattern 4 or 5, >2 positive biopsy cores or>50% involvement of any core with cancer) |
Multivariate | After adjustment for age at PCA3 measurement and date of diagnosis) | |
| Venkitamaran et al (67) | Urinary levels of either daidzein, genistein. enterolactone or equol (outcome l and 2) | Disease progression defined as: 1) adverse histology on repeat biopsy (primary Gleason grade >or= 4, or >50% positive cores) or 2) radical treatment for PSA velocity >1 ng/mL/year | Multivariate | ||
| Tausch et al (69) | NCCN risk group at entry (very low versus low risk) |
Multivariable | |||
| Van den Bergh (70) | PSADT using 1st 3 PSA’s indicative of PSADT using 5 measures (15% misclassification) | Correlation between PSADT using different number of PSA measurements | Correlations |
*
GS (Gleason score), PSA (prostate specific antigen), PSADT (prostate specific antigen doubling time), PSAV (prostate specific antigen velocity), PSAD (prostate specific antigen density), DRE (digital rectal exam)