Reduction of MRI-targeted biopsies in men with low-risk prostate cancer on active surveillance by stratifying to PI-RADS and PSA-density, with different thresholds for significant disease

Abstract

Background: The fear of undergrading prostate cancer (PCa) in men on active surveillance (AS) have led to strict criteria for monitoring, which have resulted in good long-term cancer-specific survival, proving the safety of this approach. Reducing undergrading, MRI-targeted biopsies are increasingly used in men with low-risk disease despite their undefined role yet. The objective of this study is to investigate the rate of upgrading using MRI-targeted biopsies in men with low-risk disease on AS, stratified on the basis of PI-RADS and PSA-density, with the aim to reduce potential unnecessary repeat biopsy procedures.

Methods: A total of 331 men were prospectively enrolled following the MRI-PRIAS protocol. MR imaging was according to Prostate Imaging Reporting and Data System (PI-RADSv2) guidelines. Suspicious MRI lesions (PI-RADS 3-5) were additionally targeted by MRI-TRUS fusion biopsies. Outcome measure was upgrading to Gleason score (GS) ≥3+4 with MRI-targeted biopsies, stratified for PI-RADS and PSA-density.

Results: In total, 25% (82/331) of men on AS showed upgrading from GS 3+3. Only 3% (11/331) was upgraded to GS ≥8. In 60% (198/331) a suspicious MRI lesion was identified, but in only 41% (82/198) of men upgrading was confirmed. PI-RADS 3, 4 and 5 categorized index lesions, showed upgrading in 30%, 34% and 66% of men, respectively. Stratification to PI-RADS 4-5, instead of PI-RADS 3-5, would have missed a small number of high volume Gleason 4 PCa in PI-RADS 3 category. However, further stratification into PI-RADS 3 lesions and PSA-density <0.15 ng/mL² could result in a safe targeted biopsy reduction of 36% in this category, without missing any upgrades.

Conclusions: Stratification with the combination of PI-RADS and PSA-density may reduce unnecessary additional MRI biopsy testing. Overall, the high rate of detected upgrading in men on AS may result in an unintended tightening of continuing in AS. Since patients, included under current AS criteria showed extremely favorable outcome, there might be no need to further restrict continuing on AS with MRI and targeted biopsies.

Keywords: MRI-guided targeted biopsy; PI-RADS; PSA density; Prostate cancer (PCa); biopsy; magnetic resonance imaging (MRI); risk stratification.

Figure 1

Suspicious prostate MRIs in men with initially low-risk disease on active surveillance, who underwent targeted biopsies. (A) Positive (PI-RADS 3–5) and negative MRIs (PI-RADS 1–2); (B) positive MRIs, divided into Gleason score; (C) positive MRIs, divided into Gleason score in direct relation to PI-RADS score; (D) positive MRIs, divided into PI-RADS score; (E) positive MRIs, divided into PI-RADS score in direct relation to Gleason score. MRI, magnetic resonance imaging; PI-RADS, MRI suspicion score.

Figure 2

PI-RADS distribution of (A) all men in active surveillance with a suspicious initial MRI, (B) men upgraded following targeted biopsies (true-positives) using outcome measure Gleason score (GS) ≥3+4, and (C) men without upgrading (true-negatives) in comparison to men with upgrading (true-positives). The right graph (C) depicts the unnecessary targeted biopsies in PI-RADS assessment category 3, 4 and 5 (dotted areas). MRI, magnetic resonance imaging; PI-RADS, MRI suspicion score.

Figure 3

Unnecessary MRIs (blue in left graphs) (left) and unnecessary targeted biopsies (blue in right graphs) for Gleason cut-off score GS ≥3+4 (upper half) and GS ≥4+3 (lower half), for detecting clinically significant prostate cancer (red) in men with initially low-risk disease, based in traditional criteria. AS, active surveillance; GS, Gleason score; MRI, magnetic resonance imaging; GS, Gleason score; PI-RADS, MRI suspicion score.

Figure 4

Number of positive MRIs with Gleason score outcome of MRI-targeted biopsies, stratified to PI-RADS and PSA-density. Blue: beneficial outcome of the test results, stratified to PI-RADS and PSA-density; light red: low detection of clinically significant prostate cancer, stratified to PI-RADS and PSA-density; red: high detection of clinically significant prostate cancer, stratified to PI-RADS and PSA-density. MRI, MRI, magnetic resonance imaging; PSA, prostate specific antigen.

Figure 5

Dot-plots (and integrated box-plots) of men included in active surveillance. The PI-RADS assessment category 3, 4, and 5 (x-axis) are plotted against the PSA-density (y-axis). The outcome measure is Gleason score (GS), which is dichotomized using cut-off score GS ≥3+4 (A), and GS ≥4+3 (B) for clinically significant prostate cancer. Zero [0] indicated a Gleason score below the cut-off (blue dots and boxplots), and a one [1] indicated a Gleason score above the cut-off score (red dots and boxplots). PI-RADS, MRI suspicion score; PSA, prostate specific antigen.

Figure 6

Active surveillance and initial MRI. Men included in active surveillance (circle 1), based on traditional criteria (PSA, clinical T-stage and Gleason score by systematic ultrasound-guided biopsies) have excellent prognosis as shown by long-term follow-up of several clinical trial (6,30,35). Nowadays, men undergo additional MRI, as suggested by recent reviews (8,36). These MRIs show in more than half at least one suspicious lesion. Subsequently, these lesions are biopsied by MRI-targeted approach (circle 2). A significant proportion shows upgrading (circle 3), of which the majority is Gleason score (GS) 3+4 (circle 4). In current clinical practice all upgraded men are advocated to cease active surveillance and change into active treatment, despite good prognosis (circle 5). This suggests ‘risk inflation’. In the hypothesized clinical practice, only men with upgrading to primary Gleason 4 pattern and higher are excluded from active surveillance (circle 6), correcting the present initiated ‘risk inflation’ by MRI. AS, active surveillance; GS, Gleason score; MRI, magnetic resonance imaging.

Figure 7

Current and future surveillance protocol. (A) Current surveillance protocol of men with low-risk prostate cancer. Within the MRI-PRIAS side study protocol an MRI and targeted biopsies (if indicated) are performed at baseline (3 months after diagnosis) and during every repeat standard TRUS-guided biopsies, scheduled at many time points after diagnosis. This study identified a 25% upgrading to Gleason 7 and higher, based on MRI and targeted biopsies. (B) Incorporating prostate MRI at primary prostate cancer diagnosis will result in better discrimination between true low-risk disease and intermediate-/high-risk disease. If TRUS-guided biopsies combined with MRI and targeted biopsies are able to minimize misclassification of prostate cancer, we may abandon the currently used confirmation biopsy testing at 1 year in active surveillance management. We may hypothesize that surveillance management of men with low-risk prostate cancer will incorporate results from MRI and targeted biopsies into multivariate risk models in nearby future. *, indicative % as a result from this study. PCa, prostate cancer; GS, Gleason score; TRUS, transrectal ultrasound; MRI, magnetic resonance imaging.