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based on follow-up with TRUS-Bx only (1). This long-term disease-specific survival is not expected to be worse with an MRI ± TBx strategy as the previously reported sensitivity of MRI ± TBx for high-grade PCa (71 - 89%) is at least equal as compared to the sensitivity of TRUS-Bx (63 - 76%) (6, 9, 14-16).

Although MRI seems to be helpful in patient selection for repeat biopsy, solely imple- menting an MRI ± TBx follow-up strategy does not seem to be sufficient as high-grade PCa would be missed and two thirds of men would still need to be biopsied. Recently, two robust models for the prediction of GS upgrading at repeat TRUS-Bx were presented based on large datasets of men on active surveillance who did not receive MRI (30, 31). A multivariable risk-based approach in the presence of MRI seems the way forward to reduce unnecessary biopsies (18). Walton Diaz et al. presented an acceptably discriminating pre- diction model (AUC 0.71) incorporating MRI parameters for the prediction of high-grade PCa at confirmatory MRI-TBx + TRUS-Bx (32). In a validation cohort of 85 men this model would have saved 27 – 68% of biopsies, with a corresponding NPV of 91 – 81% for high- grade PCa (15). Satasivam et al. presented a prediction model incorporating MRI and clini- cal variables with good discriminative ability (AUC 0.85) for GS upgrading at confirmatory TRUS-Bx (11). Validation of this model is needed to prove its ability to reduce unnecessary biopsies. Interestingly, the strongest predictor for GS upgrading in this model is the PSA density. PSA density was already known to be predictive for GS upgrading at repeat TRUS- Bx in the absence of MRI (33, 34). More recently, it was shown that PSA density remains a strong predictor for GS upgrading when combined with the PI-RADS score in men on active surveillance who received MRI (22-24). After stratification for the overall PI-RADS score and PSA density using the previously described cut-off of 0.15 ng/ml2 _{(24-27) no GS} upgrading was found based on MRI-TBx in men with a PI-RADS score 3 and PSA density <0.15 ng/ml2_{, nor at additional TRUS-Bx in men with PI-RADS 1 – 3 and PSA density <0.15} ng/ml2_{. In line with our findings Washino et al. showed no GS upgrading based on MRI-TBx} + TRUS-Bx in biopsy naïve men with PIRADS 1 – 3 and PSA-density <0.15 ng/ml2 _{(27). This} suggests that men on active surveillance with PI-RADS 1 – 3 and PSA-density <0.15 ng/ ml2 _{may not benefit from a follow-up biopsy. Obviously, the percentage of avoided biopsy} procedures by omitting repeat biopsy in these men depends on the characteristics of the active surveillance cohort. In our cohort 49% (37/76) of men with PI-RADS 1 – 2 and 44% (15/34) of men with PI-RADS 3 had a PSA density <0.15 ng/ml2_{. Hopefully, a robust predic-} tion model incorporating PI-RADS and PSA density will be available in the near future to enable risk-based patient selection for repeat biopsy rather than simply stratifying patients based on these clinical parameters. Such a prediction model could be built from the large dataset of the Movember GAP3 project (35).

While the risk of developing metastasis and PCa death is significantly higher in men on active surveillance with GS 3+4 as compared to GS 3+3 PCa, men with GS 4+3 PCa have

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the highest risk of clinical progression with longer follow-up (36). Therefore, active surveil- lance in men with GS ≥3+4 PCa cannot be considered standard of care yet (37). As in most other institutions, patients in our institution with GS ≥3+4 PCa are generally not enrolled in an active surveillance program and the finding of upgrading to any GS ≥3+4 PCa during follow-up usually means switch to active treatment with curative intent. Nevertheless, the high GS upgrading and/or reclassification rates of men on active surveillance trigger the need to extend the active surveillance inclusion and follow-up criteria and (limited) GS 3+4 disease is nowadays considered suitable for active surveillance by some. In the near future, selection of men with GS 3+4 PCa for active surveillance could be based on the prognostic predictors of clinical disease progression cribriform and/or intraductal carcinoma growth and the percentage of grade 4 disease (20, 38, 39).

A major strength of the present study is that is represents the true clinical setting. Men in our prospective cohort were referred from 8 different peripheral institutions and did not all fulfill the strict inclusion criteria of the PRIAS study (www.prias-project.org). Our study is mainly limited by the fact that only a subgroup of men at surveillance biopsy received an additional TRUS-Bx next to the MRI ± TBx (17/74, 23%), making it hard to draw conclusions from the comparison between both biopsy strategies. However, our findings from this comparison were in line with several previous studies. Furthermore, all men who received a first MRI were included in our study, regardless of time since diagnosis of low-grade PCa. The percentages of GS upgrading based on MRI ± TBx could be different in men who have received a previous MRI ± TBx (22, 23). Finally, multi-parametric MRI used in the present study, consisting of T2WI, DWI and DCE imaging is not yet widely available. Bi-parametric MRI (T2WI + DWI) is more feasible and less expensive and could therefore help to widely implement MRI in men on active surveillance. Within PI-RADS version 2 the DCE images are used to differentiate between PI-RADS 3 or 4 lesions in the peripheral zone (19). Only 4 out of 71 (6%) men in the present study with an overall PI-RADS score 4 would have been classified as having a suspicion score of 3 based on bi-parametric MRI, 3 of whom had high-grade PCa in MRI-TBx. However, as all 4 men had a PSA density ≥0.15 ng/ml2 _the conclusion of the present study (i.e. MRI-TBx may be avoided in men with PI-RADS 3 and PSA density <0.15 ng/ml2_{) remains unchanged with the use of bi-parametric MRI.}

In conclusion, at least one out of five men with GS 3+3 PCa at diagnostic TRUS-Bx in our present cohort had GS upgrading based on first MRI ± TBx at baseline, confirmatory or surveillance biopsy. Men with PI-RADS 1 - 3 and a PSA density <0.15 ng/ml2 _{did not} show GS upgrading at MRI ± TBx or TRUS-Bx at each time point of surveillance. Therefore, risk-stratification based on PI-RADS and PSA density may reduce unnecessary follow-up biopsy procedures in men on active surveillance.

Conflict of Interest

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