Using data from the prospective, paired-design STHLM3MRI pilot study, we report biopsy outcomes in men with significant lesions on MRI defined as any lesion scoring PI-RADS ≥ 3. We found that adding systematic biopsies to a targeted biopsy procedure increases the detection of clinically significant cancer. Furthermore, we found no statistically significant difference in the detection of clinically significant cancer when systematic biopsies were added to targeted biopsies in men with equivocal MRI lesions (PI-RADS 3); instead, there was an increased risk of overdiagnosis of insignificant cancers when systematic biopsies were added. Finally, we report that a subset of men with equivocal lesions might be identified as having a low risk of clinically significant cancer and thus be saved from a biopsy procedure based on their prostate volume, prostate-specific antigen (PSA) density or Stockholm 3 risk score.

Several other studies have compared detection in targeted and systematic biopsies, frequently also reporting on total cancer detection using the combined modality.

Rouviere et al. report on 251 men undergoing systematic and targeted biopsies using a paired design where 198 had a significant Likert-scored lesion [3]. Since 5.2% of significant cancers were missed by targeted biopsies, they suggest that systematic biopsies should not be omitted in men undergoing prostate MRI. Although not explicitly reported, one can, however, note that approximately 40% of the added effect results from systematic biopsies performed in the subset of men without MRI lesions. In the MRI-first study, combined biopsies detected more nonsignificant cancers than did targeted biopsies alone, thus increasing the risk of overdetection.

Elkhoury et al. reported a paired design in 300 men in which 248 had visible MRI lesions; cancer detection rates were approximately 60% with either systematic or fusion biopsies and 70% in total when both systematic, cognitive fusion biopsies and software fusion biopsies were performed. They report discordance of tumor locations strengthening the suggestion that the different biopsy strategies detect different tumors. Therefore, combining targeted and systematic biopsies was suggested [10]. Even though the combined strategy increased the detection of significant prostate cancer in their study, the consequences regarding overdetection are not clearly presented.

A third study by van der Leest also uses a paired design, implementing in-bore biopsies to PI-RADS ≥ 3 lesions in addition to systematic biopsies. They selectively report 7% higher detection rate of significant cancer if systematic biopsies are added to targeted in men with significant MRI lesions [2].

A review also including earlier studies indicated a nonsignificant 5 percentage point increase in significant cancer detection and a simultaneous sharp 12 percentage point increase in the detection of nonsignificant cancer; thus, a strict targeted biopsy approach was suggested [18].

Our results add to the published evidence indicating a limited 5–10 percentage points benefit in the detection of significant lesions by adding systematic biopsies to targeted lesions in men with MRI. This benefit depends on several factors, including the underlying disease prevalence and the quality of both MRI and biopsy procedures, indicating that additional studies are warranted. Furthermore, by adding systematic biopsies, a nonnegligible risk of an increase in overdiagnosis follows. We illustrate that this effect is most prominent in men with equivocal lesions where cancer detection rates are lower.

Our results support the addition of systematic biopsies to targeted biopsies in men with a higher risk of cancer findings on targeted biopsies (e.g. PI-RADS ≥ 4), giving additional staging information before treatment decisions (e.g. information on contralateral cancer) are made. Despite being out of the scope of this study, adding systematic biopsies to targeted might also limit the risk of over-assessment of disease risk associated with a targeted-only approach to prostate biopsy [21].

Our study has several strengths. First, this multicentre, prospective study used a paired design and was specifically designed to study the real-life performance of targeted biopsies. We used a structured and high-quality short radiology protocol developed for the early detection of prostate cancer and highly experienced uro-radiologists to ensure high radiological quality. However, there are also limitations. This pragmatic study performed in clinical practice included data from several clinical departments (urology/radiology/pathology/biobank/laboratory) in a complex logistic chain. MRI was executed with a bi-parametric protocol at 1.5T magnet field strength with a large proportion of PI-RADS 3 at three different sites in clinical practice with variable MRI experience between sites as described in the original study. Although the quality of the data was monitored continuously, some final data were missing. Second, the systematic biopsy were performed unblinded from the MRI results, possibly affecting the results of the systematic biopsies. Thirdly, one centre recently introduced soft-ware fusion-guided biopsies, and the learning curve for the procedure has previously been described [19]. Fourth, with the paired design of our study comes that any addition of biopsy needles in the diagnostic process (e.g. systematic biopsies) increases cancer detection. Finally, since only cancer finding, but not Gleason grading, was available in the data, conclusion from the analysis on laterality should be made with caution. The statistical significance of these findings is therefore strongly dependent on the study size, and the findings should be interpreted with caution. Finally, although it has previously been shown that TBx decreases disease misclassification [20], in the absence of prostatectomy specimens, the true disease prevalence is unknown.