Magnetic Resonance Imaging-guided Active Surveillance of Prostate Cancer: Time to Say Goodbye to Protocol-based Biopsies.

Traditional protocols for active surveillance (AS) are commonly based on digital rectal examination, prostate-specific antigen (PSA), and standard transrectal biopsy, meaning that initial classification errors and inaccurate lesion monitoring can occur. Protocol-based biopsies are performed to assess changes in cancer grade and extent at prespecified intervals, but this approach represents a barrier to AS adherence and tolerability. There is evidence to support the use of magnetic resonance imaging (MRI) during AS, as this technique (associated with favourable PSA kinetics) offers an opportunity to follow patients on AS without the need for routine, protocol-based biopsies in the absence of signs of radiological progression provided that image quality, interpretation, and reporting of serial imaging are of the highest standards. PATIENT
SUMMARY: In this report we looked at the role of magnetic resonance imaging (MRI) scans in avoiding unnecessary prostate biopsies for patients being monitored for low- or intermediate-risk prostate cancer. We conclude that patients on active surveillance can be monitored with MRI scans over time and that biopsies could be used only when there are changes on MRI or a rising prostate-specific antigen (PSA) not explained by an increase in prostate size.

Many groups worldwide perform protocol-based standard transrectal prostate biopsies to assess changes in cancer grade and extent at prespecified intervals, but this approach represents a barrier to the adherence to and tolerability of active surveillance (AS) [1]. Protocol-based biopsies are performed at different time points throughout AS and differ from confirmatory biopsies, which are usually performed within 12 mo from diagnosis and inclusion in AS programmes.

Although the compliance with prostate-specific antigen (PSA) testing is high, data from the PRIAS study [2] and the USA [3] show that the compliance with protocol-based biopsies is lower, as patients consider prostate biopsy the least pleasant aspect of AS because of the risks associated with the procedure.

The widespread adoption of magnetic resonance imaging (MRI) during AS may help to reduce the frequency of surveillance biopsies and improve the sensitivity for detecting significant cancer. Although the European Association of Urology guidelines fully recommend the use of MRI for inclusion and before confirmatory biopsies in AS, its use for surveillance biopsies is still a matter of debate [4]. By contrast, the UK National Institute of Health and Care Excellence guidelines support the use of MRI during AS in both scenarios [5].

The multicentre randomised ASIST trial initially showed no difference in upgrading rate between standard rebiopsy and MRI with two cores targeted to a lesion during AS [6]. Conversely, at 2-yr follow-up, baseline MRI before confirmatory biopsy resulted in 50% fewer failures of AS and less progression to higher-grade disease, confirming the value of MRI in the AS setting [7]. However, it should also be acknowledged that the compliance for continued AS beyond the 2-yr time point in the PRIAS study was not better in the group of patients undergoing MRI-directed biopsy [8].

The MRIAS trial [9] was a single-arm study that enrolled men suitable for AS following baseline saturation + MRI-targeted biopsy who were followed for 3 yr with annual surveillance MRI, 6-mo PSA, and exit biopsy at 3 yr. Per-protocol biopsies were performed for predefined triggers, such as a new or persistent lesion or rising PSA kinetics. The majority of patients (71%) avoided biopsy before 3 yr, the progression rate was relatively low (21%), and the incidence of high-risk cancer missed by MRI was 1%.

One of the key aspects of prostate MRI during AS is the concept of tumour visibility [10], [11], [12]. Medium-term outcomes from our imaging-based AS cohort at University College London Hospital (which includes patients with up to Gleason 3 + 4 disease at entry biopsy and baseline plus serial MRI) [13] have shown a significant difference (in terms of treatment, transition to watchful waiting, Gleason ≥ 4 + 3 on follow-up biopsy or death) between MRI-visible and -nonvisible lesions for both low- and intermediate-risk disease (Fig. 1). We observed that most patients, particularly those with Gleason 3 + 3 cancer and nonvisible disease at baseline, remained on imaging-based surveillance at 5 yr and that the treatment rate was similar to that reported from standard AS cohorts with comparable follow-up but predefined follow-up biopsies [14].

Fig. 1

Kaplan-Meier event-free survival curves with time to treatment, transition to watchful waiting, and death as events, stratified by baseline Gleason grade and MRI visibility in our cohort at University College London Hospital. There was a significant difference in event-free survival between the groups (log-rank test, p < 0.001) and although men with Gleason 3 + 4 cancer had a different trajectory to those with Gleason 3 + 3, MRI-visible disease at baseline was associated with shorter event-free survival in both Gleason groups. MRI = magnetic resonance imaging; NV = nonvisible; V = visible. Reprinted from Stavrinides V, Giganti F, Trock B, et al. Five-year outcomes of magnetic resonance imaging-based active surveillance for prostate cancer: a large cohort study. Eur Urol 2020;78:443–51.

In addition, we observed 8/672 (1.19%) metastatic events in our cohort, and metastasis was more common in the Gleason 3 + 4 MRI-visible group. This compares well to the Sunnybrook cohort [15], in which 18/980 (1.8%) patients who had follow-up biopsies developed bone metastases over median follow-up of 6.3 yr.

Given the growing adoption of serial prostate MRI during AS, it is also worth mentioning the Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) recommendations that were published to facilitate robust data collection [16]. Use of the PRECISE scoring system when reporting MRI at baseline and follow-up during AS allows assessment of the natural history of prostate cancer on MRI, and promising results have been published by different groups [17]. The data from these studies show that patients with stable MRI findings (ie, PRECISE 1–3) and PSA kinetics should avoid routine rebiopsy. However, it should be acknowledged that a recent systematic review by Rajwa and colleagues [18] showed that serial prostate MRI (using either the PRECISE or other MRI criteria) alone for patients on AS is still not accurate enough to reliably exclude prostate cancer progression, and therefore other clinical factors and blood markers (eg, PSA density) along with serial MRI are required to safely tailor the intensity of follow-up biopsies.

Furthermore, use of MRI with targeted biopsies for patients already on AS increases the cumulative probability of AS disqualification due to Gleason grade group reclassification (risk inflation), and appropriate risk thresholds have yet to be defined when MRI and MRI-targeted biopsies are used [10].

MRI, like any other tests, is not perfect and can occasionally miss high-grade disease, but as we are shifting towards an era of personalised medicine, it is reasonable to conclude that:

We should avoid routine rebiopsy in the presence of stable findings on serial MRI (especially when there is no visible lesion) associated with stable PSA kinetics (Fig. 2).

Fig. 2

Magnetic resonance images of a 73-yr-old patient presenting with prostate-specific antigen (PSA) of 5.6 ng/ml. Baseline images show a Prostate Imaging-Reporting and Data System 4/5 lesion (arrows) in the left peripheral zone at midgland on (A) T2-weighted imaging, (B) on the apparent diffusion coefficient map from diffusion-weighted imaging and (C) on dynamic contrast-enhanced sequences. Targeted biopsy revealed Gleason 3 + 3 disease in two out of four cores involving 40% of the cores. The patient opted for active surveillance. Subsequent prostate magnetic resonance images at (D–F) 1 yr and (G–I) 5 yr show the stability of the lesion on all sequences along with relatively stable PSA findings (6.7 and 6.5 ng/ml, respectively). The patient is still on active surveillance and was biopsied only after baseline imaging.

MRI will help us to define each patient’s individualised risk and document the decision to avoid or proceed with biopsy.

In conclusion, our view is that MRI (associated with favourable PSA kinetics) is the key player for avoiding unnecessary follow-up biopsies and excluding disease progression during AS provided that image quality, interpretation, and reporting of serial imaging are of the highest standards.

: Francesco Giganti had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Giganti, Stavrinides, Moore.

Acquisition of data: Giganti, Stavrinides.

Analysis and interpretation of data: Giganti, Stavrinides.

Drafting of the manuscript: Giganti, Stavrinides, Moore.

Critical revision of the manuscript for important intellectual content: Moore.

Statistical analysis: Giganti, Stavrinides.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Moore.

Other: None.

Francesco Giganti certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Francesco Giganti is the recipient of a 2020 Young Investigator Award (no. 20YOUN15) funded by the Prostate Cancer Foundation. Vasilis Stavrinides is supported by an MRC Clinical Research Training Fellowship (MR/S005897/1) and acknowledges previous support from EACR (EACR Travel Fellowship) and UCL (Bogue Fellowship). Caroline M. Moore receives grant funding from the Medical Research Council, Movember, Prostate Cancer UK, the National Institute for Health Research, Cancer Research UK, and the EAU Research Foundation, trial funding Spectracure, proctor fees from Sonablate, and speaker bureau fees from Astellas and Janssen.

None.