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A multivariable approach using magnetic resonance imaging to avoid a protocol-based prostate biopsy in men on active surveillance for prostate cancer— data from the international multicenter prospective PRIAS study

  • Henk Benjamin Luiting,
  • Sebastiaan Remmers,
  • Egbert R. Boevé,
  • Riccardo Valdagni,
  • Peter K. Chiu,
  • Axel Semjonow,
  • Viktor Berge,
  • Karl H. Tully,
  • Antti S. Rannikko,
  • Frédéric Staerman,
  • Monique J. Roobol

Publication: European Urology Oncology, April 2022

Background

There is ongoing discussion whether a multivariable approach including magnetic resonance imaging (MRI) can safely prevent unnecessary protocol-advised repeat biopsy during active surveillance (AS).

Objective

To determine predictors for grade group (GG) reclassification in patients undergoing an MRI-informed prostate biopsy (MRI-Bx) during AS and to evaluate whether a confirmatory biopsy can be omitted in patients diagnosed with upfront MRI.

Design, setting, and participants

The Prostate cancer Research International: Active Surveillance (PRIAS) study is a multicenter prospective study of patients on AS (www.prias-project.org). We selected all patients undergoing MRI-Bx (targeted ± systematic biopsy) during AS.

Outcome measurements and statistical analysis

A time-dependent Cox regression analysis was used to determine the predictors of GG progression/reclassification in patients undergoing MRI-Bx. A sensitivity analysis and a multivariable logistic regression analysis were also performed.

Results and limitations

A total of 1185 patients underwent 1488 MRI-Bx sessions. The time-dependent Cox regression analysis showed that age (per 10 yr, hazard ratio [HR] 0.84 [95% confidence interval {CI} 0.71–0.99]), MRI outcome (Prostate Imaging Reporting and Data System [PIRADS] 3 vs negative HR 2.46 [95% CI 1.56–3.88], PIRADS 4 vs negative HR 3.39 [95% CI 2.28–5.05], and PIRADS 5 vs negative HR 4.95 [95% CI 3.25–7.56]), prostate-specific antigen (PSA) density (per 0.1 ng/ml cm3, HR 1.20 [95% CI 1.12–1.30]), and percentage positive cores on the last systematic biopsy (per 10%, HR 1.16 [95% CI 1.10–1.23]) were significant predictors of GG reclassification. Of the patients with negative MRI and a PSA density of <0.15 ng/ml cm3 (n = 315), 3% were reclassified to GG ≥2 and 0.6% to GG ≥3. At the confirmatory biopsy, reclassification to GG ≥2 and ≥3 was observed in 23% and 7% of the patients diagnosed without upfront MRI and in 19% and 6% of the patients diagnosed with upfront MRI, respectively. The multivariable analysis showed no significant difference in upgrading at the confirmatory biopsy between patients diagnosed with or without upfront MRI.

Conclusions

Age, MRI outcome, PSA density, and percentage positive cores are significant predictors of reclassification at an MRI-informed biopsy. Patients with negative MRI and a PSA density of <0.15 ng/ml cm3 can safely omit a protocol-based prostate biopsy, whereas in other patients, a multivariable approach is advised. Being diagnosed with upfront MRI appears not to significantly affect reclassification risk; hence, a confirmatory MRI-Bx cannot totally be omitted yet.

Commentary by Dr. Roderick van den Bergh

Active surveillance for low and selected intermediate prostate cancer cases is an important part of prostate cancer management. It helps avoid overtreatment of cancers that would not have caused any symptoms during one’s lifetime even when remaining untreated.[1] The selection and follow-up strategy aims to balance a correct estimation of the true disease present in the prostate, with the burden of initial and repeat diagnostics for a patient.

Repeat biopsy has been a fixed and important tool used during follow-up in almost all active surveillance protocols.[2] In a confirmatory setting, repeat biopsy may identify initial undersampling. In a follow-up setting, it may identify true biological tumour progression. The outcomes of biopsy are poorly associated with PSA kinetics. Although potentially providing the strongest predictors of outcomes during active surveillance, biopsy also has the highest burden for a patient, and healthcare costs.

MRI has provided an important tool to visualise malignant lesions in the prostate. It has the potential to improve the indication for prostate biopsy, increases the detection of significant prostate cancer through targeted biopsies, and has reduced the risk of misclassification in patients selected for active surveillance.[3] Finding ways to exploit the value MRI by replacing standard repeat biopsy, has been an ongoing journey.

Luiting et al analysed predictors for ISUP grade group progression at repeat biopsy, in men who underwent MRI and repeat biopsy during follow-up.[4] A total of 1488 MRI scans performed in 1185 men were analysed. Men with a normal MRI and low PSA density had a very low 0,6% and 3% risk of upgrading to GG³3 and GG³2, respectively. The suggestion is made to omit standard repeat biopsy in these men. Reclassification was comparable between men who had and who did not have upfront MRI (19-23%). The risk of histological reclassification was associated with age (HR 0,84 per decade), PIRADS 3-4-5 lesions on MRI (HR 2,46 – 3,39 – 4,95), PSA density (HR 1,2 per 0.1 ng/ml/ml), and percentage of positive systematic biopsy cores (HR 1,16 per 10%). The analysis used data from the PRIAS study, which is the largest prospective trial on active surveillance for prostate cancer, first presented in 2007.[5] The inclusion and follow-up criteria have been constantly adapted based on study findings and the availability of new diagnostics, such as MRI. For example in 2016, the protocol advised to drop PSA kinetics and number of positive biopsy cores as the sole indication for discontinuation of active surveillance.[6]

The article provides very important guidance in how an active surveillance follow-up protocol may be individualised, reducing the burden of standard repeat biopsies. The combination of MRI PIRADS score and PSA-density again shows to provide a strong estimation of the risk of harbouring significant prostate cancer.

Besides issues on the possibility of selection bias for MRI and biopsy, on quality issues within the PRIAS study, and on the absence of information on biopsy strategy, some other considerations could put these findings into further use and perspective.

First, it could be disputed whether upgrading to GG2 should be considered as a relevant adverse outcome for men on active surveillance, since these men would also be eligible for initiating active surveillance, if no other risk factors are present.[1] The association of GG³3 with adverse outcomes after radical prostatectomy has however been clearly established.[7] Also, the accepted risk of missing reclassification to GG³3 may be increased. If instead of the 0,6% in men with normal MRI and low density, a higher rate is accepted, the number of biopsies avoided would increase dramatically.

Second, although the findings are very important, it should be realised that using MRI follow-up findings to replace standard repeat biopsy makes correct review of MRI even more important. If high quality MRI review and insight in centre specific outcomes cannot be guaranteed, the indication for systematic biopsy remains higher, as it could be seen as a method to compensate for imperfect MRI review.

Third, performing MRI at just a year after initiation of active surveillance (median 13 months in the study by Luiting), may result in limited changes compared to baseline and therefore not a cost-effective strategy. Optimisation of the timing of MRI and applying PRECISE scores could improve the predictive power of repeating MRI during active surveillance.[8]

Future research should focus on the appropriate degree of activity within an active surveillance protocol for the individual patient. It should be remembered that outcomes of active surveillance in patients who were selected using classical selection criteria when MRI was not yet available, who were followed-up with PSA and standard repeat biopsy, have been found to be very favourable.[9] New additions to the inclusion and surveillance criteria should therefore not aim to improve oncological outcomes, but to expand eligibility for expectant management and to reduce the burden of the surveillance strategy, accepting a small risk of initially undersampling the disease, benefitting many men in whom the burden of a prostate cancer diagnosis is massively reduced.  

References

  1. Mottet et al. Eur Urol 2021
  2. Dall’Era et al. Eur Urol 2012
  3. Kasivisvanathan et al. NEJM 2018
  4. Luiting et al. Eur Urol 2022
  5. van den Bergh. Eur Urol 2007
  6. Bokhorst et al. Eur Urol 2016
  7. Gandaglia et al. Urol Oncol 2015
  8. Giganti et al. Eur Radiol 2020
  9. Klotz et al. J Clin Oncol 2015