Episode 8

In episode five of the new X-ZELL blog, our editorial team first shed a light on the growing controversy around the utility of multi-parametric magnetic resonance imaging (mpMRI) as a triage test to avoid unnecessary biopsy and improve diagnostic accuracy.

Ranked one of our most-read articles to date, it has set off a vivid debate among the X-ZELL community, with one camp defending MRI-based screening as the only option with a proven improvement in patient outcomes, and one questioning the logistical feasibility of an ‘mpMRI first’ approach – especially with view to equipment accessibility inter-operator variability.

One of the most frequently cited pieces of research has been the multicentre, randomized PRECISION trial carried out by a British study group led by Dr Veeru Kasivisvanathan*.

Published in May 2018, it demonstrated that clinically significant prostate cancer (csPCa) is more likely to be detected in men undergoing mpMRI-targeted biopsy than standard biopsy – seemingly confirming the positive impact of mpMRI on pre-biopsy screening.

A recently published review of the PRECISION study by Michael Gorin and Patrick Walsh, however, is now pointing to a possible catch.

What’s the catch?

While Gorin and Walsh applaud Kasivisvanathan et al. on providing “clear evidence” that mpMRI prior to initial biopsy can indeed aid in the identification of csPCa, they are not satisfied with the way the PRECISION team brushed aside the question how to manage men with negative mpMRI results who do not undergo biopsy – after all, biopsies in the PRECISION study were only performed on mpMRI-positive lesions.

Kasivisvanathan et al. argue that periodic PSA testing would be a “routine, reasonable and safe” risk management strategy, especially after observing that less patients with negative MRI-targeted biopsy undergo further diagnostic testing than those in the standard biopsy group – indicating that multi-parametric mpMRI “must be more reassuring” to patients and clinicians than a negative result on standard TRUS-biopsy.

What’s missing here, according to Gorin and Walsh, is hard evidence: “Is it safe to assume that these patients did not harbour clinically significant disease…[or] was clinically significant disease missed in areas of their prostates that went unsampled?”

The sobering response: “Based on the findings of this study, we do not know.”

One problem solved, a new one created?

Pointing to the PROMIS study – another large, multi-centre trial carried out in 2016 – they reveal that some 24% of biopsy-naïve men with negative mpMRI were found to have clinically significant cancer after all.

Because only 1.2% of men with negative mpMRI in the PRECISION trial underwent a follow-up biopsy, it is unclear whether or not that ratio would uphold in the new cohort.

A reference study by the from University of California, however, found that 7% of patients with a positive mpMRI had csPCa detected exclusively in areas of the prostate that were non-suspicious on imaging – indicating that a negative mpMRI does not necessarily justify an ‘all clear’ ruling.

As a result, any reduction in clinically insignificant disease coming from screening with mpMRI could be outweighed by a delay or failure to diagnose clinically significant cancers – meaning the ultimate verdict on mpMRI as a standalone triage test is still out.

Interestingly, though, both Kasivisvanathan’ team as well as Gorin and Walsh have noted that circumnavigating the issue based on other pre-biopsy characteristics may be possible – even though they may not be available to us today.

One such patient characterisation tool could be X-ZELL Prostate™, a liquid biopsy slotting in neatly between PSA testing and the MRI/ biopsy stage that is capable of doubling the Positive Predictive Value (PPV) of PSA whilst maintaining the test’s high Negative Predicative Value (NPV).

By pre-qualifying equivocal PSA readings, X-ZELL Prostate™ could not only help triage the right patients to mpMRI and subsequent biopsy, but also give patients and clinicians peace of mind that a negative imaging result does in fact give the green light to proceed to active surveillance instead of biopsy.

All without the significant over-diagnosis risk associated with PSA screening, and founded on a much more reliable data set than observations into patient behaviour post-biopsy.

Because even Dr Kasivisvanathan and his team agreed that that the ideal test for prostate cancer would not only be minimally invasive and have few side effects, but also “minimize the identification of men with clinically insignificant disease”.

With an NPV of 95%, the combination of PSA and X-ZELL Prostate™ is ticking all the boxes – and when used pre-mpMRI, it might just be the missing piece we’ve been searching for all along.

*At enrolment, men with suspicion of prostate cancer who had never had a prior biopsy were randomized to undergo either a systematic TRUS-guided prostate biopsy or an mpMRI prior to prostate biopsy with targeted sampling of only suspicious lesions. Patients with a negative mpMRI did not undergo biopsy and were simply observed.