Choosing the Right Diagnostic Pathway in Biopsy-Naive Patients With Suspected Prostate Cancer (2021, JAMA invited commentary)
"In the prospective multicenter Prostate Evaluation for Clinically Important Disease: Sampling Using Image-Guidance or Not? (PRECISION) trial,1 500 biopsy-naive patients with suspected prostate cancer were randomly assigned to either classical 10- to 12-core systematic biopsy or to magnetic resonance imaging (MRI) and targeted biopsy without systematic biopsy if MRI was suggestive of cancer. The detection rate for cancers with an International Society of Urological Pathology (ISUP) grade 2 or higher was significantly higher in men assigned to MRI and targeted biopsy (38%) than in those assigned to systematic biopsy (26%; P = .005). In addition, overdiagnosis of ISUP grade 1 cancer was reduced in the MRI-targeted biopsy group (9% vs 22%, P < .001), and 28% of men in this group avoided biopsy.
In this issue of JAMA Oncology, Klotz et al2 report the results of a prospective multicenter randomized clinical trial with a similar design. One might ask whether it is worth duplicating a trial that provided such compelling evidence in favor of MRI and targeted biopsy. Nevertheless, it must not be forgotten that in science, testing the robustness of an effect and the factors influencing it is as important as demonstrating this effect in the first place. Indeed, the findings by Klotz et al do shed a slightly different light on the relative diagnostic performance of targeted biopsy and systematic biopsy. They confirm that the so-called MRI pathway, using MRI as a triage test and targeted biopsy in case of positive MRI findings, could avoid a substantial proportion (37%) of biopsy procedures and reduce the overdetection of ISUP grade 1 cancer (10% vs 22%; P < .001). As in PRECISION,1 the detection rate for ISUP grade 2 or higher cancer was also higher in the MRI and targeted biopsy group than in the systematic biopsy group. However, the difference was much lower than in the PRECISION trial (5.2 percentage points [1-sided 97.5% CI, −3.4 to infinity percentage points] vs 12 percentage points [95% CI, 4-20 percentage points]). As a result, the study by Klotz et al2 could demonstrate the noninferiority of the MRI pathway in detecting ISUP grade 2 or higher cancer, but not its superiority.
Which conclusion should be drawn from this discrepancy? It becomes clearer that the difference between targeted biopsy and systematic biopsy in detecting ISUP grade 2 or higher cancer is not as large as suggested by PRECISION.1 Indeed, the 5 percentage-point difference found by Klotz et al2 is more in line with the 2 percentage-point difference found by 2 prospective multicenter head-to-head comparisons3,4 and a recent systematic review of literature.5 These latter studies also showed that, in biopsy-naive patients, targeted biopsy and systematic biopsy did not detect the same patients. Thus, the combined pathway associating systematic biopsy and targeted biopsy can further improve the detection of ISUP grade 2 or higher cancer with a 4 to 5 percentage-point difference as compared with targeted biopsy alone.
PRECISION1 sparked hope that replacing systematic biopsy by the MRI pathway in biopsy-naive patients could altogether reduce the number of biopsy procedures, reduce the overdetection of ISUP grade 1 cancer, and improve the detection of ISUP grade 2 or higher cancer. The results of the rest of the literature suggest a more nuanced situation where one has to choose between maximizing the detection of ISUP grade 2 or higher cancer using the combined pathway and reducing the number of biopsy procedures and the overdetection of ISUP grade 1 cancer using the MRI pathway. Choosing between these 2 pathways mostly depends on the prognosis of ISUP grade 2 or higher cancers missed by targeted biopsy and diagnosed via systematic biopsy. The fact that prostate cancers visible at MRI are associated with molecular hallmarks of aggressivity6 is in favor of the MRI pathway. However, head-to-head comparisons3,7 showed that systematic biopsy performed in the same lobe as targeted biopsy had more added value than those performed in MRI negative lobes.
This suggests that systematic biopsy could detect cancers that had been seen on MRI but missed at targeted biopsy. Given the relative imprecision of magnetic resonance and ultrasound fusion systems, increasing the number of targeted cores to reach some sort of local saturation biopsy may be interesting.
In addition, the intersite analysis performed by Klotz et al2 sounds like a warning to the MRI pathway. The authors found major intersite variability in ISUP grade 2 or higher cancer detection rates yielded by targeted biopsy and systematic biopsy, with the center with the highest detection rate at targeted biopsy having the lowest detection rate at systematic biopsy and vice versa. Considering that all participating centers were experienced high-volume tertiary centers, the intersite variability is probably much higher among less experienced centers. Thus, whatever the diagnostic pathway, continuing education and quality insurance programs will become major issues in the future, not only for prostate MRI interpretation, but also for targeted biopsy, which does have a learning curve even with magnetic resonance and ultrasound fusion systems, and even for systematic biopsy.
Finally, the findings obtained by Klotz et al1 suggest another layer of complexity. At logistic regression, simple clinical variables such as prostate-specific antigen (PSA) density or digital rectal examination were significant predictors of the presence of ISUP grade 2 or higher cancer at targeted biopsy and systematic biopsy. This is in line with a large body of recent literature that showed that PSA density and MRI results are independent predictors of biopsy findings.8 Therefore, using only MRI findings to decide which patients should undergo biopsy is probably insufficient.
Do all of these elements help create a picture of what will, in the future, be the ideal diagnostic pathway for prostate cancer in biopsy-naive patients? It is unlikely that it will be a strict combined pathway in which all patients would undergo MRI and then, systematically, combined systematic biopsy and targeted biopsy. It will probably not be a strict MRI pathway either, in which MRI alone would be used as a triage test for biopsy. Most likely, MRI findings will be used in conjunction with other biomarkers such as PSA density to select, among the patients with positive MRI findings, those who need targeted biopsy (and those who may safely avoid it), and among the patients with negative MRI findings, those who may still deserve systematic biopsy. In addition, as mentioned previously, quality insurance monitoring MRI interpretation and targeted biopsy and systematic biopsy execution will need to be strictly implemented at the institution level."
[Emphasis mine] Amost every study I've seen l has concluded that targeted + systematic biopsy is the way to go to keep the changes of missing existing PCa to the minimum. I can see very little advantage to not doing cores in all zones (you are there on the table with no place to go anyway.) Personally, if you are biopsy-naive, I would insist that a planned targeted (only) biopsy be changed to targeted + systematic one. A recent study I can across found that 3 cores per MRI-identified target was the ideal number.
Djin