The FDA-approved phi test is for use in men over age 50 in the diagnostic gray zone of total prostate-specific antigen (PSA) 4–10 ng/mL and with non-suspicious digital rectal exam (DRE), which is a population in which most clinicians are looking for additional confidence in the decision to move forward with biopsy. Our clinical utility study was powered to identify the impact of phi on decision to biopsy in a community setting. The other objective, as described in the article, was to assess the biopsy yield of cancer with and without the use of phi. Summarizing the outcome for both objectives succinctly, clinicians in the study did approximately half as many biopsies as they had in the past (36.4% vs 60.3%; prospective vs historical) without diminishing the rate of positive biopsy (59.8% vs 62.4%; prospective vs historical).
Ehdaie and Carlsson  bring up two points in regard to our study which warrant further discussion. The first is the proportion of low-grade vs high-grade cancers detected between the cohorts. Secondary to that, they are concerned that high-grade cancers are being missed when phi is used to guide the decision to biopsy.
We captured data on Gleason score, but have already acknowledged that this study was not powered to address high-grade vs low-grade cancers. There is literature on this area which we have already cited. Considering our enrollment criteria restricted patients to pre-test total PSA 4–10 ng/mL and non-suspicious DRE, our study expected to identify very few patients with high-grade prostate cancer. That said, we did observe an enrichment of GS (4 + 3) cancers in the prospective group compared to the historical group. However, we chose only to report GS 6 vs >GS 6, as the N was too small to warrant comparison of individual Gleason scores. In our opinion, conducting additional statistical analysis and drawing conclusions based on those results would not be appropriate. Instead, we noted a trend in the data that mirrors findings in other publications. A considerably larger study would be needed to appropriately address this question.
Another key observation that deserves to be restated, was the utilization or modification of monitoring strategy when phi was available. Clinicians changed their decision from biopsy to monitor based on a lower phi (28.7%), opted to biopsy when phi was elevated (14.3%) and modified the frequency and/or type of monitoring based on phi (18.9%). Therefore, in nearly three-quarters of the prospective cohort (72.5%), the phi score contributed to a change in management of men in the diagnostic gray zone, something that would not have been possible in the absence of phi (historical group). The most recent NCCN guidelines recommend repeat assessment of PSA and DRE in 6–12 months for men in the diagnostic gray zone that are not biopsied. Patients not biopsied following their assessment in this study are expected to be monitored more closely or by additional methodologies. We maintain that a biopsy was safely deferred and the use of phi in the management of these patients did not interfere with the detection of high-grade disease.
Ehdaie B, Carlsson S. Reply to ‘Clinical utility of the Prostate Health Index (phi) for biopsy decision management in a large group urology practice setting’. Prostate Cancer Prostatic Dis. 2018.
Conflict of interest
The authors declare that they have no conflict of interest.
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White, J., Tutrone, R.F. Reply to Letter to the Editor re: ‘Clinical utility of the Prostate Health Index (phi) for biopsy decision management in a large group urology practice setting’. Prostate Cancer Prostatic Dis 21, 604 (2018). https://doi.org/10.1038/s41391-018-0063-8
Second Reply to Letter to the Editor re: “Clinical utility of the Prostate Health Index (phi) for biopsy decision management in a large group urology practice setting”
Prostate Cancer and Prostatic Diseases (2019)