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1. JOURNAL ON CORRELATION OF PROSTATIC HEALTH INDEX AND
MULTIPARAMETRIC MRI
INTRODUCTION :-
Several advancements have been made in recent years with regards to the
detection and evaluation of prostate cancer (PCa). The low specificity of
prostate specific antigen (PSA) has left much to be desired in a test.
In recent years, numerous biomarker tests have been developed to help
account for the shortcomings of PSA. Ranging from blood-, to urine-, to tissue-
based tests, these biomarkers aim to optimize the sensitivity and specificity of
clinically significant Ca prostate detection.
In addition to laboratory tests, advancements in multiparametric magnetic
resonance imaging (mpMRI) and PIRADSv.2 scoring have provided significant
benefit to the evaluation of PCa. With the widespread use of prostate imaging,
it is important to re evaluate the impact of novel biomarkers in the context of
furthering PCa screening and management
Weinreb JC et al study in 2015 Multiparametric magnetic resonance imaging
(mpMRI) has emerged as a useful tool not only for screening, but also for
diagnosis and surveillance of PCa.
MULTI PARAMETRIC MRI involves a combination of
1) T1- and T2-weighted images,
2)diffusion weighted images (DWI),
3)dynamic contrast-enhanced images (DCE) to identify prostate lesions. From
these sequences, lesions are graded using the PIRADS v2 grading system
according to the risk of csPCa
Ahmed HU et al study in (2017) When comparing mpMRI with standard
biopsy, studies have shown mpMRI to have a higher sensitivity for csPCa [93%;
95% confidence interval (CI) .

2. American Urological Association (AUA) guidelines :- suggest the use of mpMRI
for targeted biopsy of suspicious lesions in men with prior negative biopsies,
while the EAU guidelines strongly suggest the use of mpMRI for men with low-
risk disease but suspicion for progression.
National Institute for Health and Care Excellence (NICE) guidelines :- published
in 2019 recommend the use of mpMRI in all men suspected of having localized
prostate cancer followed by MRI-influenced biopsy in men with Likert scale
scores of 3 or more on MRI.
BIOMARKERS FOR PROSTATE CARCINOMA:-
Some even consider mpMRI of the prostate to represent another “biomarker”
for PCa. In a systematic review of MRI-conspicuous lesions and the molecular
patterns of the corresponding tissue, Norris et al. in 2020 describe an
association seen between genetic markers of disease aggressivity with lesions
seen on mpMRI.
FDA APPROVED BIOMARKERS:-
PSA, PHI, PCA3, and Prolaris are approved by the US FDA
Clinical Laboratory Improvement Amendments (CLIA) approved :-
4Kscore, MiPS, Confirm MDx, Oncotype Dx, and Decipher, while miRNA has
not received institutional approval for use in prostate cancer.
PROSTATIC HEALTH INDEX
The Prostate Health Index (PHI) is a new formula that combines all three forms
(total PSA, free PSA and p2PSA) into a single score that can be used to aid in
clinical decision-making [Catalona et al. 2011].
PHI is calculated using the following formula :-
([-2]pro PSA/free PSA) × √PSA.

3. US studies on PHI in prostate cancer screening In 2011, :- Catalona and
colleagues published the results of a large multicenter trial of PHI for prostate
cancer detection in 892 men with total PSA levels from 2 to 10 ng/ml and
normal digital rectal examination (DRE) who were undergoing prostate biopsy
[Catalona et al. 2011]
Several large international studies have also reported on PHI, including the
PRO-PSA Multicentric European Study by Lazzeri and colleagues in 2013 -
Among 646 European men from five centres undergoing prostate biopsy for a
PSA of 2–10 ng/ml or suspicious DRE, It showed that using p2PSA or PHI
significantly improved the prediction of biopsy outcome over total and free
PSA. While the use of %p2PSA or PHI would reduce the number of unnecessary
biopsies by ≥15% at 90% sensitivity, PHI would miss the fewest high-grade
tumours.
In 2012 the FDA approved the use of a different isoform of PSA, proenzyme
PSA (pro PSA), to be used as a novel biomarker for the detection of csPCa.
Ng CF, Chiu PKF et al study 2014 :- It was shown to be the best predictor of
biopsy grade in men with negative DRE, especially those with a serum PSA 4–
10ng/ml. This correlation allows PHI to be useful as a decision-making tool to
limit the need for unnecessary biopsies. This correlation allows PHI to be useful
as a decision-making tool to limit the need for unnecessary biopsies.
Wang W, Wang M, Wang L, et al. 2014 These findings of the clinical usefulness
of PHI were further proven in a 16-study meta-analysis showing a sensitivity of
0.85 and specificity of 0.70.55 Additionally, when discriminating between high
(⩾7) versus low (<7) gleason lesion PHI had a sensitivity of 0.90.
With PHI’s strength for predicting aggressive lesions, this diagnostic tool is
most useful when determining the need for prostate biopsy. Several studies
examining PHI have looked for a cut off to maximize the sensitivity and
specificity of the marker while minimizing missing csPCa.

4. de la Calle C, et al A multicenter trial of men with a PHI cut off of 24 had a
sensitivity of 95% and led to a 58% decrease of unnecessary biopsies in men
with no cancer or clinically insignificant cancer.
RISK STRATIFICATION :-
Risk stratification is also important for men undergoing definitive treatment
and those with more advanced disease. Although relatively fewer studies have
been studied using phi in this clinical context, a recent pilot study of men with
biochemical recurrence reported significantly higher p2PSA and phi in men
with metastatic progression compared those without clinical metastasis
[Sottile et al. 2012].
Correlation between PHI and PI-RADS Score:-
Tan et al (2017) showed that a PHI cut off value of ≥ 27 would have allowed
34% of the patients with PI-RADS 3 lesions (n = 35) to avoid a targeted biopsy,
with both sensitivity and NPV of 100%.
Gnanapragasam V et al (2019) When studied for its role in the context of MRI,
the PRIM study demonstrated PHI as an independent predictive factor of a
positive MRI.
Schwen et al. 2020 demonstrates that the combination of PHI with mpMRI
raises the NPV for PCa to 98%, exceeding that for PSA density with mpMRI and
mpMRI alone (95.4 and 91.6%, respectively). These studies thus provide
evidence that PHI and mpMRI are complementary, such that more information
can be obtained from the use of both tests before proceeding to biopsy.
Kim et al (2020) showed that a model for a hypothetical cohort of 1000
patients with elevated PSA using PHI with a cut-off ≥ 30 as a triage test could

5. save both MRI and biopsies by 25% missing the identification of csPCa in a
percentage lower than 10% and reducing the cost per referred patient by
about 20%.
Fan et al (2021) demonstrated that PHI, among PSA-derivative biomarkers, was
the best predictor of csPCa in men with PI-RADS score 3 and 4/5. These
findings suggested that in patients with PI-RADS 3 index lesions, which is a gray
zone for PI-RADS v2, PHI may help to identify high-risk groups for csPCa and
may enable several patients to avoid unnecessary biopsy.
In a study published by Stejskal et al (2021) including 395 men, the authors
performed a head-to-head comparison between PHI and mpMRI, reporting
that PHI achieved more accurate prediction for csPCa both in the first (n = 249)
and repeated (n = 144) biopsy subgroups. The Study also showed that adding
PHI to PI-RADS significantly increased the accuracy for the prediction of any
cancer and csPCa in both the subgroups.