Editing Prostate Cancer: Diagnosis and evaluation (section)

=== <span style="color:#ff0000">Imaging</span> ===

==== <span style="color:#ff0000">Primary</span> ====

===== <span style="color:#ff0000">Transrectal ultrasound (TRUS)</span> =====
* '''<span style="color:#ff0000">Compared to DRE, TRUS does not improve the ability to stage prostate cancer</span>'''
* '''<span style="color:#ff0000">In general, TRUS under-stages rather than over-stages prostate cancer</span>'''
*Limited detection of transition zone lesions

===== <span style="color:#ff0000">Magnetic Resonance Imaging (MRI)</span> =====
* See [https://www.youtube.com/watch?v=TfUt-Ai8DF4 Video on Approach and Principles to Prostate MRI]
*'''MRI uses strong magnetic fields and the electromagnetic properties of hydrogen protons to generate the signal that is used to create images[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503950/#]'''
**Signal intensities vary based on the hydrogen content of the tissue
**For details, see [https://pubmed.ncbi.nlm.nih.gov/16009826/ Pooley, Robert A.] "Fundamental physics of MR imaging." ''Radiographics'' 25.4 (2005): 1087-1099.

====== <span style="color:#ff0000">Imaging sequences</span> ======
* Sequences relevant for prostate imaging
**T1-weighted imaging (T1WI)
**T2-weighted imaging (T2WI)
**Diffusion weighted imaging (DWI) with apparent diffusion coefficient (ADC) maps
**Dynamic contrast enhanced (DCE) imaging
**Magnetic resonance spectroscopic imaging (MRSI)
*Multi-parametric (mpMRI) is the combination of multiple MRI sequences
*'''<span style="color:#ff0000">In prostate cancer, the primary diagnostic parameters are (2):</span>[https://pubmed.ncbi.nlm.nih.gov/31392526/]'''
**'''<span style="color:#ff0000">T2WI</span>'''
**'''<span style="color:#ff0000">DWI with ADC maps</span>'''
* '''<span style="color:#ff0000">T2WI</span>'''
** Captures the movement of protons in the xy-axis (transverse)
** '''<span style="color:#ff0000">Primary uses (3):</span>'''
**#'''<span style="color:#ff0000">Visualization of zonal and anatomical features of the prostate.</span>'''
**#*See [https://www.researchgate.net/figure/Zonal-prostate-anatomy-on-axial-T2-weighted-MRI-image-peripheral-zone-PZ-and_fig1_346570342 Figure]
**#'''<span style="color:#ff0000">Optimal sequence in establishing the anatomic relation of the tumor with critical structures, such as the prostatic capsule and neurovascular bundles</span>'''.[https://pubmed.ncbi.nlm.nih.gov/26594835/]
**#'''<span style="color:#ff0000">Optimal sequence to evaluate lesions in the transition zone[https://pubmed.ncbi.nlm.nih.gov/31392526/]</span>'''
** '''<span style="color:#ff0000">Signal intensity</span>''' 
***'''<span style="color:#ff0000">High intensity</span>'''
****'''<span style="color:#ff0000">Fluids (CSF, urine)</span>'''
****'''<span style="color:#ff0000">Fat</span>'''
****'''<span style="color:#ff0000">Normal peripheral zone (due to its high water content)</span>'''
****'''<span style="color:#ff0000">Seminal vesicles</span>'''
***'''Intermediate intensity'''
****'''Central zone'''
*****Clinical implication: differential diagnosis of intermediate/low intensity lesions on T2 at the base of prostate and paramedian includes central zone that is being pushed out by BPH nodules of transition zone or cancer
***'''<span style="color:#ff0000">Low intensity (7): </span><span style="color:#0000ff">CHAPPSS</span>'''
***#'''<span style="color:#ff0000">Prostate </span><span style="color:#0000ff">C</span><span style="color:#ff0000">ancer</span>'''
***#*As 70% of all prostate cancers occur within the peripheral zone, the tissue characteristics allow for T2WI to detect a significant number of tumors in this zone
***#*
***#'''<span style="color:#0000ff">H</span><span style="color:#ff0000">emorrhage</span>'''
***#*Post-biopsy hemorrhage can interfere with tumor detection[https://pubmed.ncbi.nlm.nih.gov/26594835/], since areas of hemorrhage appear similar to cancer on T2WI
***#**If obtaining prostate MRI post-biopsy, a delay of 6-8 weeks after biopsy is recommended; but even with this delay, significant hemorrhage may be discovered, and, if present, the examination should be rescheduled[https://pubmed.ncbi.nlm.nih.gov/26594835/]
***#*Can be distinguished from cancer with T1WI (hemorrhage has high intensity on T1WI, cancer has low intensity on T2WI)
***#'''<span style="color:#0000ff">A</span><span style="color:#ff0000">trophy</span>'''
***#'''<span style="color:#0000ff">P</span><span style="color:#ff0000">rostatitis</span>'''
***#'''<span style="color:#0000ff">P</span><span style="color:#ff0000">ost-treatment changes</span>'''
***#'''<span style="color:#0000ff">S</span><span style="color:#ff0000">cars</span>'''
***#'''<span style="color:#0000ff">S</span><span style="color:#ff0000">tromal hyperplasia i.e. benign prostatic hyperplasia (BPH)</span>'''
***#*'''Clinical implication: On T2WI, BPH nodules can be difficult to distinguish from cancer'''
**Lesion shape
***Wedge-shaped/linear lesions are more likely benign 
* '''<span style="color:#ff0000">Diffusion weighted imaging (DWI)</span>'''
** '''Measures the diffusion of water protons within tissue'''
***'''In normal water-rich glandular tissue, protons are mobile'''
***'''In densely packed water-poor tissue such as that found in tumors, protons have restricted movement.'''
**Images are acquired by sequentially applying multiple magnetic field gradients, known as b-values, to calculate ADC values and construct ADC maps. 
***b-value is a factor that reflects the strength and timing of the gradients used to generate diffusion-weighted images. The higher the ''b''-value, the stronger the diffusion effects.
****Typical ''b''-values available on modern MRI scanners range from 0 to about 4000 s/mm²[https://mriquestions.com/what-is-the-b-value.html]
***ADC values are calculated by the software and displayed as a parametric map reflecting the degree of diffusion of water molecules through different tissues.
****Different b-values will produce different ADC maps
****In general, ADC values decrease when b-values increase above 1000 s/mm²[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4730971/]
**'''<span style="color:#ff0000">Primary use:</span>'''
***'''<span style="color:#ff0000">Optimal sequence to evaluate lesions in the peripheral zone[https://pubmed.ncbi.nlm.nih.gov/31392526/]</span>'''
**'''<span style="color:#ff0000">Signal intensity</span>'''
***'''<span style="color:#ff0000">ADC maps</span>'''
****'''Intermediate intensity'''
*****'''Normal glandular prostate tissue allows unrestricted free water movement'''
****'''<span style="color:#ff0000">Low intensity</span>'''
*****'''<span style="color:#ff0000">Prostate cancer</span>[https://pubmed.ncbi.nlm.nih.gov/23878284/]'''
******'''Appears as high signal intensity focus on high b-value images'''
*******Image with highest b-value (lowest ADC) likely to be most useful
******'''<span style="color:#ff0000">Tumors with the higher restriction (low ADC values) tend to be higher grade</span>'''
*'''<span style="color:#ff0000">T1WI</span>'''
** Captures the movement of protons in the z-axis
** '''<span style="color:#ff0000">Primary uses (2):</span>'''
**#'''<span style="color:#ff0000">Optimal sequence to identify areas of hemorrhage within the prostate</span>'''
**#'''Often used to look at normal anatomical details.'''
** '''<span style="color:#ff0000">Signal intensity</span>'''
***'''<span style="color:#ff0000">High intensity</span>'''
****'''<span style="color:#ff0000">Hemorrhage/blood has high signal intensity on T1</span>, against a homogenous low signal background.'''
****'''<span style="color:#ff0000">Fat</span>'''
***'''<span style="color:#ff0000">Low intensity'''
****'''<span style="color:#ff0000">Fluids (CSF, urine)</span>'''
****'''<span style="color:#ff0000">Prostate cancer'''
* '''<span style="color:#ff0000">Dynamic contrast enhancement (DCE)</span>'''
** A series of T1WI obtained before, during, and after the injection of intravenous gadolinium-based contrast media
**'''<span style="color:#ff0000">Primary use (1):</span>'''
***'''<span style="color:#ff0000">Measures the vascularity of prostate tissue</span>'''.
**** '''Focal early hyperenhancement is suggestive of a malignancy'''
*****Tumors have increased vascularity due to neo-angiogenesis and, therefore, take up the contrast agent more rapidly than normal tissue. Moreover, this contrast washes out of tumor regions quickly leading to a steep wash-in-wash-out enhancement curve.
*****There is considerable overlap of with benign conditions, such as benign prostatic hyperplasia and prostatitis.
******DCE MRI is most helpful when the T2W MRI and DWI are equivocal.
*******In these cases, strong early enhancement or rapid washout of contrast media from the lesion increases the suspicion that the lesion is a clinically significant malignancy. 
****Very useful in detecting sites of recurrent prostate cancer after prostatectomy or radiation therapy where focal enhancement may indicate a site of focal recurrence
* '''<span style="color:#ff0000">Magnetic resonance spectroscopic imaging (MRSI)</span>'''
** '''Uses the relative concentration of cellular metabolites in the prostate, specifically citrate and choline, to detect prostate cancer.'''
*** '''Citrate is a marker of normal prostatic tissue, whereas high levels of choline can be found in cancerous cells owing to increased cell turnover, which, in turn, leads to an increased choline-to-citrate ratio in patients with prostate cancer'''
** '''<span style="color:#ff0000">When combined with T2WI, MRSI has been found to have the highest sensitivity of all MRI sequences (92%) in detecting prostate cancer.</span>'''
** While MRSI is a promising imaging sequence, it requires an extra 10 to 15 minutes of examination time. Also, for this phase an endorectal coil (see below) is mandatory at 1.5T and optional at 3T. For these reasons, MRSI is less commonly performed than other mpMRI sequences in prostate MRI studies.
* '''Bi-parametric MRI (bpMRI)'''
** '''Combination of only non-contrast T2WI and DWI (with ADC maps) series''' 
**Advantages[https://pubmed.ncbi.nlm.nih.gov/26594835/]
***Can be performed without an endorectal coil
***Can be performed intravenous access and contrast administration
***Fewer sequences reduces time/costs to complete study
****Requires less than half the in-bore magnet time to perform compared with the complete mpMRI
**Disadvantages
***Fewer imaging sequences which may limit adequate interpretation
**'''No significant difference in sensitivity or specificity compared to mpMRI'''
***Systematic review and meta-analysis (2018)
****20 studies involving 2142 patients
****Results
*****No significant difference in pooled sensitivity and specificity
******Sensitivity: 0.74 (95% CI, 0.66–0.81) bpMRI vs. 0.76 (95% CI, 0.69–0.82) mpMRI
******Specificity: 0.90 (95% CI, 0.86–0.93) bpMRI vs. 0.89 (95% CI, 0.85–0.93) mpMRI
****[https://pubmed.ncbi.nlm.nih.gov/30240296/ Woo, Sungmin, et al.] "Head-to-head comparison between biparametric and multiparametric MRI for the diagnosis of prostate cancer: a systematic review and meta-analysis." ''American Journal of Roentgenology'' (2018): W226-W241.

====== <span style="color:#ff0000">Magnet strength</span> ======
* '''mpMRI can be performed at field strengths of 1.5T or 3T with or without an endorectal coil.'''
** 3T magnets reduce image acquisition time and improve spatial resolution
** Greater magnet strength does not necessarily mean greater cancer detection rates.

====== <span style="color:#ff0000">Endorectal coil</span> ======
* '''Advantages'''
**'''<span style="color:#ff0000">Improves image resolution by increasing the SNR</span>''' 
***'''Standard clinical field strengths of 1.5T do not provide sufficient signal-to-noise ratio for clinical diagnosis of prostate cancer. To compensate for this deficiency, the use of surface and/or endorectal coil arrays has been proposed'''
***'''There is consensus regarding the use of a surface body coil and an endorectal coil at 1.5T but controversy remains regarding the need for an endorectal coil at 3T.'''
**** '''<span style="color:#ff0000">The highest signal-to-noise ratio (SNR) is achieved at 3T with an endorectal coil</span> but acceptable results can be achieved at 3T without an endorectal coil.'''
*Disadvantages
**Patient discomfort
**Additional time required for proper placement and verification
**Cost
**Deformation of the gland which may affect the image registration for targeted biopsy or radiation planning
***Concerns regarding alterations in prostate volume have largely been dispelled.

====== <span style="color:#ff0000">Prostate Imaging and Reporting Archiving Data System (PI-RADS) ======
* '''Provides guidance for interpretation of different sequences and prostate zones'''
*Introduced in 2012, revised in 2015 (version 2.0)
*'''Each lesion is scored, using a 5-point scale based on the likelihood (probability) that mpMRI findings correlate with the presence of a clinically significant cancer'''
**Clinically significant cancer is defined on pathology/histology as (3):[https://pubmed.ncbi.nlm.nih.gov/26427566/]
**#Gleason score ≥7 (including 3+4 with prominent but not predominant Gleason 4 component) and/or 
**#Volume ≥0.5cc and/or 
**#Extra prostatic extension(EPE).
**'''Detection rates by PI-RADS score for any prostate cancer[https://pubmed.ncbi.nlm.nih.gov/37096582/]'''
*** '''PR 1-2: 15%'''
*** '''PR 3: 25%'''
*** '''PR 4: 58%'''
*** '''PR 5: 85%'''
**'''<span style="color:#ff0000">Positive predictive values for ISUP grade group ≥2 based on PI-RADS score:</span>[https://pubmed.ncbi.nlm.nih.gov/35393568/]'''
***'''<span style="color:#ff0000">PI-RADS 1-2: 7%[https://pubmed.ncbi.nlm.nih.gov/37096582/]</span>'''
***'''<span style="color:#ff0000">PI-RADS 3: 12–15%</span>'''
***'''<span style="color:#ff0000">PI-RADS 4: 39–48%</span>'''
***'''<span style="color:#ff0000">PI-RADS 5: 72%</span>'''
**If PIRADS[https://pubmed.ncbi.nlm.nih.gov/26427566/]
***≥4 or 5, biopsy should be considered
***≤3, biopsy may or may not be appropriate, depending on factors other than mpMRI alone
* Lesions in the peripheral zone appear round or irregular, and are focally hypointense, whereas transition zone lesions are non-circumscribed and moderately hypointense, and may exhibit a characteristic ‘‘erased charcoal’’ sign.

====== <span style="color:#ff0000">Test Characteristics ======

* '''<span style="color:#ff00ff">Cochrane Systematic Review and Meta-analysis (2019)</span>'''
** '''MRI compared with template‐guided biopsy'''
***'''Detection of grade 2 or higher prostate cancer'''
****'''Sensitivity: 0.91 (95% CI 0.83 to 0.95)'''
****'''Specificity: 0.37 (95% CI 0.29 to 0.46)'''
***'''Detection of grade 3 or higher prostate cancer'''
****'''Sensitivity: 0.95 (95% CI 0.87 to 0.99)'''
****'''Specificity: 0.35 (95% CI 0.26 to 0.46)'''
**[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483565/ Drost, Frank‐Jan H., et al.] "Prostate MRI, with or without MRI‐targeted biopsy, and systematic biopsy for detecting prostate cancer." ''Cochrane Database of Systematic Reviews'' 4 (2019).
*'''<span style="color:#ff00ff">PROMIS (2017)</span>'''
** '''<span style="color:#ff0000">Objective: evaluate sensitivity/specificity of prostate MRI vs. standard TRUS biopsy,</span> with template prostate mapping biopsy as gold standard reference'''
** Population: 576 men with a clinical suspicion of prostate cancer (elevated serum PSA (up to 15 ng/mL) within previous 3 months, suspicious digital rectal examination, suspected organ confined stage T2 or lower on rectal examination, or family history) and no previous prostate biopsy
** '''Intervention: prostate MRI followed by template prostate mapping biopsy as gold standard reference and then standard TRUS biopsy'''
***MRI was done with 1.5 Tesla magnet
***Patients with positive MRI did not undergo targeted biopsy
** Primary outcomes: sensitivity and specificity of prostate MRI vs. standard TRUS biopsy for detection of clinically significant prostate cancer
***Clinically significant prostate cancer defined as Gleason score ≥4 + 3 or a maximum cancer core length 6 mm or longer
**'''<span style="color:#ff0000">Results:</span>'''
*** '''<span style="color:#ff0000">mpMRI displayed a moderate sensitivity</span>''' (88%) and negative predictive value (76%), '''<span style="color:#ff0000">but poor specificity</span>''' (45%) and positive predictive value (65%).
**Authors' interpretation: MP-MRI, used as a triage test before first prostate biopsy, could reduce unnecessary biopsies by ≈25% (based on negative-predictive value). MP-MRI can also reduce over-diagnosis of clinically insignificant prostate cancer and improve detection of clinically significant cancer.
**[https://pubmed.ncbi.nlm.nih.gov/28110982/ Ahmed, Hashim U., et al.] "Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study." The Lancet 389.10071 (2017): 815-822.

====== <span style="color:#ff0000">Advantages</span> ======

* '''Compared to pathway of elevated PSA to TRUS-guided biopsy without MRI, pathway of elevated PSA to MRI with targeted biopsy''' 
** '''Improves identification of anterior tumors'''
** '''Reduces over diagnosis of clinically insignificant prostate cancer'''
** '''Increases diagnosis of clinically significant prostate cancer'''
*** '''≈10%''' (but up to 20%) '''of negative MRI have clinically significant prostate cancer'''
* '''<span style="color:#ff00ff">PRECISION (2018)</span>'''
** Objective: in males with clinical suspicious of prostate cancer, determine whether prostate MRI with targeted biopsy only can increase detection of clinically significant prostate cancer and decrease detection of clinically insignificant prostate cancer
** '''Design: Non-inferiority trial'''
** '''<span style="color:#ff0000">Population: 500 males with clinical suspicion of prostate cancer based on elevated PSA or abnormal DRE</span>'''
** '''<span style="color:#ff0000">Randomized to standard TRUS–guided biopsy vs. MRI +/- targeted biopsy</span>'''
*** '''Males in the MRI group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; if MRI results were not suggestive of prostate cancer, males were not offered biopsy'''
** '''Outcomes'''
*** '''Primary: proportion of males who received a diagnosis of clinically significant cancer'''
*** Secondary: proportion of males who received a diagnosis of clinically insignificant cancer
** '''<span style="color:#ff0000">Results:</span>'''
*** '''<span style="color:#ff0000">MRI-targeted biopsy was non-inferior and superior to detecting clinically significant cancer</span>''' (absolute risk difference 12%, 38% MRI vs. 26% standard TRUS)
*** '''<span style="color:#ff0000">MRI-targeted biopsy was associated with fever patients being diagnosed with clinically insignificant cancer</span>''' (absolute risk difference -13%)
** Authors’ conclusion: Using MP-MRI to triage men might allow 27% of patients avoid a primary biopsy and diagnosis of 5% fewer clinically insignificant cancers. If subsequent TRUS-biopsies were directed by MP-MRI findings, up to 18% more cases of clinically significant cancer might be detected compared with the standard pathway of TRUS-biopsy for all. MP-MRI, used as a triage test before first prostate biopsy, could reduce unnecessary biopsies by a quarter. MP-MRI can also reduce over-diagnosis of clinically insignificant prostate cancer and improve detection of clinically significant cancer.
** [https://pubmed.ncbi.nlm.nih.gov/29552975/ Kasivisvanathan, Veeru, et al.] "MRI-targeted or standard biopsy for prostate-cancer diagnosis." New England Journal of Medicine 378.19 (2018): 1767-1777.
* '''<span style="color:#ff00ff">STHLM3 - MRI-targeted vs. standard biopsy in prostate cancer screening</span>'''
**'''Population: 1532 males aged 50-74 years with screening PSA > 3 ng/mL'''
***Screening population in STHLM3, compared to patients referred for abnormal PSA or DRE in PRECISION
**'''Randomized to standard TRUS-guided biopsy vs. MRI and if MRI positive then standard biopsy with targeted biopsy'''
***If MRI negative, biopsies were not performed unless Stockholm3 test scores ≥25% or greater
** Primary outcome: proportion of males diagnosed with clinically significant cancer (Gleason score ≥7)
** Secondary outcome: proportion of males diagnosed with clinically insignificant cancers (Gleason score 6).
** Results
*** MRI non-inferior to diagnose clinically significant disease (21% MRI vs. 18% standard biopsy)
*** Significantly fewer clinically insignificant disease with MRI (4% MRI vs. 12% standard biopsy)
** [https://pubmed.ncbi.nlm.nih.gov/34237810/ Eklund, Martin, et al.] "MRI-targeted or standard biopsy in prostate cancer screening." ''New England Journal of Medicine'' (2021).

====== <span style="color:#ff0000">Disadvantages</span> ======

* '''Availability/cost'''
* '''Interobserver reproducibility remains a challenge.[https://pubmed.ncbi.nlm.nih.gov/32315265/]'''
* '''Learning curve related to reading MRI and to performing fusion biopsies'''
* '''Use of MRI for tumor staging remains controversial.'''
**Variable sensitivities (13-91%) and specificities (49-97%) have been reported for predicting extra-capsular extension.

====== Guidelines on Use of MRI Before Biopsy ======

* '''2023 AUA Guidelines on Early Detection of Prostate Cancer'''
**'''<span style="color:#ff0000">May be used prior to initial biopsy to increase the detection of GG2+ prostate cancer[https://pubmed.ncbi.nlm.nih.gov/23659877/]</span>'''
***It is reasonable to obtain an mpMRI in biopsy-naïve patients prior to their first biopsy, but such a practice cannot be regarded as the standard approach based on the currently available evidence. 
*'''2023 NCCN (PROSD-3)'''
**'''Multiparametric MRI is strongly recommended, if available'''
*'''2022 EAU[https://uroweb.org/guidelines/prostate-cancer/chapter/diagnostic-evaluation]'''
**'''Systematic biopsy is an acceptable approach in case MRI is unavailable''' 
*2017 Cancer Care Ontario Guidelines
** '''<span style="color:#ff0000">Biopsy-naïve: MRI should not be considered standard of care'''
** '''<span style="color:#ff0000">Prior negative biopsy: MRI followed by targeted biopsy may be considered</span>'''

====== Targeted biopsy only vs. targeted and systematic ======
* '''<span style="color:#ff00ff">MRI-FIRST (2019)</span>'''
** Objective: determine whether biopsy of MRI detected lesions increases detection of clinically significant prostate cancer compared to standard biopsy i.e. can we omit standard biopsy and do only targeted biopsy?
** '''Design: paired-diagnostic study (non-randomized)'''
**'''Population: 275 patients with clinical suspicion of prostate cancer'''
** '''Intervention: MRI followed by standard systematic biopsy then targeted biopsy of up to 2 lesions on MRI. Patients with negative multiparametric MRI (Likert score ≤2) had systematic biopsy only.'''
** '''Primary outcome: detection of clinically significant prostate cancer'''
** '''Results:'''
*** '''No difference in detection of clinically significant prostate cancer''' (30% systematic biopsy vs. 32% targeted biopsy)
*** Clinically significant prostate cancer would have been missed in 5% of patients had systematic biopsy not been done, and in 8% of patients had targeted biopsy not been done
** '''Obtaining a multiparametric MRI before biopsy in biopsy-naive patients can improve the detection of clinically significant prostate cancer compared to systematic biopsy alone but does not seem to avoid the need for systematic biopsy'''
** '''</span>'''[https://pubmed.ncbi.nlm.nih.gov/30470502/ Rouvière, Olivier, et al.] "Use of prostate systematic and targeted biopsy on the basis of multiparametric MRI in biopsy-naive patients (MRI-FIRST): a prospective, multicentre, paired diagnostic study." The Lancet Oncology 20.1 (2019): 100-109.
*'''<span style="color:#ff00ff">Ahdoot et al. (2020)</span>'''
**Study design: cohort study
**Population: 2103 males with an elevated PSA or abnormal DRE with a positive MRI underwent a targeted and systematic biopsy
**Outcomes:
***Primary outcomes: cancer detection rates by grade group for each biopsy method
**Results
***Use of MRI-targeted biopsy led to more diagnoses of cancers in grade groups 3, 4, and 5 than systematic biopsy and fewer cancers in grade group 1
***The addition of MRI-targeted biopsy to systematic biopsy led to 208 (9.9%) more prostate cancer diagnoses. Of these new diagnoses, 59 (28.4%) were clinically significant (grade group ≥3) disease.
***MRI-targeted biopsy was responsible for upgrading of events in 458 patients (21.8%) when added to systematic biopsy
***MRI-targeted biopsy alone without systematic biopsy would have led to no detection of cancers of grade group 2 or higher in 123 patients (5.8%) and no detection of cancers of grade group 3 or higher in 41 patients (1.9%)
***Among the patients who underwent radical prostatectomy, upgrading on histopathological analysis after undergoing combined biopsy occurred 14% of patients. The rates of any upgrading or clinically significant upgrading on whole-mount histopathological analysis were substantially higher for systematic biopsy and MRI-targeted biopsy (30.9% and 8.7%, respectively) than for combined biopsy
**Authors' interpretation: Among patients with MRI-visible lesions, combined biopsy led to more detection of all prostate cancers. However, MRI-targeted biopsy alone underestimated the histologic grade of some tumors. After radical prostatectomy, upgrades to grade group 3 or higher on histopathological analysis were substantially lower after combined biopsy.
**[https://pubmed.ncbi.nlm.nih.gov/32130814/ Ahdoot, Michael, et al.] "MRI-targeted, systematic, and combined biopsy for prostate cancer diagnosis." ''New England Journal of Medicine'' 382.10 (2020): 917-928.
*'''<span style="color:#ff00ff">GOTEBORG-2 (2022/2024)</span>'''
**Objective: Determine whether targeted-biopsy only (and avoid systematic) is adequate in patients with elevated PSA (3-10 ng/ml) and prostate MRI
**Population: Swedish males aged 50-60 living in Gothenburg, Sweden, without previous diagnosis of prostate cancer
**Randomized to invited screening with PSA test vs. no invitation
***If PSA > 3 ng/mL, patients underwent prostate MRI
****Further randomized to
*****Reference group: Systematic (regardless of MRI results) +/- targeted biopsy if MRI positive (PR3-5) vs.
*****Experimental group: Targeted biopsy only if MRI positive (PR3-5) (experimental group); If PSA>10, patients underwent systematic biopsy, with or without targeted biopsy, regardless of MRI results
******If low-grade prostate cancer (mainly with Gleason 3+3 cancer but also some with Gleason 3+4 cancer) detected by targeted biopsy in the experimental group, were invited to undergo follow-up systematic biopsy. The Gleason score was thus based on both targeted and systematic biopsies after a cancer diagnosis in both groups in order to avoid sampling bias due to different primary biopsy techniques. 
**Outcomes:
***Primary outcome: detection of clinically insignificant prostate cancer, defined as a Gleason score of 3+3.
***Secondary outcome: detection of clinically significant prostate cancer, defined as a Gleason score of 3+4 or higher
**Results:
***19,733 (52%) of those randomized to invitation to screening underwent PSA testing
****1371 (7%) had PSA > 3 ng/mL
*****95% of patients with PSA > 3 ng/mL underwent MRI
***Risk of clinically insignificant prostate cancer at screening or at interval: significantly more common in patients undergoing systematic +/- targeted biopsy compared to targeted biopsy only (2.4% vs. 1.0%)
***Risk of clinically significant prostate cancer at screening or at interval: no significant difference (2.1% systematic +/- targeted vs. 1.8% targeted biopsy only)
***(2022 publication) 10 patients in reference group found to have clinically significant prostate cancer on systematic only
****9 with negative MRI, 1 with false-positive MRI
*****All GG2, GG4 <5% in 6 patients
******6 managed with AS
***(2022 publication) 128 patients in experimental group with PSA <10 diagnosed with cancer by targeted biopsy only
****72/128 (56%) had GG1
*****86% underwent systematic biopsy
*****26% upgraded (all GG2 except 1 to 3+5)
****Gleason 3+3 lesions that had been detected by systematic biopsy differed only in tumor extension from those that had been detected by targeted biopsy of suspicious lesions shown on MRI, with greater volume measured in tumors that were visible on MRI
**Author's interpretation: omitting prostate biopsy in men with negative MRI results, and thereby delaying a potential cancer diagnosis, was associated with a substantial reduction in the detection of clinically insignificant cancer and a very low risk of detecting incurable cancers at repeat screening rounds or as interval cancers.
**[https://pubmed.ncbi.nlm.nih.gov/39321360/ Hugosson, Jonas, et al.] "Results after Four Years of Screening for Prostate Cancer with PSA and MRI." ''New England Journal of Medicine'' 391.12 (2024): 1083-1095.
**[https://pubmed.ncbi.nlm.nih.gov/36477032/ Hugosson, Jonas, et al.] "Prostate cancer screening with PSA and MRI followed by targeted biopsy only." ''New England Journal of Medicine'' 387.23 (2022): 2126-2137.

====== Biopsy after Negative MRI ======

* '''≈10%''' (but up to 20%) '''of negative MRI have clinically significant prostate cancer'''
* '''Predictors of clinically significant prostate cancer in presence of negative MRI[https://pubmed.ncbi.nlm.nih.gov/31967522/]'''
** PSA density > 0.15 ng/ml/cc[https://pubmed.ncbi.nlm.nih.gov/30189186/][https://pubmed.ncbi.nlm.nih.gov/33080153/]
** History of previous negative biopsy[https://pubmed.ncbi.nlm.nih.gov/30189186/]
** Abnormal DRE[https://pubmed.ncbi.nlm.nih.gov/33080153/]/Clinical stage T2a or greater[https://pubmed.ncbi.nlm.nih.gov/33080153/]
** Prostate cancer family history[https://pubmed.ncbi.nlm.nih.gov/33080153/]

===== Modalities under investigation =====
* Positron Emission Tomography (PET)
** One potential advantage of PSMA PET over mpMRI is that interpretation is not influenced by biopsy-related artifacts such as hemorrhage or inflammation
* Multiparametric Ultrasonography
** Contrast-enhanced (CE) TRUS produces a detailed image of microvascular distribution within the prostate using highly echogenic microbubble contrast agents that are minute enough to flow within capillaries.

==== <span style="color:#ff0000">Metastasis</span> ====

===== "Conventional" imaging =====
* '''<span style="color:#ff0000">Regional</span>'''
** '''<span style="color:#ff0000">CT/MRI is used for regional lymph node staging</span>'''
* '''<span style="color:#ff0000">Distant</span>'''
** '''<span style="color:#ff0000">Radionuclide bone scan (bone scintigraphy) is the most commonly used test for the detection of skeletal metastases</span>'''

===== Novel Positron Emission Tomography (PET)-CT imaging[https://pubmed.ncbi.nlm.nih.gov/33661093/] =====
* '''PET scans use a radioactive tracer to show both normal and abnormal metabolic activity.'''
**Use of either hybrid PET/computed tomography (CT) or PET/magnetic resonance (MR) scanners with PSMA-targeted radiopharmaceuticals allows anatomical localization and characterization of PSMA-avid lesions
*'''<span style="color:#ff0000">Advantage over conventional imaging</span>'''
** '''<span style="color:#ff0000">Higher sensitivity for the detection of prostate cancer recurrence and metastases at low PSA values (<2.0ng/mL).</span>'''
*** 38% of PSMA-targeted PET scans show disease sites in males with PSA <0.5 ng/ml[https://pubmed.ncbi.nlm.nih.gov/30850500/]
**'''<span style="color:#ff0000">18F-PET provides the best sensitivity and specificity for the detection of bony metastases in prostate cancer</span>'''

====== Prostate cancer PET radiopharmaceutical tracers ======
* '''<span style="color:#ff0000">Not PSMA-specific radiopharmaceutical tracers'''
** Examples include '''<span style="color:#ff0000">18F-fluciclovine (trade name Axumin)</span>''', 18F-fluorodeoxyglucose (FDG), and 11C-choline
*** 18F-fluciclovine FDA approved in 2016
** '''Replaced by PSMA-specific tracers'''
*** '''Lower sensitivity and specificity than PSMA-specific ligands'''
**** In a 2019 prospective study of males who had undergone prostatectomy and had a rising PSA still under 2.0ng/mL, 68Ga-PSMA-PET detected occult metastases 4.54x significantly more frequently than 18F-fluciclovine-PET[https://pubmed.ncbi.nlm.nih.gov/31375469/]
* '''<span style="color:#ff0000">PSMA-specific radiopharmaceuticals tracers</span>'''
** '''PET tracers that bind to Prostate-Specific Membrane Antigen (PSMA)'''
*** '''PSMA'''
**** Also known as glutamate carboxypeptidase II (GCP II)
**** A transmembrane glycoprotein
**** '''Highly overexpressed in >90% of prostate cancers'''
***** Increased expression with
****** Increased pathological Gleason grade
****** Castrate-resistance
** '''<span style="color:#ff0000">PSMA-specific radiopharmaceutical tracers used in prostate cancer (2):</span>'''
***'''<span style="color:#ff0000">Fluorine-18 (18F)-labeled PSMA-specific</span>''' (18F-DCFPyL ('''piflufolastat''' F 18) (trade name '''<span style="color:#ff0000">Pylarify</span>'''), 18F-PSMA-1007)
****'''Most commonly used radiotracer in the US and''' (18F-DCFPyL) '''Canada'''
****18F-DCFPyL adverse reactions: headache, altered taste, fatigue[https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-second-psma-targeted-pet-imaging-drug-men-prostate-cancer]
***'''<span style="color:#ff0000">Gallium-68 (68Ga)-labeled PSMA-specific</span>'''
****'''High specificity and sensitivity'''
*****'''Outperforms standard CT and MRI in detection of nodal and osseous metastases.'''
****As of May 2021, only available locally at two sites in California[https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-second-psma-targeted-pet-imaging-drug-men-prostate-cancer]
****'''Excretion: urinary'''
**'''<span style="color:#ff0000">Uptake of PSMA-specific radiopharmaceuticals</span>[https://pubmed.ncbi.nlm.nih.gov/33661093/]'''
***'''<span style="color:#ff0000">Physiological</span>'''
****'''<span style="color:#ff0000">High uptake: lacrimal and salivary glands, kidneys</span>'''
****'''<span style="color:#ff0000">Moderate uptake: spleen, nasopharynx</span>''' 
**** '''Variable uptake: vocal cords, trachea, bronchi, proximal GI tract'''
**** '''Uptake also seen in central nervous system and peripheral nervous system''' (ganglia and nerve routes)
***** Celiac and stellate ganglia may be false-positives for retroperitoneal and supraclavicular lymphadenopathy
*** '''<span style="color:#ff0000">Benign disease</span>'''
***# '''<span style="color:#ff0000">Infectious and inflammatory processes</span> (e.g., sarcoidosis)'''
***#* Increased blood flow and vascular permeability may partly explain the increased PSMA uptake in inflammatory conditions.
***# '''<span style="color:#ff0000">Benign neoplasms</span>''' (mesenchymal tumors (vascular, neurogenic, connective tissue origin) and epithelial tumors (edenoma and thymoma))
***# '''<span style="color:#ff0000">Bone remodelling</span>''' (healing fractures, degenerative or arthritic processes (e.g., osteophytes), Paget's disease)
***# '''<span style="color:#ff0000">Amyloidosis</span>'''
*** '''<span style="color:#ff0000">Malignancy</span>'''
**** '''<span style="color:#ff0000">Prostate cancer</span>'''
**** '''<span style="color:#ff0000">Non-prostate malignancies</span>'''
***** '''<span style="color:#ff0000">Renal cell carcinoma</span>,''' leiomyosarcoma, thyroid cancer, nasopharyngeal cancer, GI tract cancer, breast cancer, neuroendocrine cancer
** '''<span style="color:#ff0000">Clearance of PET tracers used in prostate cancer</span>[https://pubmed.ncbi.nlm.nih.gov/33661093/]'''
*** '''<span style="color:#ff0000">Most are cleared via the urinary tract</span>, with high accumulation in the urinary tract and bladder and moderate uptake in the liver'''
**** '''Exception: 18F-PSMA-1007, 18F-fluciclovine, and 11-choline</span> are cleared primarily by the hepatobiliary tract, with higher uptake in the liver, and little accumulation in the ureters and bladder'''
***** '''<span style="color:#ff0000">Clinical implication: since 18F-PSMA-1007, 18F-fluciclovine, and 11-choline have minimal excretion from the urinary tract, use of these tracers may aid in identifying disease sites adjacent to the bladder and ureters, such as local tumor recurrence after prostatectomy.</span>'''
** '''<span style="color:#ff0000">Causes of false-negative PSMA-targeted PET</span>'''
**# '''<span style="color:#ff0000">Small tumor volume</span>'''
**#* May be seen in early-stage biochemical recurrence when the serum PSA <0.5 ng/ml
**# '''<span style="color:#ff0000">Neuroendocrine differentiation of prostate cancer</span>''' with downregulation of PSMA expression
**#* Neuroendocrine differentiation occurs in 5–10% of prostate cancers overall and approximately 30% of men with advanced disease
**# '''<span style="color:#ff0000">Androgen receptor inhibition</span>'''
**#* '''Short-term ADT likely increases PSMA-targeted PET positivity, whereas prolonged, continuous ADT is associated with a higher likelihood of a negative PSMA-targeted PET'''

====== Potential roles of PSMA-PET imaging in prostate cancer ======

# '''<span style="color:#ff0000">Primary staging of high-risk prostate cancer</span>'''
#* '''<span style="color:#ff00ff">proPSMA (2020)</span>'''
#**Objective: determine whether PSMA PET-CT prior to treatment in patient with high risk prostate cancer increases detection of metastases, compared to conventional imaging
#**'''Population: 300 males with high-risk (PSA ≥20, grade group ≥3, or ≥cT3) prostate cancer being considered for radical prostatectomy or radiotherapy'''
#**'''Randomized to Ga-PSMA-11 PET-CT vs. conventional imaging (CT and bone scan), followed by second-line cross-over imaging.'''
#***Second-line cross-over imaging was done within 14 days of baseline imaging, unless ≥3 distant metastases identified on first-line imaging.
#***At 6 months, patients underwent repeat imaging as per randomised group with cross-over if
#****Baseline imaging evidence of metastasis (N1 or M1)
#****Biochemical or clinical suspicion of residual or recurrent disease.
#***'''Primary outcome: accuracy (based on area under the curve (AUC)) of first-line imaging at identifying either pelvic nodal or distant metastatic disease, compared to assessment of metastases at 6 months (reference standard)'''
#****Metastatic disease disease was defined by hard and soft criteria based on histopathologic, imaging, clinical, and biochemical findings.
#***'''Results:'''
#****'''Primary outcome: accuracy (based on AUC) significantly improved with PSMA PET-CT compared to conventional imaging (absolute difference: 27%, 92% PSMA PET-CT vs. 65% conventional imaging)'''
#*****Sensitivity: 85% PSMA PET-CT vs. 38% conventional imaging
#*****Specificity: 98% PSMA PET-CT vs. 91% conventional imaging
#***** PSMA PET-CT more sensitive and specific than conventional imaging for both pelvic nodal or distant metastases
#**** '''Secondary outcomes:'''
#***** '''Change in management more common with PSMA PET-CT (28% PSMA PET-CT vs. 15% conventional imaging)'''
#***** Less equivocal findings with PSMA PET-CT
#***** Radiation exposure reduced with PSMA PET-CT (8 mSv PSMA PET-CT vs. 19 mSv conventional imaging)
#*** Limitations:
#****Lack of histopathological evidence of metastasis in majority of cases; unclear validity of reference standard used in this study
#*****Only 23% of positive cases (pelvic nodal or distant metastasis) met "hard" criteria to define metastasis (true positive).
#******Hard criteria were histopathology showing prostate adenocarcinoma, or change of a bone lesion to sclerotic or blastic on follow-up imaging.
#*** [https://pubmed.ncbi.nlm.nih.gov/32209449/ Hofman, Michael S., et al.] "Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study." ''The Lancet'' 395.10231 (2020): 1208-1216.
#** '''Clinical implications (2):'''
#**# '''PSMA PET/CT may identify nodes outside of the routine surgical field, as well as additional sites of distant disease'''
#**# '''Sensitivity of PSMA PET/CT in detecting nodal disease not high enough to avoid treatment of lymph nodes''' in patients with risk of lymph node involvement
# '''<span style="color:#ff0000">Improved quantification of metastatic burden</span>'''
#* '''Oligometastatic disease may be identified, and such patients may be offered management in clinical trials or metastasis-directed surgery.'''
# '''<span style="color:#ff0000">Staging of biochemical recurrence</span>'''
#* '''Most common indication for PSMA-targeted PET'''
#* '''Management of biochemical recurrence depends on disease extent:''' local recurrence of local recurrence with regional nodal metastases vs. distant metastatic disease
# '''<span style="color:#ff0000">Determining patient suitability for PSMA-targeted radionuclide therapy</span>'''
#* '''Both 177Lu and 225Ac PSMA-targeted radioligand therapy are emerging as promising therapies for castration-resistant disease.'''
# '''<span style="color:#ff0000">Primary detection of tumor as an adjunct to multiparametric MRI</span>'''
#* Role of PSMA-targeted PET as an adjunct to mpMRI for primary detection of clinically significant prostate cancer is not well-established

====== Indications ======
* '''<span style="color:#ff0000">FDA approved for (2)</span>[https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-second-psma-targeted-pet-imaging-drug-men-prostate-cancer]'''
*# '''<span style="color:#ff0000">To identify metastases, not demonstrated on conventional imaging, that are potentially curable by surgery or other therapy</span>'''
*# '''<span style="color:#ff0000">After biochemical recurrence, to evaluate for role of locoregional salvage treatment</span>'''
* '''<span style="color:#ff0000">2021 CUA Best Practice Report Recommendations for PSMA PET/CT</span>[https://pubmed.ncbi.nlm.nih.gov/33661093/]'''
** '''<span style="color:#ff0000">PSMA-targeted PET may be helpful (3)</span>''':
**# '''<span style="color:#ff0000">To identify clinically significant prostate cancer when systematic biopsies and MRI are negative</span>'''
**#* Recommendation strength = 4 where "Strength of recommendation: 1=strong; 2=moderate; 3=weak."
**# '''<span style="color:#ff0000">To identify metastases, not demonstrated on conventional imaging, that may influence management</span>'''
**## Primary staging of high-risk prostate cancer
**## Castration-sensitive prostate cancer (confirm oligometastatic vs. extensive disease)
**##* In metastatic, hormone-sensitive prostate cancer, docetaxel has level 1 evidence in males with high-volume disease, defined as visceral metastasis or ≥4 bone metastases with ≥ 1 beyond the vertebral bodies and pelvis
**## Non-metastatic, castrate-resistant prostate cancer
**##* If metastatic, consider systemic therapy
**# '''<span style="color:#ff0000">After biochemical recurrence, to evaluate for role of locoregional salvage treatment</span>'''
*'''<span style="color:#ff0000">Unknown if adoption of PSMA-PET resulting in improved staging of high-risk or after biochemical recurrence will result in improved overall survival.</span>'''
** Impact of PSMA-targeted PET on management ranged from 30–76%; modifications made to pre-PSMA-targeted PET planned management included avoidance of systemic therapy (19–50%) and PET-directed local therapy in up to 60% of cases[https://pubmed.ncbi.nlm.nih.gov/30850500/]