Prostate Cancer: Diagnosis and evaluation

Includes 2021 CUA Best Practice Report on PET/CT and PET/MR in Prostate Cancer

Clinical Presentation of Prostate Cancer

Only GU malignancy diagnosed by screening
- Kidney cancer usually detected incidentally on imaging
- Bladder cancer usually presents with hematuria
At the time of diagnosis§
- ≈80% present with localized disease
- ≈12% present with regional disease
- 5% present with metastatic disease
  - The proportion of patients presenting with metastatic disease has decreased over time, partly due to PSA screening

Diagnosis and Evaluation

History and physical exam

History
1. Signs and symptoms of prostate cancer
  - Localized disease is usually asymptomatic
  - Advanced disease may be associated with signs and symptoms
    - Regional symptoms: lower urinary tract symptoms, hematuria, hematospermia, bladder outlet obstruction causing renal failure, decreased ejaculate volume, and rarely, impotence
    - Metastatic symptoms: bone pain, lethargy, anemia, weight loss, pathologic fractures, and lower extremity edema; less common are malignant retroperitoneal fibrosis, paraneoplastic syndromes, disseminated intravascular coagulation, and paralysis
2. Risk factors for prostate cancer
3. Eligibility for investigations/treatment
  - PMHx, FHx, Meds, All, Social, etc.
    - Will patient benefit from investigations/treatment (age, competing risk (comorbidity))?
      - Is a TRUS biopsy of benefit in a 95 year-old male with a PSA 400 ng/mL ?
    - Is the patient a candidate for treatment (contraindications to radiotherapy, for example)?
    - Family history of BRCA/Lynch syndrome cancers may prompt genetic screening in patient
4. Patient preference for investigations/treatment
  - Benefits/harms of treatment (sexual function, for example)
Physical exam
- Body habitus
  - Determine candidacy for intervention
- Digital rectal examination
  - A palpable tumour and the extent is associated with local disease extent (clinical T stage)
  - In a screened population, an abnormal DRE is also associated with an increased risk for detecting high-grade (Gleason 8 to 10) prostate cancer
  - Can both overestimate and underestimate the extent of disease because of its poor sensitivity and lack of reproducibility
  - Consider useful to detect presence, but not useful to assess stage
  - When DRE and PSA tests are used in prostate cancer screening, detection rates are higher with PSA testing alone vs. DRE alone, and highest with the tests together
    - See PSA and Other Markers Chapter Notes
    - The 2018 AUA and 2017 CUA Guidelines support the role of DRE in screening

Labs

See PSA and Other Markers Chapter Notes
PSA
- Likely elevated in prostate cancer due to disruption of cellular architecture within the prostate gland
  - Prostate cancer lacks basal cells, resulting in the disruption of the basement membrane and normal lumen architecture
  - Prostate cancer cells produce less PSA than normal prostatic tissue
- The single test with the highest positive predictive value for prostate cancer
- Inversely correlated with risk of pathologically organ-confined disease
  - PSA < 4.0 ng/mL: 80%
  - PSA 4-10 ng/mL: 66%
  - PSA > 10.0 ng/mL: <50%
- Inversely correlated with risk of pelvic lymph node involvement
  - PSA >20 ng/ml: 20%
  - PSA >50 ng/mL: 75%
- Benign causes of elevated PSA
  1. Prostatic disease (BPH, prostatitis, prostate cancer)
  2. Prostate manipulation (prostate massage, biopsy)
  - Prostate manipulation
    - Biopsy[1][2]
      - Results in immediate elevation in the serum PSA level, with a median increase of 6-8 ng/mL
      - Usually returns to a stable, baseline level within 2-3 weeks
    - Cystoscopy[3][4]
      - Results in small (0.05-0.15 ng/mL) increase in PSA
      - Serum PSA determination after either a flexible or a rigid cystoscopy is accurate and reliable
    - TRUS[5]
      - Results in small (0.3 ng/mL) increase in PSA
      - Serum PSA determination after TRUS without biopsy is accurate and reliable
    - TURP[6][7]
      - Results in immediate elevation in the serum PSA level, with a median increase of 6-13 ng/mL[8]
      - Usually returns to a stable, baseline level within 2-3 weeks[9]
    - DRE: can lead to slight increases in serum PSA level; however, the resultant change in PSA values falls within the error of the assay and rarely causes false-positive test results
    - Ejaculation: studies examining the effect of ejaculation on serum PSA have reported conflicting results. A repeat PSA test after 48 hours of sexual abstinence may be helpful for interpreting serum PSA levels that are minimally elevated or newly elevated.
    - Cycling: long-distance cycling is a potential cause of false PSA elevation, with PSA levels increasing by ≈10% after bicycle rides > 55km
    - Urethral catheterization: very little effect on PSA level; in patients with urethral catheter, routine evaluation of PSA rising should be considered.[10]
    - Most of the rise in total PSA after prostate manipulation is contributed by the free (non-bound) component.
      - In general, complexed PSA is the most stable component and relatively little rise occurs following prostate manipulation.
  - Although as many as 30% of men seen with an elevated PSA level may be diagnosed with prostate cancer after TRUS biopsy, as many as 75-80% will not be found to have cancer
- Clinical factors that influence PSA
  - In the absence of prostate cancer, PSA levels vary with (4):
    1. Age
    2. Race
      - African-American males without prostate cancer have higher PSA values than Caucasians
    3. Prostate volume
      - PSA increases 4%/mL prostate volume
        BPH surgery can lead to reductions in the serum PSA level
        
        Annual rate of change in PSA is higher in men with BPH compared to men without BPH
    4. BMI
      - Increasing BMI independently associated with decreasing serum PSA
- PSA-derivatives
  - See Section in PSA and Other Markers Chapter Notes

Imaging

Primary

Transrectal ultrasound (TRUS)

Compared to DRE, TRUS does not improve the ability to stage prostate cancer
In general, TRUS under-stages rather than over-stages prostate cancer
Limited detection of transition zone lesions

Magnetic Resonance Imaging (MRI)

See 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[11]
- Signal intensities from tissues vary based on the hydrogen/proton content of that tissue

Imaging sequences

Anatomic MRI sequences
- T1-weighted imaging (T1WI)
- T2-weighted imaging (T2WI)
Functional MRI sequences
- Diffusion weighted imaging (DWI) with apparent diffusion coefficient (ADC) maps
- Dynamic contrast enhanced (DCE) imaging
- Magnetic resonance spectroscopic imaging
Multi-parametric (mpMRI) is the combination of multiple MRI sequences
In prostate cancer, the primary diagnostic parameters are (2):[12]
- T2WI
- DWI with ADC maps
Bi-parametric MRI (bpMRI)
- Combination of T2WI and DWI (with ADC maps)
- Advantages
  - Fewer sequences reduces time/costs to complete study
- 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
    - 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.
T2WI
- Captures the movement of protons in the xy-axis (transverse)
- Primary uses (2):
  1. Visualization of zonal and anatomical features of the prostate.
    - See Figure
  2. Optimal sequence to evaluate lesions in the transition zone[13]
- Signal intensity
  - High signal intensity
    - Fluids (CSF, urine)
    - Normal peripheral zone (due to its high water content)
    - Seminal vesicles
  - Intermediate intensity
    - Central zone
      - Intermediate/low intensity lesions on T2 at base of prostate and paramedian may be central zone that is being pushed out by BPH nodules of transition zone
  - Low signal intensity (7):
    1. Prostate cancer
      - 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
    2. Prostatitis
    3. Hemorrhage
      - Post-biopsy hemorrhage can interfere with tumor detection, since areas of hemorrhage appear similar to tumor on T2WI. For this reason, it is recommended to wait an interval of at least 6-8 weeks after prostate biopsy for resolution of hemorrhage or hematoma before performing prostate MRI.
    4. Atrophy
    5. Scars
    6. Post-treatment changes
    7. Stromal hyperplasia i.e. benign prostatic hyperplasia (BPH)
      - Clinical implication: Benign prostatic hyperplasia nodules can be difficult to distinguish from low signal intensity tumours
- Lesion shape
  - Wedge-shaped/linear lesions are more likely benign
Diffusion weighted imaging (DWI)
- Measures the diffusion of water protons within tissue
  - Protons are mobile in normal water-rich glandular tissue but have restricted movement in densely packed water-poor tissue such as that found in tumors.
- 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[14]
  - 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[15]
  - Normal glandular prostate tissue allows unrestricted free water movement and appears as isointense regions on ADC maps
  - Prostate cancer restricts diffusion and appears as
    - High signal intensity focus on high b-value images
      - Image with highest b-value (lowest ADC) likely to be most useful
    - Decreased signal, ie restricted diffusion, on the ADC map[16]
- Primary use:
  - Optimal sequence to evaluate lesions in the peripheral zone[17]
- Tumors with the higher restriction (low ADC values) tend to be higher grade
T1WI
- Captures the movement of protons in the z-axis
- Primary uses (2):
  1. Often used to look at normal anatomical details.
  2. Optimal sequence to identify areas of hemorrhage within the prostate
    1. Residual areas of hemorrhage post-biopsy can obscure underlying cancers[18]
      1. 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[19]
- Signal intensity
  - High intensity
    - Blood has high signal intensity on T1, against a homogenous low signal background.
  - Low intensity
    - Fluids (CSF, urine)
    - Prostate cancer
Dynamic contrast enhancement (DCE)
- DCE imaging uses a series of T1WI obtained shortly after injection of an intravenous gadolinium based contrast agent to measure the vascularity of prostate tissue.
  - 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.
- While DCE imaging has a high sensitivity, there remains a variability in the evaluation methods questioning it’s value; preferentially detects larger and higher-grade cancer foci
Magnetic resonance spectroscopic imaging (MRSI)
- 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
- When combined with T2WI, MRSI has been found to have the highest sensitivity of all MRI sequences (92%) in detecting prostate cancer.
- 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.
Biparametric MRI
- A limitation of mpMRI for implementation as an adjunct tool for prostate cancer screening is the time required to complete the study, including the placement of an endorectal coil and the use of gadolinium based contrast agents requiring intravenous access. To overcome these limitations, it has been suggested that a limited mpMRI study incorporating only non-contrast T2WI and DWI series be performed.
- This biparametric MRI requires less than half the in-bore magnet time to perform compared with the complete mpMRI, can be performed without an endorectal coil, and obviates the need for intravenous access and contrast administration.

Magnet strength

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.

Endorectal coil

Advantages
- Increase the SNR
  - 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.
    - The highest signal-to-noise ratio (SNR) is achieved at 3T with an endorectal coil but acceptable results can be achieved at 3T without an endorectal coil.
- improves the staging of prostate cancer, particularly for the determination of extraprostatic extension (EPE) and seminal vesicle invasion, tumor volume, and tumor laterality
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.

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):[20]
  1. Gleason score ≥7 (including 3+4 with prominent but not predominant Gleason 4 component) and/or
  2. Volume ≥0.5cc and/or
  3. Extra prostatic extension(EPE).
- Positive predictive values ISUP grade group ≥2 based on PI-RADS score:[21]
  - PI-RADS 3: 12–15%
  - PI-RADS 4: 39–48%
  - PI-RADS 5: 72%
- If PIRADS[22]
  - ≥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.

Test Characteristics

Cochrane Systematic Review and Meta-analysis (2019)
- 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)
- 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).
PROMIS (2017)
- Objective: evaluate sensitivity/specificity of prostate MRI vs. standard TRUS biopsy, 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
- Results:
  - mpMRI displayed a moderate sensitivity (88%) and negative predictive value (76%), but poor specificity (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.
- 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.

Advantages

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
PRECISION (2018)
- 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
- Population: 500 males with clinical suspicion of prostate cancer based on elevated PSA or abnormal DRE
- Randomized to standard TRUS–guided biopsy vs. MRI +/- targeted biopsy
  - 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
- Results:
  - MRI-targeted biopsy was non-inferior and superior to detecting clinically significant cancer (absolute risk difference 12%, 38% MRI vs. 26% standard TRUS)
  - MRI-targeted biopsy was associated with fever patients being diagnosed with clinically insignificant cancer (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.
- Kasivisvanathan, Veeru, et al. "MRI-targeted or standard biopsy for prostate-cancer diagnosis." New England Journal of Medicine 378.19 (2018): 1767-1777.
STHLM3 - MRI-targeted vs. standard biopsy in prostate cancer screening
- 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)
- Eklund, Martin, et al. "MRI-targeted or standard biopsy in prostate cancer screening." New England Journal of Medicine (2021).

Disadvantages

Availability/cost
Interobserver reproducibility remains a challenge.[23]
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

2023 NCCN (PROSD-3)
- Multiparametric MRI is strongly recommended, if available [before biopsy]
2022 EAU[24]
- Systematic biopsy is an acceptable approach in case MRI is unavailable
2017 Cancer Care Ontario Guidelines
- Biopsy-naïve: MRI should not be considered standard of care
- Prior negative biopsy: MRI followed by targeted biopsy may be considered

Targeted biopsy only vs. targeted and systematic

MRI-FIRST (2019)
- 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
- 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.
Ahdoot et al. (2020)
- 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.
- Ahdoot, Michael, et al. "MRI-targeted, systematic, and combined biopsy for prostate cancer diagnosis." New England Journal of Medicine 382.10 (2020): 917-928.
GOTEBORG-2 (2022)
- Objective: Determine whether targeted-biopsy only (and avoid systematic) is adequate in patients with elevated PSA 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:
  - 17,980 (47%) of those randomized to invitation to screening underwent PSA testing
    - 7% had PSA > 3 ng/mL
      - 95% of patients with PSA > 3 ng/mL underwent MRI
  - Clinically insignificant prostate cancer: significantly more common in patients undergoing systematic +/- targeted biopsy compared to targeted biopsy only (1.2% vs. 0.6%)
  - Clinically significant prostate cancer: no significant difference (1.1% systematic +/- targeted vs. 0.9% targeted biopsy only)
  - 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
  - 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: The avoidance of systematic biopsy in favor of MRI-directed targeted biopsy for screening and early detection in persons with elevated PSA levels reduced the risk of overdiagnosis by half at the cost of delaying detection of intermediate-risk tumors in a small proportion of patients.
- 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
- PSA density > 0.15 ng/ml/cc[25][26]
- History of previous negative biopsy[27]
- Abnormal DRE[28]/Clinical stage T2a or greater[29]
- Prostate cancer family history[30]

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.

Metastasis

"Conventional" imaging
- Regional
  - CT is used for regional lymph node staging
- Distant
  - Radionuclide bone scan (bone scintigraphy) is the most commonly employed modality for the detection of skeletal metastases
    - 18F-PET provides the best sensitivity and specificity for the detection of bony metastases in prostate cancer
Novel PET-CT imaging[31]
- Advantage over conventional imaging
  - Higher sensitivity for the detection of prostate cancer recurrence and metastases at low PSA values (<2.0ng/mL).
    - 38% of PSMA-targeted PET scans show disease sites in males with PSA <0.5 ng/ml[32]
- Positron emission tomography (PET) scan uses 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
  - Prostate cancer PET radiopharmaceutical tracers
    - Not PSMA-specific radiopharmaceutical tracers
      - Examples include 18F-fluciclovine (trade name Axumin), 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[33]
    - PSMA-specific radiopharmaceuticals tracers
      - 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
      - PSMA-specific radiopharmaceutical tracers used in prostate cancer (2):
        Fluorine-18 (18F)-labeled PSMA-specific (18F-DCFPyL (trade name Pylarify), 18F-PSMA-1007)
        Most commonly used radiotracer in the US and (18F-DCFPyL) Canada
        
        18F-DCFPyL adverse reactions: headache, altered taste, fatigue[34]
        
        Gallium-68 (68Ga)-labeled PSMA-specific
        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[35]
        
        Excretion: urinary
      - Uptake of PSMA-specific radiopharmaceuticals[36]
        Physiological
        High uptake: lacrimal and salivary glands, kidneys
        
        Moderate uptake: spleen, nasopharynx
        
        Variable uptake: vocal cords, trachea, bronchi, proximal GI tract
        
        Uptake also seen in central nervious system and peripheral nervous system (ganglia and nerve routes)
        Celiac and stellate ganglia may be false-positives for retroperitoneal and supraclavicular lymphadenopathy
        
        Benign disease
        Infectious and inflammatory processes (e.g., sarcoidosis)
        Increased blood flow and vascular permeability may partly explain the increased PSMA uptake in inflammatory conditions.
        
        Benign neoplasms (mesenchymal tumors (vascular, neurogenic, connective tissue origin) and epithelial tumors (edenoma and thymoma))
        
        Bone remodelling (healing fractures, degenerative or arthritic processes (e.g., osteophytes), Paget's disease)
        
        Amyloidosis
        
        Malignancy
        Prostate cancer
        
        Non-prostate malignancies
        Renal cell carcinoma, leiomyosarcoma, thyroid cancer, nasopharyngeal cancer, GI tract cancer, breast cancer, neuroendocrine cancer
      - Clearance of PET tracers used in prostate cancer[37]
        Most are cleared via the urinary tract, with high accumulation in the urinary tract and bladder and moderate uptake in the liver
        Exception: 18F-PSMA-1007, 18F-fluciclovine, and 11-choline are cleared primarily by the hepatobiliary tract, with higher uptake in the liver, and little accumulation in the ureters and bladder
        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.
      - Causes of false-negative PSMA-targeted PET
        Small tumor volume
        May be seen in early-stage biochemical recurrence when the serum PSA <0.5 ng/ml
        
        Neuroendocrine differentiation of prostate cancer with downregulation of PSMA expression
        Neuroendocrine differentiation occurs in 5–10% of prostate cancers overall and approximately 30% of men with advanced disease
        
        Androgen receptor inhibition
        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
- Indications
  - FDA approved for (2)[38]
    1. To identify metastases, not demonstrated on conventional imaging, that are potentially curable by surgery or other therapy
    2. After biochemical recurrence, to evaluate for role of locoregional salvage treatment
  - 2021 CUA Best Practice Report Recommendations for PSMA PET/CT[39]
    - PSMA-targeted PET may be helpful (3):
      1. To identify clinically significant prostate cancer when systematic biopsies and MRI are negative
        Recommendation strength = 4 where "Strength of recommendation: 1=strong; 2=moderate; 3=weak."
      2. To identify metastases, not demonstrated on conventional imaging, that may influence management
        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
      3. After biochemical recurrence, to evaluate for role of locoregional salvage treatment
- Evaluation of metastatic prostate cancer
  - Primary staging of high-risk prostate cancer
    - proPSMA (2020)
      - 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.
        
        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
    - Improved quantification of metastatic burden
      - Oligometastatic disease may be identified, and such patients may be offered management in clinical trials or metastatis-directed surgery.
        Unknown if earlier identification of metastatic disease with the use of novel PET-CT scans improves overall survival.
        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[40]
    - Determining patient suitability for PSMA-targeted radionuclide therapy
      - Both 177Lu and 225Ac PSMA-targeted radioligand therapy are emerging as promising therapies for castration-resistant disease.
  - Staging of biochemical recurrence
    - 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
  - Primary detection of tumor as an adjunct to multiparametric MRI
    - Role of PSMA-targeted PET as an adjunct to mpMRI for primary detection of clinically significant prostate cancer is not well-established

Other

Risk calculators

Concept: improve prediction models by combining variables
Most widely used in prostate cancer: ERSPC and PCPT

Genetic testing

Germline mutations are inherited from parents; all cells have the mutation except red blood cells
Somatic mutations are acquired
Indications
- NCCN (version 2.2021)
  - Recommended (5)
    1. Metastatic (distant or regional (node-positive) prostate cancer
    2. High- or very-high risk localized prostate cancer
    3. Personal history of breast cancer
    4. Positive family history of high-risk germline mutations (e.g. BRCA 1/2, Lynch syndrome)
      - BRCA-cancers (5): breast, ovarian, pancreatic, prostate, melanoma
      - Lynch syndrome cancers: (8) colonic (most common), endometrial (second most common), prostate, urothelial, adrenal, gastric, pancreatic, uterine, ovarian, and sebaceous carcinomas
    5. Ashkenazi Jewish ancestry
  - Optional (2)
    1. Intermediate-risk with intraductal or cribiform histology
    2. Personal history of colorectal, gastric, melanoma, uppert tract urothelial, glioblastoma, biliary tract, or small intestine

Transrectal Ultrasound (TRUS) Biopsy

Patients with clinical indications to confirm diagnosis of prostate cancer undergo TRUS biopy
Triggers for biopsy
- A PSA level that is considered suspicious for prostate cancer should be remeasured before performing a prostate biopsy because of fluctuations in PSA levels that could create false-positive elevations.
  - According to the AUA Choosing Wisely Campaign, empirical antibiotics should not be given to patients exclusively for an elevated PSA without any other urinary symptoms
- The choice of a PSA threshold for recommending a prostate biopsy is controversial.
  - Historically, many would recommend prostate biopsy once a patient’s serum PSA level is >4.0 ng/mL. However, data from the Prostate Cancer Prevention Trial demonstrated an overall prostate cancer detection rate of 15% for all men with a PSA level < 4.0 ng/mL and nearly 15% having a Gleason score of 7 or greater, suggesting no absolute safe threshold.
- Numerous organizations now recommend using PSA together with other methods of risk assessment, such as family history, race, DRE findings, and risk calculators

Questions

What is the optimal MRI sequence to evaluate
1. Hemorrhage
2. Transition zone
3. Vascularity of the prostate
4. Peripheral zone
Describe the PROMIS and PRECISION trials
What is the differential diagnosis for an area of low signal intensity on T2WI?

Answers

What is the optimal MRI sequence to evaluate
1. Hemorrhage
2. Transition zone
3. Vascularity of the prostate
4. Peripheral zone
Describe the PROMIS and PRECISION trials
What is the differential diagnosis for an area of low signal intensity on T2WI?

Next Chapter: PSA and Other Markers

References

Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 111
AUA Update Series (2016) Lesson 14: Multiparametric Magnetic Resonance Imaging for Prostate Cancer
Shaygan, Bobby, et al. "Canadian Urological Association best practice report: Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) and PET/magnetic resonance (MR) in prostate cancer." Canadian Urological Association Journal 15.6 (2021): 162.