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PROSTATE CANCER: DIAGNOSIS & 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
  2. Risk factors for prostate cancer
  3. Eligibility for investigations/treatment
  4. Patient preference for investigations/treatment
- 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)
    - 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
    - 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
    - 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.
  - Clinical factors that influence PSA
    - In the absence of prostate cancer, PSA levels vary with (4):
      1. Age
      2. Race
      3. Prostate volume
      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
  - Multi-parametric MRI (mpMRI)
    - MRI acquires imaging data by detecting varying signal intensities from tissues based on the proton content of that tissue
    - mpMRI is the combination of multiple MRI sequences usually consisting of T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), diffusion weighted imaging (DWI), dynamic contrast enhanced (DCE) imaging and magnetic resonance spectroscopic imaging.
    - Imaging sequences
      - The primary diagnostic parameters are T2WI and DWI
      - T1WI
        
        Captures the movement of protons in the z-axis
        
        Often used to look at normal anatomical details.
        
        Optimal sequence to identify areas of hemorrhage within the prostate
        
        Blood has high signal intensity on T1, against a homogenous low signal background.
        
        Prostate cancer has low signal intensity on T1
      - T2WI
        
        Captures the movement of protons in the xy-axis (transverse)
        
        Primary means of visualization of zonal and anatomical features of the prostate.
        
        Optimal sequence to measure lesions in the transition zone
        
        Due to its high water content, the peripheral zone normally displays high signal intensity. By contrast, prostate cancer has low signal intensity on T2 allowing for identification of suspicious lesions
        
        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
        
        Various conditions such as prostatitis, hemorrhage, atrophy, scars and post-treatment changes have low signal intensity on T2 and can mimic cancer on T2WI.
        
        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.
        
        Low signal intensity tumors on T2WI of the central gland are more difficult to distinguish from the similarly hypointense stromal hyperplasia, ie benign prostatic hyperplasia
        
        Central zone also displays intermediate signal intensity while seminal vesicles display high signal intensity
      - Diffusion weighted imaging (DWI)
        
        Measures the diffusion of water protons within tissue
        
        The images are acquired by sequentially applying multiple magnetic field gradients, known as b-values, to calculate apparent diffusion coefficient values and construct ADC maps. The higher the b-value, the stronger the diffusion effects
        
        ADC values are calculated by the software and displayed as a parametric map reflecting the degree of diffusion of water molecules through different tissues.
        
        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.
        
        Normal glandular prostate tissue allows unrestricted free water movement and displays isointense regions on ADC maps, which results in prostate cancer appearing as a decreased signal, ie restricted diffusion, on the ADC map and as high signal intensity focus on high b-value images.
        
        Tumors with the higher restriction (low ADC values) tend to be higher grade
        
        Optimal sequence to evaluate suspicious lesions in the peripheral zone
      - 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
      - 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 to increase the SNR
      - An ERC can lead to deformation of the gland which may affect the image registration for targeted biopsy or radiation planning, although concerns regarding alterations in prostate volume have largely been dispelled.
      - The absolute benefit of an ERC may be offset by patient discomfort, additional time required for proper placement and verification, and associated cost
      - 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.
    - Prostate imaging and reporting archiving data system
      - The PI-RADS score provided guidance for interpretation of different sequences and prostate zones
      - 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.
    - MRI in Prostate Cancer
      - PROMIS (2017)
        
        Objective: compare the accuracy of mpMRI with TRUS biopsy to determine the utility of mpMRI as a triage test to decide which men with an elevated PSA may be able to avoid biopsy
        
        Population: 576 men with a clinical suspicion of prostate cancer (PSA ≤15 ng/mL)
        
        Intervention: mpMRI followed by standard TRUS biopsy with template prostate mapping biopsy as gold standard reference
        
        Results:
        
        mpMRI displayed a moderate sensitivity and negative predictive value for predicting Gleason ≥3+4 disease (88% and 76%, respectively), but poor specificity and positive predictive value (45% and 65%, respectively).
        
        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.
      - PRECISION (2018)
        
        Objective: can MRI be used to increase detection of clinically significant prostate cancer and decrease detection of clinically insignificant prostate cancer
        
        Design: Non-inferiority trial
        
        Population: 500 men with clinical suspicion of prostate cancer
        
        Randomized to MRI +/- targeted biopsy vs. standard TRUS–guided biopsy
        
        Men in the MRI group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy
        
        Outcomes
        
        Primary: proportion of men who received a diagnosis of clinically significant cancer
        
        Secondary: proportion of men 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.
      - MRI-FIRST (2019)
        
        Objective: determine whether MRI prior to biopsy increases detection of clinically significant prostate cancer
        
        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.
      - MRI may identify more clinically significant disease, avoid clinically insignificant disease, and help tailor treatment; however, up to 20% of negative MRI have clinically significant prostate cancer
        
        STHLM3 - MRI-targetted vs. standard biopsy in prostate cancer screening
        
        Population: 1532 males aged 50-74 years with screening PSA > 3 ng/mL
        
        Randomized to standard biopsy vs. MRI, with targeted and standard biopsy if the MRI results suggested prostate cancer
        
        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 insignificiant 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).
        
        Use of MRI in prostate cancer diagnosis as per the 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
      - MRI better at identifying anterior tumours
      - MRI interobserver reproducibility remains a challenge.
      - MRI has a learning curve related to reading 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.
  - 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§
    - 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§
    - 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
    - Indications
      - FDA approved for (2)§
        To identify metastases, not demonstrated on conventional imaging, that are potentially curable by surgery or other therapy
        
        After biochemical recurrence, to evaluate for role of locoregional salvage treatment
      - 2021 CUA Best Practice Report Recommendations for PSMA PET/CT§
        
        PSMA-targeted PET may be helpful (3):
        
        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."
        
        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
        
        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.
    - Prmary 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 equivacol findings with PSMA PET-CT
        
        Radiation exposure reduced with PSMA PET-CT (8 mSv PSMA PET-CT vs. 19 mSv conventional imaging)
    - Limitations:
- 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§
- 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 widley 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)
        
        Metastatic (distant or regional (node-positive) prostate cancer
        
        High- or very-high risk localized prostate cancer
        
        Personal history of breast cancer
        
        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
        
        Ashkenazi Jewish ancestry
      - Optional (2)
        
        Intermediate-risk with intraductal or cribiform histology
        
        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

Answers

Next Chapter: Screening

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.