Editing Prostate Cancer: Diagnosis and evaluation (section)

==== <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/]