Editing Management of Localized Prostate Cancer (section)

== Conservative management ==

=== <span style="color:#ff0000">Observation/watchful waiting</span> ===

* '''<span style="color:#ff0000">Refers to monitoring the patient until he develops metastases that requires palliative treatment</span>'''
* '''<span style="color:#ff0000">Indications</span>'''
*# '''<span style="color:#ff0000">Asymptomatic males with limited life expectancy</span>'''
*#* '''Threshold varies between guidelines'''
*#** '''<span style="color:#ff0000">2022 AUA: < 5-years life expectancy</span>'''
*#** 2021 NCCN:< 5-10 years life expectancy
*#** '''Symptomatic men should be treated'''
* '''<span style="color:#ff0000">Life expectancy calculators (listed above) can help estimate the patient's risk of death from competing causes.</span>'''
** Clinician-based life expectancy estimates are not robust.[https://pubmed.ncbi.nlm.nih.gov/9495697/][https://pubmed.ncbi.nlm.nih.gov/12137823/][https://pubmed.ncbi.nlm.nih.gov/17979925/][https://pubmed.ncbi.nlm.nih.gov/23093629/]
* '''<span style="color:#ff0000">RCTs comparing treatment and observation (3): PIVOT, SPCG-5, PROTECT</span>'''
** '''<span style="color:#ff00ff">PIVOT – NO BENEFIT</span>'''
*** '''<span style="color:#ff0000">Population: 731 US men</span>''' from Department of Veterans Affairs and National Cancer Institute medical centers, '''with:'''
**** '''cT1-2'''NxM0 prostate cancer
**** Any grade
**** PSA < 50
**** Life expectancy ≥ 10 years
*** '''<span style="color:#ff0000">Randomized to observation vs. radical prostatectomy</span>'''
*** '''<span style="color:#ff0000">Outcomes:</span>'''
**** '''<span style="color:#ff0000">Primary: overall survival</span>'''
**** '''Secondary: cancer-specific survival</span>'''
*** '''<span style="color:#ff0000">Results:</span>'''
**** Cohort characteristics:
***** Mean age ≈67
***** Mean PSA ≈10 (median ≈8)
***** ≈50% cT1c
***** ≈70% Gleason score ≤ 6
***** ≈40% low-risk
**** Median follow-up: 10 years (initial 2012 publication, updated in 2020 to 18.6 years)
**** '''<span style="color:#ff0000">Primary outcome: no significant difference in overall survival in initial publication</span>'''
***** '''<span style="color:#ff0000">In 2020 publication with median follow-up in survivors 18.6 years, overall survival significantly improved in radical prostatectomy group</span>'''
****** Emphasizes importance of long-term follow-up in studies evaluating survival in prostate cancer.
***** 2020 subgroup analyses:
****** Age: benefit less pronounced in age ≥ 65
****** Risk stratum: benefit less pronounced in low-risk
**** '''<span style="color:#ff0000">Secondary outcome: no significant difference cancer-specific survival</span>''' in initial publication
*** Criticisms:
**** Underpowered to detect a difference in survival, enrollment could not be achieved
**** Conducted in Veterans Affairs hospitals where many men had relatively poor health; disease; other-cause mortality in this trial was higher than in other trials, suggesting that men enrolled had more comorbidities
**** Radical prostatectomies were performed with higher complication rates with worse cancer control outcomes compared with the series from the centers of excellence
**** Follow-up is insufficient to assess the mortality caused by prostate cancer
*** [https://pubmed.ncbi.nlm.nih.gov/22808955/ Wilt, Timothy J., et al.] "Radical prostatectomy versus observation for localized prostate cancer." N Engl J Med 367 (2012): 203-213.
*** [https://www.nejm.org/doi/full/10.1056/NEJMoa1615869 Wilt, Timothy J., et al.] "Follow-up of prostatectomy versus observation for early prostate cancer." New England Journal of Medicine 377.2 (2017): 132-142.
*** [https://pubmed.ncbi.nlm.nih.gov/32089359/ Wilt, Timothy J., et al.] "Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer: Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT)." ''European urology'' (2020).
** '''<span style="color:#ff00ff">SPCG-4</span> – <span style="color:#ff0000">NET BENEFIT</span>'''
*** '''<span style="color:#ff0000">Population: 695 men from Sweden, Finland, and Iceland, with localized prostate cancer with</span>'''
**** '''cT1-2'''NxM0 prostate cancer
**** Well differentiated to moderately well differentiated
**** PSA < 50
**** Life expectancy ≥ 10 years
*** '''<span style="color:#ff0000">Randomized to observation vs. radical prostatectomy</span>'''
*** '''<span style="color:#ff0000">Outcomes: survival</span>'''
*** '''<span style="color:#ff0000">Results</span>'''
**** Cohort characteristics:
***** Mean age ≈65
***** '''Higher-risk population than PIVOT'''
****** cT2 75% vs. 45% PIVOT
****** Mean PSA 13 vs. 10 PIVOT
**** Median follow-up: 8.2 years (initial 2005 publication, updated in 2018 to 23.6 years)
**** '''<span style="color:#ff0000">Overall, cancer–specific, distant metastases-free survival were significantly worse in patients managed with watchful waiting</span>''' (in initial and updated publication)
**** '''Men on watchful waiting experienced significantly more obstructive voiding complaints and bowel problems'''
***[https://pubmed.ncbi.nlm.nih.gov/15888698/ Bill-Axelson, Anna, et al.] "Radical prostatectomy versus watchful waiting in early prostate cancer." ''N Engl J Med'' 352 (2005): 1977-1984.
*** [https://www.nejm.org/doi/full/10.1056/NEJMoa1807801 Bill-Axelson, Anna, et al.] "Radical prostatectomy or watchful waiting in prostate cancer—29-year follow-up." New England Journal of Medicine 379.24 (2018): 2319-2329.
** '''<span style="color:#ff00ff">PROTECT</span> – <span style="color:#ff0000">SOME BENEFIT</span>'''
*** '''<span style="color:#ff0000">Population: 1643 men from UK with localized prostate cancer</span>'''
*** '''<span style="color:#ff0000">Randomized to surgery, radiotherapy, vs. “active monitoring”</span>'''
**** Among those assigned to
*****Active monitoring, ≈15% underwent prostatectomy or radiotherapy
******No rigorous AS follow-up protocol; patients followed with serial PSA, no mandated repeat biopsy
*****Prostatectomy, ≈17% underwent prostatectomy or radiotherapy
*****Radiotherapy, ≈14% underwent prostatectomy or radiotherapy
*** '''<span style="color:#ff0000">Outcomes:</span>'''
**** '''<span style="color:#ff0000">Primary: cancer-specific survival</span>'''
**** Secondary: overall survival, metastases, clinical progression, primary treatment failure, treatment complications.
*** '''<span style="color:#ff0000">Results</span>'''
**** Cohort characteristics:
***** Mean age 62
***** Lowest risk, compared to PIVOT and SPCG-4
****** Median PSA 4.7-4.9
****** ≈75% Gleason score 6, ≈20% Gleason score 7
****** ≈75% cT1c, ≈25% cT2
**** Median follow-up: 15 years
**** '''<span style="color:#ff0000">Primary outcome: no significant difference in cancer-specific survival</span>'''
**** '''<span style="color:#ff0000"><span style="color:#ff0000">Secondary outcomes:</span>'''
***** '''<span style="color:#ff0000">No significant difference in overall survival</span>'''
***** '''<span style="color:#ff0000">Metastasis significantly increased in active monitoring group</span>'''
*****'''<span style="color:#ff0000">ADT significantly increased in active monitoring group</span>'''
*** Hamdy, Freddie C., et al."10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer." New England Journal of Medicine 375.15 (2016): 1415-1424.
***[https://www.nejm.org/doi/full/10.1056/NEJMoa2214122 Hamdy, Freddie C., et al.] "Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer." New England Journal of Medicine (2023)
** '''Trials in context: older men with low-risk disease, especially those with associated comorbidities are unlikely to benefit from curative intervention.'''
* '''<span style="color:#ff0000">At 10-years, the risk of metastasis is ≈20% in men on observation/watchful waiting</span>'''
* '''Follow-up'''
** '''History and physical examination (including DRE), PSA and creatinine measurement at 6-month intervals, and an annual bone scan''' has been suggested
*** '''Progression of disease among men on watchful waiting could occur as a result of local tumor growth and/or metastatic spread of disease to lymph nodes or bone'''.
**** Local extension of disease may result in lower urinary tract symptoms (irritative and obstructive) or upper tract obstruction from invasion into the trigone of the bladder
*** '''While disease progression would most often be accompanied by increases in PSA, poorly differentiated cancers producing little PSA can progress without a rising PSA, especially with neuroendocrine differentiation. Thus, follow-up should not rely on serial PSA measurements alone.'''
*** Campbells: "Because the goal of watchful waiting is to limit morbidity and not to administer potentially curative treatment, PSA testing, repeat biopsy, and imaging studies are unimportant."
** '''<span style="color:#ff0000">Indications for intervention (androgen deprivation therapy as palliative care) on watchful waiting:</span>'''
**# '''<span style="color:#ff0000">Symptomatic progression</span>'''
**# '''<span style="color:#ff0000">Evidence of upper urinary tract obstruction</span>'''
**# '''<span style="color:#ff0000">Evidence of metastatic disease</span>'''

=== <span style="color:#ff0000">Active surveillance</span> ===

* '''<span style="color:#ff0000">Active surveillance (AS) refers to delayed primary treatment (with curative intent) if there is evidence of cancer progression</span>'''
* '''Disease-specific and all-cause survival have been high and compare favorably with longer-term outcomes after prostatectomy or various forms of radiotherapy in similar-risk men of low-risk tumors'''
**Observational studies demonstrate cumulative incidence of prostate cancer-specific mortality or metastasis of <1% at 10 years[https://pubmed.ncbi.nlm.nih.gov/31918957/][https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480884/]
*Use of AS for low-risk disease increasing over time, but remains suboptimal[https://pubmed.ncbi.nlm.nih.gov/36862409/]
* '''<span style="color:#ff0000">Advantage of surveillance:</span>'''
*# '''<span style="color:#ff0000">Reduce overdiagnosis/overtreatment of prostate cancer</span>'''
*#* '''Overdiagnosis refers to a cancer detected by screening that would not be detected during the patient’s lifetime without screening or would never cause disability or death.'''
*#** There is substantial overdiagnosis of prostate cancer as a result of widespread PSA screening coupled with aggressive biopsy regimens.
*#** Any screening program will involve detection of some cancers that would not have been otherwise detected.
*#* '''Overtreatment refers to treatment of men who would otherwise not have known about their cancer in the absence of PSA testing.'''
*#** The risk of overtreatment of prostate cancer is high when prostate cancer is discovered on prostate biopsies triggered by PSA testing—the most common scenario.
* '''<span style="color:#ff0000">Disadvantages of surveillance:</span>'''
*# '''<span style="color:#ff0000">Risk of multiple biopsy procedures</span>'''
*#* '''Risks of repeat biopsies include infections, erectile dysfunction, complicate subsequent attempts at nerve-sparing surgery'''
*# '''<span style="color:#ff0000">Delaying treatment and possibly missing the window of opportunity for cure</span>'''
* '''<span style="color:#ff0000">Disease Reclassification on AS</span>'''
** '''Reclassification vs. progression'''
*** '''The term progression while on AS should be replaced with disease reclassification, since most patients meeting surveillance criteria who are found to have high-grade or more extensive disease on surveillance biopsies are thought to have been misclassified initially, rather than experiencing true disease progression'''
**** One study found that 36% of men with Gleason score 5-6 on needle biopsy were found to have higher-grade disease at radical prostatectomy when tertiary grade was considered. Another study found that the 10-year actuarial rate of upgrading on annual surveillance biopsies in a large active surveillance experience was ≈30%. The similarity in the rate of upgrading at radical prostatectomy, and reclassification to high-grade disease on annual biopsies for men with low-grade cancer, strongly suggest that initial misclassification is the more common reason for re-classification on surveillance, and not “true” disease progression from low to high grade.
** '''<span style="color:#ff0000">≈25-50% of patients on AS develop evidence of disease reclassification within 5 years, depending on their individual risk factors:</span>'''
*** '''<span style="color:#ff0000">Patient factors</span>'''
**** '''<span style="color:#ff0000">Race</span>'''
***** '''<span style="color:#ff0000">African-American males are at increased risk of progression on AS[https://pubmed.ncbi.nlm.nih.gov/34239046/]</span>'''
**** '''<span style="color:#ff0000">Germline mutations[https://pubmed.ncbi.nlm.nih.gov/30309687/]</span>'''
***** '''<span style="color:#ff0000">BRCA</span>'''
****** '''<span style="color:#ff0000">BRCA 2 associated with higher risk than BRCA 1</span>'''
******* '''<span style="color:#ff0000">BRCA 1 associated with 4x higher risk of prostate cancer</span>'''
******* '''<span style="color:#ff0000">BRCA 2 associated with 9x higher risk of prostate cancer</span>, higher Gleason scores, more advanced tumor stage, and shorter median survival'''
**** Body mass index[https://pubmed.ncbi.nlm.nih.gov/32852532/]
****Age[https://pubmed.ncbi.nlm.nih.gov/27469419/]
****'''Age, comorbid illness, and willingness to adhere to surveillance strategies must also be considered during patient selection'''
*** '''<span style="color:#ff0000">Disease factors</span>'''
**** '''PSA density''' has been a consistent '''independent predictor of disease reclassification''' (both cancer volume on biopsy and grade) during surveillance.[https://pubmed.ncbi.nlm.nih.gov/34181465/][https://pubmed.ncbi.nlm.nih.gov/27469419/]
****Bilateral disease[https://pubmed.ncbi.nlm.nih.gov/34181465/]
****Percent of positive cores[https://pubmed.ncbi.nlm.nih.gov/32852532/][https://pubmed.ncbi.nlm.nih.gov/25819722/] (not percentage of core involvement) on most recent biopsy
****History of any negative biopsy after diagnosis[https://pubmed.ncbi.nlm.nih.gov/32852532/][https://pubmed.ncbi.nlm.nih.gov/25819722/] 
****Total number of biopsies without grade reclassification[https://pubmed.ncbi.nlm.nih.gov/27469419/]
****Time since diagnosis[https://pubmed.ncbi.nlm.nih.gov/32852532/]
****'''PSA kinetics (velocity or doubling time)''' has been associated with adverse pathology in men on surveillance, but '''not consistently associated with disease reclassification'''
**** 2 gene expression (Oncotype DX and Polaris, see PSA and Other Markers Chapter Notes) assays are now commercially available for prostate cancer and are integrated with baseline clinical variables to provide more precise risk assessment for patients; however, to date it is unknown what role these tests will have in AS
* '''<span style="color:#ff0000"><span style="color:#ff0000">Indications</span> (2022 AUA Guidelines)'''
** '''<span style="color:#ff0000">Preferred option for low-risk patients</span>'''
***The Epstein criteria were selected to identify potentially low-risk tumors and are among the most popular used for patient selection for active surveillance. By these criteria, “insignificant” tumors are predicted by''':'''
**** Grade group 1 disease on biopsy and
**** Clinical stage T1c and either
***** PSA density ≤ 0.1 ng/mL per gram, ≤ 2 positive biopsy cores, and no cores with > 50% involvement or
***** PSA density of ≤ 0.15 ng/mL per gram or less and cancer smaller than 3 mm on only one biopsy core.
*** More extensive biopsies during the standard 12-core biopsy have not been shown to be helpful in selecting patients for AS
** '''May be offered to select patients with favorable intermediate-risk disease'''
*** '''Patients with favorable intermediate-risk disease who may be considered for active surveillance include those with (3):'''
***#'''Low PSA density'''
***#'''Low tumor volume'''
***#'''Low percentage of Gleason pattern 4 disease on biopsy'''
* '''<span style="color:#ff0000">Surveillance protocol</span>'''
** '''<span style="color:#ff0000">Patients should be monitored with (4):</span>'''
**#'''<span style="color:#ff0000">Serial PSA values</span>'''
**#'''<span style="color:#ff0000">Symptom assessments</span>'''
**#'''<span style="color:#ff0000">DRE</span>'''
**#'''<span style="color:#ff0000">Repeat prostate biopsy</span>'''
**'''<span style="color:#ff0000">Tumour grade is the best predictor of cancer biology</span>''' and is is the strongest predictor of long-term freedom from disease in untreated men. As such, there has been an effort to predict grade reclassification among men considered for surveillance or being monitored, through the use of:
*** Prostate biopsy features
*** Imaging
*** Biomarkers.
** '''<span style="color:#ff0000">Reclassification Biopsy</span>'''
*** '''Repeat prostate biopsies over time are the cornerstone of active surveillance.'''
**** The critical role of repeat prostate biopsy for successful identification of higher-risk disease during surveillance cannot be overemphasized.
*** Biopsy re-classification on surveillance can be defined in terms of a greater extent of disease at biopsy and/or higher grade of disease at biopsy, both predictive of adverse features at radical prostatectomy
*** '''Early “confirmatory” biopsy serves to limit the risk of clinical undergrading resulting from sampling'''
**** '''Many advocate for this repeat biopsy within 3-6 months of diagnosis'''
***** Gleason grade changes and thus risk reclassification occur in 2.5-28% after the first repeat biopsy. These numbers are sensitive to selection criteria and biopsy technique.
*** '''Serial prostate biopsies are variably performed from an annual basis to once every 3 to 4 years.'''
**** The risk of disease reclassification continues over time while on surveillance, likely a result of both undersampling and true histologic disease progression in either tumor grade or volume.
** '''Imaging'''
*** '''mpMRI has been reported to have high sensitivity and specificity for high-grade prostate cancers and thus could be of value in reducing disease misclassification and selecting and monitoring individuals interested in active surveillance'''
**** '''<span style="color:#ff00ff">ASIST (2019)</span>'''
***** '''Objective: determine if the addition of MRI with targeted biopsies could identify progression on active surveillance better than systematic biopsy alone'''
***** Population: 273 men diagnosed with Grade Group 1 cancer within 1 yr prior to study entry in whom a confirmatory biopsy was indicated
***** Randomized to systematic biopsy vs. MRI with systematic and targeted biopsy
***** Primary end point: proportion upgraded to Grade Group ≥2
***** Results: no significant difference in rate of upgrading
******In a follow-up study of 199 patients with GG ≤ 1 on confirmatory biopsy and continued AS, there were fewer men with AS failures in the MRI (19%) compared to the non-MRI group (35%). 
***** Klotz, Laurence, et al. "[https://pubmed.ncbi.nlm.nih.gov/30017404/ Active Surveillance Magnetic Resonance Imaging Study (ASIST): results of a randomized multicenter prospective trial.]" European urology 75.2 (2019): 300-309.
*****Klotz, Laurence, et al. "[https://pubmed.ncbi.nlm.nih.gov/31708295/ Randomized study of systematic biopsy versus magnetic resonance imaging and targeted and systematic biopsy in men on active surveillance (ASIST): 2-year postbiopsy follow-up.]" ''European urology'' 77.3 (2020): 311-317.
***'''mpMRI should be used to augment risk stratification in patients on active surveillance, but this should not replace periodic surveillance biopsy[https://pubmed.ncbi.nlm.nih.gov/35536144/]'''
****The Panel believes that an mpMRI should be obtained if the initial (diagnostic) prostate biopsy was performed without mpMRI guidance.
*****If the mpMRI demonstrates findings suspicious for clinically-significant prostate cancer (PIRADS 4 or 5), then timely repeat (confirmatory) targeted biopsy is recommended, with disease risk re-established based on these biopsy results.
*****Conversely, if the mpMRI is assessed as PIRADS 1, 2, or 3, then repeat biopsy may be performed within approximately 12 months after diagnosis.
*****Thereafter, serial surveillance biopsies are recommended every one to four years depending on patient age, health, risk of progression, and preference
****Evidence for the utility of serial prostate mpMRI to evaluate for changes in disease risk among patients on surveillance remains mixed; as such, mpMRI cannot be recommended as a stand-alone replacement for periodic repeat biopsy.
*****Meta-analysis found a pooled sensitivity and specificity for detecting Grade Group of 2 or more of 0.59 (95% CI 0.44 to 0.73) and 0.75 (95% CI 0.66 to 0.84), respectively.
** '''<span style="color:#ff0000">Frequency of Testing</span>'''
*** '''<span style="color:#ff0000">AUA</span>''' '''(2022 AUA Guidelines)'''
***#'''<span style="color:#ff0000">Serial PSA values: should not be obtained more frequently than every 6 months</span>'''
***#'''<span style="color:#ff0000">Symptom assessment and DRE: should be updated every 2 years</span>'''
***#'''<span style="color:#ff0000">Serial surveillance biopsies: recommended every 1-4 years depending on patient age, health, risk of progression, and preference</span>'''
***##The monitoring regimen for patients managed with active surveillance may be individualized.
***##*Among patients at low risk of progression or with a more limited life expectancy, a less intense follow-up schedule may be implemented
***##Serial genomic testing among patients on active surveillance should be discouraged.
*** '''<span style="color:#ff0000">CUA</span> (2015 CUA Guideline on Prostate Cancer Active Surveillance Notes)'''
***# '''<span style="color:#ff0000">PSA every 3-6 months</span>'''
***# '''<span style="color:#ff0000">DRE every year</span>'''
***# '''<span style="color:#ff0000">Confirmatory biopsy within the initial 6-12 months, then serial biopsy a minimum of 3-5 years thereafter</span>'''
*** '''None of the current active surveillance studies have found DRE to be an independent predictor of cancer progression, although it can be useful in determining that a repeat biopsy should be taken'''.
* '''<span style="color:#ff0000">Changes in Management on Surveillance</span>'''
**'''<span style="color:#ff0000">Increase in PSA while on active surveillance should initially prompt re-testing of PSA[https://pubmed.ncbi.nlm.nih.gov/35536144/]'''
***Transient PSA elevations are common and PSA kinetics have variably been associated with pathology among patients on surveillance.
** '''<span style="color:#ff0000">Serial PSA increases, new DRE abnormalities, or other concerns for clinical progression should prompt re-evaluation with MRI and possible prostate biopsy[https://pubmed.ncbi.nlm.nih.gov/35536144/]</span>'''***Direct conversion to treatment may be considered less frequently,
***Detection of significantly higher-volume or higher-grade disease on surveillance biopsy should then prompt discussion of definitive therapy.
**'''<span style="color:#ff0000">Indications for intervention on AS (4):</span>'''
**# '''<span style="color:#ff0000">Progression in cancer grade</span>''' on repeat biopsy
**#* '''<span style="color:#ff0000">High-grade disease (Gleason score ≥7) on surveillance biopsies has been considered a trigger for intervention in most active surveillance programs.</span>'''
**# '''<span style="color:#ff0000">Progression in cancer volume</span>''' on repeat biopsy
**# '''<span style="color:#ff0000">Rapidly rising PSA</span>'''
**# '''<span style="color:#ff0000">Patient anxiety</span>'''