Editing Management of Localized Prostate Cancer (section)

=== <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>'''