Editing Prostate Cancer: Screening (section)

== Evidence on Prostate Cancer Screening ==
* '''Randomized controlled trials to date on prostate cancer screening (7):'''
*# '''Stockholm'''
*# '''Norrkoping'''
*# '''Quebec'''
*# '''PLCO (Prostate, Lung, Colorectal, Ovarian, 2008)'''
*# '''ERSPC (European Randomized Study of Screening for Prostate Cancer, 2009)'''
*# '''Goteborg (2010)'''
*# '''CAP (2018)'''
* Among other design problems, the Stockholm trial screened with only one test and a high cut-off of PSA for biopsy; the Stockholm, Norrkoping and Quebec trials lacked allocation concealment; and the Quebec trial did not report according to intention to screen. As such, '''<span style="color:#ff0000">3 (key as per CUA/AUA) most informative randomized trials on prostate cancer screening:</span>'''
*#'''<span style="color:#ff0000">PLCO – NO NET BENEFIT</span>'''
*#'''<span style="color:#ff0000">ERSPC – NET BENEFIT</span>'''
*#'''<span style="color:#ff0000">Goteborg – NET BENEFIT</span>'''
**Primary outcome is always cancer-specific mortality

=== <span style="color:#ff00ff">PLCO</span> ===
* '''<span style="color:#ff0000">Population: 76,685 US men aged 55-74</span>''' from 10 centers
* '''<span style="color:#ff0000">Randomized to annual screening</span> (PSA annually x 6 years, DRE annually x 4 years) <span style="color:#ff0000">vs. standard care</span>'''
** '''Biopsy recommended If PSA >4.0 or suspicious DRE'''
* Primary outcome: cancer-specific mortality
* '''<span style="color:#ff0000">Results:</span>'''
** '''<span style="color:#ff0000">No difference in PC mortality</span>''' (Rate ratio (RR) 0.93 (95% CI 0.81–1.08) 17-year follow-up)
** '''Increased incidence of prostate cancer in screening group''' (RR 1.05 (95% CI 1.01–1.09) 17-year follow-up)
** '''No difference in disease stage'''
** '''No difference in metastasis''' (RR 0.85 (95% CI 0.67 – 1.06))
** '''Higher proportion Gleason 2-6 in screening arm; higher proportion Gleason ≥ 8 in control arm'''
*** Gleason 2–6: RR 1.17 (95% CI 1.11–1.23)
*** Gleason 7 disease RR 1.00
*** Gleason 8–10 disease RR 0.89 (95% CI 0.80–0.99)
* '''<span style="color:#ff0000">Criticisms (4)</span>''':
*# '''<span style="color:#ff0000">High rates of contamination</span>''' (77% as per 2018 AUA early detection prostate cancer guidelines)
*# '''<span style="color:#ff0000">High rates of pre-screening</span>'''
*#* In control group at baseline, 34.3% had PSA test once within past 3 years, 9.8% had PSA tests two or more times within past 3 years; 31.9% had DRE once within past 3 years, 22.0% had DRE two or more times within past 3 years
*#* After 1995, trial implemented exclusion criteria of more than one PSA test within last 3 years[https://pubmed.ncbi.nlm.nih.gov/11189684/ §]
*# '''<span style="color:#ff0000">High rates of l</span><span style="color:#ff0000">Lack of adherence to diagnostic biopsies</span>''' among patients with abnormal screening results in the screening arm
*# '''<span style="color:#ff0000">Underpowered to detect mortality benefit</span>'''
* [https://pubmed.ncbi.nlm.nih.gov/19297565/ Andriole, Gerald L., et al.] "Mortality results from a randomized prostate-cancer screening trial." New England Journal of Medicine 360.13 (2009): 1310-1319.
* [https://pubmed.ncbi.nlm.nih.gov/30288918/ Pinsky, Paul F., et al.] "Extended follow‐up for prostate cancer incidence and mortality among participants in the Prostate, Lung, Colorectal and Ovarian randomized cancer screening trial." BJU international 123.5 (2019): 854-860.

=== <span style="color:#ff00ff">European Randomized study of Screening for Prostate Cancer (ERSPC)</span> ===
* '''<span style="color:#ff0000">Population: 162,243 males aged 55-69 (almost twice the size of PLCO) from 8 European countries;</span>''' collection of trials conducted, some differences between individual trials
* '''<span style="color:#ff0000">Randomized to screening every 4 years</span> (PSA in most centres; some centres offered DRE) <span style="color:#ff0000">vs. standard care</span>'''
* Primary outcome: prostate cancer-specific mortality
* '''<span style="color:#ff0000">Results</span>''' (2019 results):
** '''PC mortality: RR 0.80''' (0.72–0.89)
*** '''Number needed to invite (NNI) to screening to prevent one prostate cancer death: 570'''
*** '''Number needed to diagnose (NND) to prevent one prostate cancer death: 18'''
*** Estimated that annual screening of men in the ERSPC aged 55 to 69 years would result in a 28% reduction in prostate cancer deaths (37% in those actually screened). The estimated number needed to screen to prevent one prostate cancer death was 98, and the number of cancers needed to be detected was 5
** Incidence: RR 1.41 (1.36–1.45)
* '''Lower rate (≈20-25%) of contamination'''
* [https://pubmed.ncbi.nlm.nih.gov/19297566/ Schröder, Fritz H., et al.] "Screening and prostate-cancer mortality in a randomized European study." New England Journal of Medicine 360.13 (2009): 1320-1328.
* [https://pubmed.ncbi.nlm.nih.gov/30824296/ Hugosson, Jonas, et al.] "A 16-yr Follow-up of the European Randomized study of Screening for Prostate Cancer." European urology 76.1 (2019): 43-51.
*'''Subgoup analysis'''
**'''Population: 7,052 males aged 70-74 at their last screening visit after a maximum of 3 consecutive screening rounds and who had completed screening without a PCa diagnosis.'''
**Primary outcome: cumulative incidence of prostate cancer-specific mortality by the age of 85
**'''Results'''
***324 males diagnosed with prostate cancer, after a median time period between last screening visit and diagnosis of 7 years
***107 males found to have metastasis
***81 males died of disease
***'''Cumulative incidence of prostate cancer-specific survival by the age of 85 was 0.54%'''
****Cumulative incidence higher in patients with higher PSA or no previous biopsy
** [https://pubmed.ncbi.nlm.nih.gov/37919190/ de Vos, Ivo I., et al. "Prostate Cancer Mortality Among Elderly Men After Discontinuing Organised Screening: Long-term Results from the European Randomized Study of Screening for Prostate Cancer Rotterdam." ''European Urology'' 85.1 (2024): 74-81.]

=== <span style="color:#ff00ff">Goteburg</span> ===
* '''<span style="color:#ff0000">Population: 20,000 men aged 50-64 from Sweden</span>'''
** '''Was included in ERSPC but was independently designed, initiated and reported separately from ERSPC. 60% of participants were included in ERSPC.'''
* '''<span style="color:#ff0000">Randomized screening every 2 years</span> (PSA) <span style="color:#ff0000">vs. control</span>'''
** Men with PSA at or above threshold (3.4 ng/ml between 1995 and 1998, 2.9 ng/ml between 1999 and 2004, and 2.5 ng/ml after 2004 (lower than others)) were invited for clinical follow-up with DRE, transrectal ultrasound and laterally directed sextant biopsies
** Only 3% screening of controls; 93% complied with a biopsy recommendation
* '''Primary outcome: prostate cancer-specific mortality'''
*'''<span style="color:#ff0000">Results:</span>'''
** '''PC mortality: RR 0.65''' (95% CI 0.49–0.87) 18-year follow-up
*** '''NNI: 231'''
*** '''NND: 10'''
** Incidence: RR 1.51 (1.39–1.64)
** 41% '''fewer advanced cases at diagnosis in the screening arm'''
* [https://pubmed.ncbi.nlm.nih.gov/20598634/ Hugosson, Jonas, et al.] "Mortality results from the Göteborg randomised population-based prostate-cancer screening trial." The lancet oncology 11.8 (2010): 725-732.
* [https://pubmed.ncbi.nlm.nih.gov/29254399/ Hugosson, Jonas, et al.] "Eighteen-year follow-up of the Göteborg Randomized Population-based Prostate Cancer Screening Trial: effect of sociodemographic variables on participation, prostate cancer incidence and mortality." Scandinavian journal of urology 52.1 (2018): 27-37.
There was contamination in the control arms for both ERSPC and Gotteburg trials but significantly lower than PLCO.

=== <span style="color:#ff00ff">CAP</span> ===
* '''Population: 415,357 men aged 50-69 years from 573 primary care practices across the United Kingdom'''
* '''Randomized to an invitation to attend a PSA testing clinic and receive a single PSA test vs standard (unscreened) practice'''
** Males diagnosed with cancer were then offered inclusion in the ProtecT (Prostate Testing for Cancer and Treatment) trial, in which they were randomized to monitoring, surgery or radiation, regardless of risk stratum.
* '''Primary outcome: prostate cancer-specific mortality'''
* '''Results'''
** '''PC mortality:''' 
***Median follow-up 10 years: RR 0.93 (0.67 to 1.29)
***Median follow-up 15 years: RR 0.92 (0.85 to 0.99)
****Absolute risk difference 0.09% (0.69% intervention vs. 0.78% control)
**Overall survival:
***Median follow-up 15 years: RR 0.97 (0.94 to 1.01)
** Detection of low-risk prostate cancer cases increased
* Criticisms:
** High nonadherence rate with the intervention
** Modest contamination in the controls
** Inadequate follow-up to truly assess mortality
* [https://pubmed.ncbi.nlm.nih.gov/29509864/ Martin, Richard M., et al.] "Effect of a low-intensity PSA-based screening intervention on prostate cancer mortality: the CAP randomized clinical trial." Jama 319.9 (2018): 883-895.
*[https://pubmed.ncbi.nlm.nih.gov/38581198/ Martin, Richard M., et al. "Prostate-specific antigen screening and 15-year prostate cancer mortality: a secondary analysis of the CAP randomized clinical trial." ''JAMA'' (2024).]