Programas Nacionales Multisectoriales

prostate cancer mortality reduction was probably due to the combination of a favorable stage shift and active treatment.

Two largest randomized screening trials

The two largest randomized PSA-based screening trials are the prostate arm of the Pros- tate, Lung, Colorectal and Ovarian (PLCO) trial and the ongoing European Randomized Study of Screening for Prostate Cancer (ERSPC). The Göteborg screening trial has random- ized 20.000 men between biannual PSA-based screening and a control group and forms part of the ERSPC (23). Both the PLCO trial and the ERSPC reported their outcomes on prostate cancer mortality reduction after a median follow-up of 9 years (24, 25) and 12 years (26, 27), remarkably with contradictory results. The PLCO trial was conducted in 10 centers across the United States from 1993 to 2001. A total of 76.693 men aged 55-74 years were randomized to a screening or control arm in a 1:1 ratio. Screened men were offered an annual PSA test for 6 years and DRE for 4 years. At a follow-up of 7 years, the prostate cancer incidence was 116 per 10.000 person-years in the screening arm and 95 per 10.000 person-years in the control arm (25). There was no difference in prostate cancer mortality between the screening (50 deaths) and control arm (44 deaths). The outcome at a follow- up of 10 years was similar. After 13 years of follow-up, the prostate cancer incidence was 108 per 10.000 person-years in the screening arm and 97 per 10.000 person-years in the control arm (26). Again, there was no difference in prostate cancer mortality between the screening (158 deaths) and control arm (145) (RR = 1.09).

Due to the excessive contamination rate in the control arm (53%), confirmed by the similar incidence figures in both arms, and the poor biopsy rate (≈ 40%) of men that were positive at screening the PLCO trial lacks sufficient power to demonstrate an effect on prostate cancer mortality (28). The ERSPC was initiated in 1991 and is still ongoing. Men between 50-74 years, with a predefined core age group between 55-69 years, from eight different European countries were randomized between a screening (72.952) and control arm (89.435). Numbers reflect 7 centers since France joined too late to be part of currently reported mortality analyses. Men were screened with an interval of 2-4 years. Prostate biopsies were performed when PSA was > 3.0 ng/ml in most centers. The main outcome of the study was reported for the core age group of 55-69 years. After a median follow-up of 9 years, the cumulative prostate cancer incidence was 8.2% in the screening arm and 4.8% in the control arm (24). A significant prostate cancer mortality reduction was seen in the screening arm (214 deaths) compared with the control arm (326 deaths) yielding a

RR of 0.80 and thus a relative risk reduction of 20% of prostate cancer death. The absolute

risk reduction was 0.71 deaths per 1000 men, yielding a NNI of 1410 and NND of 48. After a median follow-up of 11 years, the relative risk reduction of prostate cancer death was 21% (p=0.001) and thus similar (27). The relative risk reduction adjusted for noncompli-

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ance was 29%. The absolute risk reduction increased however and was 1.07 deaths per 1000 men, giving a NNI of 1055 and a NND of 37. The overall risk reduction of metastases, causing symptomatic disease that precedes death by 2 to 3 years, was 31% in favor of screening. After a median follow-up of 13 years, the relative prostate cancer mortality re- duction remained stable at 21%, with a relative risk reduction of 27% after adjustment for noncompliance (29). The absolute prostate cancer mortality reduction increased further to 1.28 deaths per 1000 men, translating into a NNI of 781 and NND of 27. These findings support the outcome of modeling studies which all predict much lower NNI (98) and NND (5) when looking at the effect of PSA-based screening over a life time (30, 31). Sub analysis of the Rotterdam section of the ERSPC showed a relative prostate cancer mortality reduc- tion of no less than 51% after adjustment for non-participation and PSA contamination (32). This indirectly shows that the prostate cancer mortality reduction by population- based screening could be substantially greater in Asian countries, with a low exposure rate to opportunistic screening, compared to Western countries. The two largest prostate cancer screening trials are different in design and conduct. The ERSPC shows an effect on the prostate cancer mortality of systematic, strictly protocol, PSA-based screening as compared to little opportunistic screening. The PLCO did or could not show this effect on prostate cancer mortality; the biopsy protocol was less strict and large scale opportunistic screening took place in the control arm. Therefor the outcomes of both trials on prostate cancer mortality cannot be compared (33, 34). During the running period of the two trials, the prostate cancer mortality declined by 42% (1991 and 2005) (35). Modeling studies estimate that 45-70% of the observed decline in prostate cancer mortality in the United States is attributed to the stage shift at disease diagnosis, while advances in the primary treatment (22-33%) and other interventions play a less important role (30, 35).

Meta-analyses on PSA-based screening

Despite the fundamental differences in performance of the ERSPC and PLCO trial, several meta-analyses have been conducted combining the main outcome (i.e. prostate cancer mortality) of both trials, along with the outcome of the smaller PSA-based screening trials (36-38). Djulbegovic et al. conducted a meta-analysis of six randomized controlled trials on prostate cancer screening, involving 387.286 men (36). This study showed an increase in prostate cancer detection by screening, but no significant reduction of the prostate cancer mortality (RR = 0.88, p=0.25). Both the Cochrane meta-analyses of Ilic et al., conducted in 2011 (RR = 0.95, p=0.38) and 2013 (RR = 1.00, p=0.99), were not able to show a significant reduction of the prostate cancer mortality by PSA-based screening (37, 38). However, these meta-analyses have been heavily criticized on their limitations, making the conclusions invalid (39). Methodological shortcomings of the individual trials included in the meta-analyses were bias during and after randomization, contamination of the unscreened arm and short duration of follow-up.

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