Prostate-Specific Antigen Screening Trials and Prostate Cancer Deaths: The Androgen Deprivation Connection

Abstract

Major clinical trials using prostate-specific antigen (PSA) as the screening test to detect localized early-stage prostate cancer and to attempt to change its natural history with early intervention have yielded conflicting interpretations. The US Prostate, Lung, Colorectal, and Ovarian (US PLCO) cancer screening trial concluded that PSA-based screening conferred no meaningful survival benefit, whereas the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the GOTEBORG clinical trial (GOTEBORG) trials claimed statistically significant life-saving benefits. These divergent outcomes have not provided physicians with clarity on the best evidence-based treatment. To determine the extent to which these divergent outcomes are clinically meaningful, we evaluated these data and those of a long-term prospective cohort study in the context of the clinically documented harms of androgen deprivation therapy (ADT). We noted the unheralded fact that in both European trials far more patients received hormonal treatment in the control than the prostatectomy arm, whereas hormonal therapy in the US trial was balanced between arms. We examined this imbalance in ADT treatment and prostate cancer-related deaths in the contexts of contamination, stage migration, and attribution of cause of death, all of which impinge on data interpretation. The ERSPC and GOTEBORG data are compatible with the hypothesis that ADT treatment contributes differentially to an increase in prostate cancer deaths in control patients. If so, the claim of a reduction in prostate cancer deaths in the screened cohort requires reappraisal. The conventional interpretation that PSA screening and radical treatment intervention are the major contributors to the results of these two studies needs more rigorous scientific scrutiny, as does the role of ADT treatment of nonmetastatic disease.

Trends in prostate cancer incidence and mortality in Canada during the era of prostate-specific antigen screening

“…[42][43][44] It is possible that when these agents are used to treat early prostate cancer, this effect increases total deaths, but which are ascribed to cardiovascular disease. Because less than 5% of men now diagnosed with prostate cancer die from it, 33,45 even small changes in the cause of death among men who have received treatment for prostate cancer could substantially affect estimates of prostate cancer mortality.…”

“…Since PSA use became common, men with a history of prostate cancer but low PSA at the time of death are likely to have prostate cancer listed as an "other significant condition" instead of the underlying cause, as might have occurred previously. 42 Thus, much of the apparent mortality change could be due to secular changes in the cause of death attributed to men with known prostate cancer.…”

Cancer surveillance using registry data: Results and recommendations for the Lithuanian national prostate cancer early detection programme

“…Further urological evaluation is offered when PSA levels exceed 3 ng/ml. Although the European Randomized study of screening for prostate cancer (ERSPC) demonstrated a potential for mortality decline [2,3], the very long lead time of cancer detection [4], the potentially very serious side-effects of the treatment and large variation in the life expectancy of different populations [5], as well as concern about the overall validity of the ERSPC results [6] keep PSA-based early detection highly controversial [7][8][9].…”

Response

“…We concluded that the data had serious flaws, including differential hormonal treatment of identical risk groups of patients (1). The data were consistent with the effects of increased use of androgen deprivation therapy (ADT) in men with nonmetastatic disease, which contributed to a relative increase in prostate cancer deaths in the control arm.…”