Abstract
Ashraf et al 1 conducted an evidence-based review of the literature and clinical guidelines on prostate cancer screening. They describe a widely used “common sense approach,” which seeks to reduce the harms of overdiagnosis by incorporating risk stratification tools such as MRI, with the goal of improving the balance between benefits and harms.
In practice, however, prostate cancer screening has not been characterized by an active scientific controversy or debate. Instead, there has long been a persistent divergence between guidelines developed by the U.S. Preventive Services Task Force (USPSTF), 2 largely composed of general internists and public health physicians, and those developed by urologists, including the American Urological Association (AUA), the European Association of Urology (EAU), and the National Comprehensive Cancer Network (NCCN). 1 The USPSTF recommendations are based on systematic reviews that emphasize evidence from randomized controlled trials (RCTs). In contrast, urology-led guidelines rely primarily on expert opinion informed by case reports or case series. Within the hierarchy of evidence, RCTs represent the highest level, whereas case series and expert opinion occupy the lowest levels or fall outside the hierarchy altogether. 3
Lucassen et al 4 has recently offered a clear and balanced critique, noting that studies of prostate cancer screening generally lack appropriate control groups and do not use overall survival (OS)—a patient-important outcome—as the primary endpoint. Such studies may demonstrate feasibility but do not establish clinical benefit. This observation reflects fundamental principles of scientific and medical research rather than advanced methodological debate. Although originally directed at polygenic risk scores used for risk stratification, the same reasoning applies broadly to most clinical research on prostate cancer screening. This includes PSA testing, pathological grading such as the Gleason score, imaging modalities (CT, MRI, and ultrasound), and treatment strategies including surgery, radiotherapy, and active surveillance. 5
Because the natural history of screen-detected prostate cancer has not been shown to result in worse overall survival than that of the general healthy population, 6 it is difficult to establish appropriate control groups or to design trials with OS as the endpoint. As a result, much of the existing literature is more appropriately classified as case reports, case series, or feasibility studies rather than definitive trials capable of demonstrating benefit.
Only 3 large trials—PLCO, ERSPC, and CAP—have evaluated prostate cancer screening using appropriate control groups and overall survival as the endpoint. 2 All 3 reported the same result: screening did not improve overall survival. This represents level 1 evidence. While the USPSTF systematic review includes OS outcomes, it does not emphasize them as decisive. In contrast, urology guidelines frequently highlight reductions in prostate cancer–specific mortality reported in ERSPC and suggest that screening reduces cancer mortality.
Cancer-specific mortality is commonly used in epidemiologic studies and registry analyses; however, it is a descriptive outcome based on clinical judgment at the time of death and lacks a reproducible scientific definition. 7 For this reason, it is not a robust endpoint for clinical trials. Even in the 3 RCTs, there is no detailed description of how cancer-specific mortality was defined or measured. Outcomes that were not prespecified as trial endpoints cannot be interpreted as valid RCT results, as the benefits of randomization no longer apply. At best, such findings should be considered descriptive. Consequently, statements that screening “reduces cancer mortality” are better understood as expert interpretation rather than conclusions supported by high-level evidence.
The USPSTF has revised its recommendation grade from D to C and expanded discussion of cancer-specific mortality, yet it explicitly states that the certainty of evidence regarding benefit remains insufficient. This cautious wording reflects the conclusion that a survival benefit has not been demonstrated.
The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. While clinician perspectives are valuable, evidence—and patient preferences—should take precedence. Given that RCTs consistently show no improvement in overall survival, expert opinion alone is insufficient to outweigh this evidence.
Even if MRI-based risk stratification were to reduce some harms of screening, the absence of demonstrated benefit means that the overall balance may still favor harm.
When an intervention without proven benefit is offered to healthy individuals, it should be treated as a clinical trial rather than as established medical practice. Under the Declaration of Helsinki, individuals should therefore receive clear advance information, including disclosure that there is no evidence of improved overall survival. The U.S. Preventive Services Task Force (USPSTF) states that “the decision to undergo periodic PSA-based screening for prostate cancer should be an individual one and should include discussion of the potential benefits and harms of screening with their clinician,” and that “clinicians should not screen men who do not express a preference for screening.” These recommendations are consistent with this ethical framework. Whether screening is organized or opportunistic, it should be held to the same ethical standards.
If prostate cancer screening is to be promoted in the future, participants should be adequately informed, appropriate control groups should be used, and overall survival should be the primary endpoint. Without these conditions, further efforts risk generating descriptive data that cannot meaningfully inform clinical decision-making. The costs of such research should be borne by investigators or funding agencies, not by patients or public insurance systems, 8 given the ethical and economic implications of interventions with uncertain benefit.
Finally, clinicians outside urology, as well as policymakers, should be familiar with the principles of scientific research, evidence-based medicine, and the Declaration of Helsinki to support informed and responsible decision-making.
