Harms of PSA Screening
The foregoing discussion highlights the important possibility that the harms inherent in PSA screening for prostate cancer may ultimately outweigh the benefits. Although the blood draw itself has nominal effects, false-positive results are of some concern. Analyses of the PLCO trial and the Finnish portion of the ERSPC trial have found that 10.4% and 12.5% of the participants, respectively, received at least one false-positive test result after four or three screening rounds.[33,34] Several studies have demonstrated that false-positive results can have an important psychological impact on men, including a higher probability of worry about prostate cancer, an inaccurately elevated perceived risk for the disease, and an increase in sexual dysfunction issues compared to men with negative screening results. Fowler et al found that these effects persisted for at least 1 year after receipt of a normal biopsy; they also found that men who received a false-positive test result were more likely to have additional PSA tests, biopsies, and urologist visits for the first year after the test than those with a negative screening result.[35,36] Prostatic biopsies may result in modest harms, including pain, fever, and urinary tract infections. There is a 0.4% post-procedure sepsis rate.
Potential harms associated with treatment must also be factored into the overall risk-benefit profile for PSA screening, because the exam can confer no benefit without associated therapy. Sanda et al examined quality of life among localized prostate cancer survivors one year after treatment with radical prostatectomy, brachytherapy, or external-beam radiotherapy. They reported that 54% to 75% could not maintain erections sufficient for sex, 6% to 16% had urinary incontinence at least once a day, and 3% to 14% experienced bowel urgency that was “a moderate or big problem.” These complications are frequently long-term issues: in the Prostate Cancer Outcomes Study (PCOS), 4% to 15% of men experienced frequent urinary leakage, 15% to 18% had rectal wetness, and 64% to 79% reported impotence severe enough to prohibit intercourse at five years after radical prostatectomy or radiation therapy. Depending on the analysis, 30-day post-operative mortality rates after radical prostatectomy range between 0.5% and 4.5% (rates increase with age), and 30-day complication rates of up to 29% have been documented.[40-42]
Overdiagnosis and overtreatment of prostate cancer are of great concern. As previously discussed, autopsy studies have shown that a considerable proportion of men—even men in their forties and fifties—harbor histologically evident but clinically silent prostate cancer. SEER data suggest that more than 1 million additional men in the United States have been diagnosed and treated for prostate cancer since the introduction of PSA screening, and that even with the most optimistic estimation of the magnitude of benefit, the majority of these men were not helped by early detection. The PLCO trial’s trend toward a higher mortality rate in the screened arm reinforces this concept, and the ERSPC trial suggests that up to 48 men would be at risk for potentially life-altering harms for each man who benefited from the PSA test.
The Future of Prostate Cancer Screening
The best quality evidence currently available suggests that PSA screening for prostate cancer is either ineffective at reducing deaths due to prostate cancer, or confers a modest mortality advantage, but at the cost of an important degree of overdiagnosis and overtreatment in the population. Responses to this revelation by professional medical societies, advocacy organizations, clinicians, and researchers have varied significantly. Some have stressed the importance of developing better risk stratification methods in order to mitigate the potential for net harm that PSA screening incurs.[43,44] Methods such as determining PSA velocity; free PSA; complexed PSA; or combining the standard PSA test with PSA derivatives or other markers, such as hK2, proPSA, and nicked PSA, are under active investigation, but their ultimate utility is unproven.
The US Preventive Services Task Force, the American College of Preventive Medicine, and the American Academy of Family Physicians have not updated their recommendation statements since the release of the interim results of the PLCO and ERSPC trials (Table). In the wake of the publication of these results, the American Cancer Society chose to emphasize the necessity of informed decision-making as a prerequisite to prostate cancer screening (ie, testing should not be automatic). In contrast, the American Urological Association (AUA) and the National Comprehensive Cancer Network (NCCN) revised their guidelines to recommend beginning screening earlier in life (at age 40 rather than age 50), although neither the PLCO trial nor the ERSPC trial included men between the ages of 40 and 50 in their study populations.[47,48] The NCCN explains their decision to recommend expanding the pool of men exposed to PSA testing by describing the findings of the Baltimore Longitudinal Study on Aging. This 2001 observational study found an increased risk of men aged 40 to 49.9 years being diagnosed with prostate cancer within 10 to 25 years (median age at diagnosis, 67.5 years) if their PSA level was greater than the median for that age group (RR, 3.75; 95% CI, 1.6-8.6). No information on health outcomes was provided in the study. Autopsy studies documenting a 25% histological prostate cancer prevalence rate for men in their 40s (discussed above in the context of overdiagnosis) were also emphasized as a reason to initiate screening earlier. The AUA also references the Baltimore Longitudinal Study; other considerations behind the AUA recommendation were the improved specificity of PSA testing in this population (due to a lower incidence of BPH) and the rates of curable cancers identified in several older observational studies in younger age groups.
In light of the above, an important question to consider is what manner of evidence, if any, once mass screening has been introduced into the general population and embraced by clinicians and the public alike, will be sufficient to change practice patterns? The concept of cancer screening as a system without negative feedback has been eloquently set forth by David Ransohoff et al, who note that strong positive feedback is generated at each step along the screening, diagnosis, and treatment pathway, when viewed from the individual experiential level of the practitioner and the patient; this holds true even though the test could incur net harm. For patients, a negative screening test provides emotional reassurance and relief, whereas a positive test results in gratitude to the practitioner for catching the tumor early. For providers, counseling against a commonly advertised practice takes time that is not compensated and that can limit the provision of other services; in addition, a medical malpractice allegation could follow if cancer were to be diagnosed later on. Once cancer is diagnosed, the adverse effects of aggressive treatment may simply be accepted as the price of survival, and the patient feels fortunate to have bested the disease (and grateful once again to the practitioner). The positive feedback loop may be further reinforced in the individual practitioner by the spike in incidence within his or her own practice that will likely accompany the introduction of a new screening test, falsely inflating the relative impact of the disease compared with other illnesses. Furthermore, because it is likely that screening will generate a greater proportion of diagnoses of milder forms of the disease, screened patients will also appear to do better than those who present symptomatically. All of the above make it nearly impossible for a patient or clinician to get direct experience that early detection and aggressive treatment did not work.
It is hoped that the final results from the PLCO and ERSPC trials will clarify the ultimate net impact of PSA screening. However, interim findings from these landmark studies have already demonstrated that much of the original health messaging surrounding the promise of PSA testing was overstated. It is of interest to note that the scientist who first discovered the marker—Dr. Richard Albin—recently wrote that he has come to believe that the widespread deployment of screening for men over age 50 constitutes “a public health disaster.” As we move ahead, it is critical that we admit our past enthusiasm was too strong, and that clinicians have clear and careful discussions with men about the continued uncertainty of the overall value of PSA screening, including information about the documented potential for harm, particularly in terms of overdiagnosis and overtreatment.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
Disclaimer: All opinions expressed in this manuscript are those of the authors and should not be interpreted as official positions or statements of the US Federal Government or the Department of Health and Human Services.