Study Supporting Lower Threshold on PSA Risk Levels Wins Award

E. David Crawford, MD

Professor, Surgery and Radiation Oncology, Head, Urologic Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO

A 2011 study suggesting that men face a significantly increased risk of prostate cancer if their prostate-specific antigen (PSA) level is ≥1.5 mg/ mL—a much lower threshold than that typically applied in practice—is attracting attention.

In May, E. David Crawford, MD, accepted the Robert J. Krane Prize for Best Clinical Paper of 2011 from the British Journal of Urology International, in which the study was published.¹ Titled “Prostate- Specific Antigen 1.5—4.0 ng/mL: A Diagnostic Challenge and Danger Zone,” the paper summarizes the results of a retrospective analysis that Crawford and his fellow investigators conducted.

In the study, the team found that men with a baseline PSA between 1.5 and 4.0 ng/mL faced a 15-fold increase in prostate cancer over a four-year period as compared with men whose baseline PSA levels were <1.5 ng/mL. That finding raises questions, the authors wrote, about the predictive value of the current standard threshold for identifying men at high risk for prostate cancer, which is defined as a PSA level ≥4.0 ng/mL.

In addition, Crawford et al wrote, several studies “suggest that men with BPH [benign prostatic hyperplasia] symptoms and a PSA of ≥1.5 ng/mL are at increased risk of clinically significant BPH progression, and therefore physicians should recognize an increased potential need for prostate volume-reducing therapies.”

The authors suggested establishing an Early Warning PSA Zone between 1.5 and 4.0 ng/mL that “may help physicians to identify at-risk men who would most benefit from PSA screening and risk reduction therapies,” and could lead to the diagnosis of cancers that otherwise might be missed.

To prevent unnecessary and expensive testing and overtreatment of clinically insignificant cancers that could result from reliance on the lower threshold, the authors suggested “a priority system under which physicians screen men with low baseline PSA values only every 2-5 years.”

“We estimate that screening every 5 years for men with PSA levels <1.0 ng/mL and every 2 years for men with PSA between 1.0 and 2.0 ng/ mL would miss only a small percentage of earlier potentially positive tests, while reducing the total number of PSA tests conducted in the USA by 70%,” they wrote. “This could save the US healthcare system approximately $1 billion annually, without missing a substantial number of cancers that would be likely to progress to incurable stages before a patient’s next scheduled screening.”

The retrospective study included 21,502 men at least 40 years old with initial PSA values between 0 and 4.0 ng/mL who were followed for at least four years after their first PSA measurement. The primary outcome was a diagnosis of prostate cancer within four years of a baseline PSA test.

Of patients with a baseline PSA ≥1.5 ng/mL, 7.85% were diagnosed with prostate cancer, compared with 0.51% of patients with a baseline PSA <1.5 ng/mL—a 15-fold increase. Among African-American patients with PSA levels between 1.5 and 4.0 ng/mL, 10.39% were diagnosed with the disease, a 19-fold increase in the prostate cancer rate as compared with African-American patients with PSA levels <1.5 ng/mL, whose chances of having the condition were similar to that of lower-PSA patients in the study as a whole.

In a multivariate analysis adjusting for age and race, men of all groups with baseline PSA levels of ≥1.5 faced a 12.4% increase in their likelihood of developing prostate cancer within four years as compared with men with baseline PSAs <1.5 ng/mL.

Prostate Cancer Rates by Baseline PSA Level¹

PSA indicates prostate-specific antigen level measured by ng/mL.

Several other studies have suggested that a PSA level substantially lower than 4.0 ng/mL should be used as the threshold for predicting prostate cancer risk, Crawford et al wrote.

The investigators cited the Prostate Cancer Prevention Trial,² which included 2950 men whose PSA levels had never reached 4.0 ng/mL. In that trial, 10.1% of men with PSA levels between 0.6 and 1.0 ng/mL had prostate cancer; 17.0% of men with PSAs between 1.1 and 2.0 ng/mL had the disease; 23.9% of men with PSAs between 2.1 and 3.0 ng/mL had prostate cancer; and 26.9% of men with PSAs between 3.1 and 4.0 ng/mL had the condition. Overall, 15.2% of men in the study, despite having PSA levels considered normal under current standards, had prostate cancer.

A number of studies have also indicated that, when PSA levels exceed 1.5 ng/mL, men with BPH face an increased risk of the condition’s progression, Crawford and his team pointed out. In the Medical Therapy of Prostatic Symptoms (MTOPS) study,³ they noted, researchers found that men with PSA levels above 1.6 ng/mL were more likely than men with PSAs below that level to experience a four-point or greater worsening, over time, of their American Urological Association Symptom Score, along with acute urinary retention and the need for invasive surgical treatment.

“Our study falls in line with a growing body of research that suggests lowering the high-risk PSA threshold from 4.0 ng/mL,” Crawford and his co-authors wrote. “Patients with a baseline PSA level between 1.5 and 4.0 ng/mL not only face the same future risk of diagnosis of prostate cancer as patients with PSA levels above 4.0 ng/mL, but PSA levels >1.5 ng/mL also signal the presence of more generalized prostatic disease, namely, BPH and progression to troublesome symptoms.”

Crawford accepted the Robert J. Crane Prize during the American Urological Association’s Annual Meeting.

“I am humbled to receive this prestigious award, and thank the committee for selecting our article,” Crawford said. “All the co-authors deserve recognition.”

References

1. Crawford ED, Moul JW, Rove KO, et al. Prostate-specific antigen 1.5—4.0 ng/mL: a diagnostic challenge and danger zone [published online ahead of print June 28, 2011]. BJU Int. 2011;108(11):1743-1749. doi: 10.1111/j.1464-410X.2011.10224.x.
2. Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level ≤4.0 ng per milliliter. N Engl J Med. 2004; 350(22):2239—2246.
3. Crawford ED, Wilson SS, McConnell JD, et al. Baseline factors as predictors of clinical progression of benign prostatic hyperplasia in men treated with placebo. J Urol. 2006;175(4):1422—1426.