A new study indicates there is no specific PSA value that has both high sensitivity and high specificity for monitoring healthy men for prostate cancer, but rather there is a continuum of prostate cancer risk at all values of PSA, according to a study in the July 6 issue of JAMA: The Journal of the American Medical Association.
One of the most common cancer screening activities in the United States is the measurement of prostate-specific antigen (PSA) levels for the early detection of prostate cancer, according to background information in the article. In 2001, approximately 75 percent of men in the United States aged 50 years and older reported that they had previously undergone PSA screening and 54 percent have reported regular PSA screening. In general, prostate biopsy has not been recommended unless PSA levels exceed a threshold value, generally 4.0 ng/mL, with slightly lower values recommended recently by some researchers. Prostate cancer screening with PSA has been controversial, as no studies have proven that this strategy reduces death from prostate cancer.
Ian M. Thompson, M.D., of the University of Texas Health Science Center at San Antonio, and colleagues conducted a study to determine the effectiveness of PSA testing by estimating the receiver operating characteristic (ROC) curve (a measure of diagnostic accuracy) for PSA. The researchers analyzed data from the Prostate Cancer Prevention Trial, a randomized, prospective study conducted from 1993 to 2003 at 221 U.S. centers. Participants were 18,882 healthy men aged 55 years or older without prostate cancer and with PSA levels less than or equal to 3.0 ng/mL and normal digital rectal examination results, followed up for 7 years with annual PSA measurement and digital rectal examination. If PSA level exceeded 4.0 ng/mL or rectal examination result was abnormal, a prostate biopsy was recommended. After 7 years of study participation, an end-of-study prostate biopsy was recommended in all cancer-free men.
For this analysis, the authors included 8,575 men in the placebo group of the trial who had at least 1 PSA measurement and digital rectal exam in the same year. Of these men, 5,587 (65.2 percent) had at least 1 biopsy, and of these, 1,225 (21.9 percent) were diagnosed with prostate cancer.
The researchers found that for detecting any prostate cancer, PSA cutoff values of 1.1, 2.1, 3.1, and 4.1 ng/mL yielded sensitivities of 83.4 percent, 52.6 percent, 32.2 percent, and 20.5 percent, and specificities of 38.9 percent, 72.5 percent, 86.7 percent, and 93.8 percent, respectively.
"… a clear-cut decision rule for prostate biopsy based on PSA values would be challenging to derive from these data. On one hand, the commonly used cutoff value of 4.1 ng/mL would have a 6.2 percent false-positive rate (1-specificity) but would detect only 20.5 percent of cancer cases (sensitivity). To improve cancer detection, the cutoff could be lowered to 1.1 ng/mL, thus detecting 83.4 percent of cancer cases, but would subject 61.1 percent of men without cancer to prostate biopsy. The recently recommended cutoff of 2.6 ng/mL would detect only 40.5 percent of cancer cases. … there is no single cutoff that would simultaneously yield both high sensitivity and high specificity," the authors write.
"The delay in diagnosis of high-grade tumors until PSA levels exceed current threshold 'normal' values could also explain why there is a 35 percent risk of subsequent treatment after radical prostatectomy, presumably due to disease recurrence. However, lowering the threshold would have 2 consequences: increased biopsy rates and the possibility of increased detection and treatment of biologically inconsequential cancers. Currently, men in the United States have a 17.3 percent lifetime risk of prostate cancer diagnosis, while the lifetime risk of prostate cancer death is 3 percent," the researchers write.
"The implications of this analysis are substantial. Prior to clinical use of biomarkers or other tests for cancer screening, properly designed validation studies are essential. A multi-step process for validation is currently used by the Early Detection Research Network of the National Cancer Institute. While prostate cancer is not unique, it has a variable natural history, ranging from markedly aggressive to indolent. Consideration should be given to the development of biomarkers that incorporate disease prognosis. Finally, it will be a challenge to the medical community to change the long-held notion that there is a 'normal' PSA level. Patients and health care professionals must be re-educated that there is a continuum of risk and no clearly defined PSA cutpoint at which to recommend biopsy. It will be the patient, in concert with his health care professional, who will ultimately have to weigh the sensitivity-specificity tradeoffs in combination with the uncertain natural history of the disease to determine whether further evaluation with a prostate biopsy is appropriate," the authors conclude.