PSA Screening Should Emphasize Changes Over Time, Study Finds

ABSTRACT: PSA velocity, not a man's absolute PSA level, is a better predictor of prostate cancer risk, according to a study from the Johns Hopkins School of Medicine. The findings suggest screening should begin at age 40, not 50.

A recent study from the Johns Hopkins School of Medicine finds that how quickly a man’s PSA level rises over time is more important than any single PSA value for detecting potentially deadly prostate cancer, at a time when the disease is curable. Given those findings, says the study's lead author, physicians should screen for prostate cancer much differently than they do now-starting at age 40 instead of 50, and repeating the test at varying intervals depending on the baseline result. In fact, says study author Ballentine Carter, MD the rate of change for PSA-known as PSA velocity-is so important that medical offices would do well to review their male patients' past PSA results, to identify and refer those most at risk.

Such an effort could save lives, says Carter, director of the Division of Adult Urology at Hopkins. "There is absolutely no test that's more predictive of death from prostate cancer [than PSA] before a biopsy is even performed," he says. “When you have a test that powerful, you should use it.” Carter's study, in the Nov. 1 Journal of the National Cancer Institute, and other recent findings on PSA velocity are poised to significantly change the clinical practice guidelines for prostate cancer screening.

Current guidelines from the American Urological Association recommend that all men have a PSA test annually beginning at age 50. Those guidelines are being revised to reflect recent evidence on PSA velocity, says Peter Carroll, MD chair of the Department of Urology at the University of California-San Francisco and chair of the association's PSA best-practices guidelines committee. "We're no longer going to use PSA results at one point in time, but we'll be looking at the change over time," Carroll said. He added that "we'll be going to earlier testing and lower cutpoints in general, and more or less frequency of testing based on the patient's risk." The revised guidelines are expected out in summer 2007.

PSA Velocity Predicts Cancer Death Decades Later

For the JNCI study-"Detection of Life-Threatening Prostate Cancer with Prostate Specific Antigen During a Window of Curability"-Carter’s team analyzed frozen serum samples from the Baltimore Longitudinal Study of Aging, which has participants from as early as 1958. The researchers determined PSA velocity in 980 participants, of whom 856 did not have prostate cancer, 104 had the disease and 20 died from it. They found that PSA velocity-determined at a time when PSA levels were too low to trigger a biopsy-predicted death from prostate cancer 20-30 years later. Specifically, the survival rate was 92% among men with a PSA velocity of 0.35 ng/mL per year or less, but was just 54% among men with a PSA velocity above that level.

"PSA velocity may provide useful information for identifying men who need further evaluation and/or close surveillance for the presence of life-threatening prostate cancer," the authors write. "We believe PSA velocity may have the greatest value in predicting the presence of biologically important cancers at a curable stage in younger men (below 60) without prostate enlargement and PSA levels below 4.0 ng/mL," they add.

Controversy Persists

There's still considerable controversy around the value of PSA screening, as Carter and Carroll both acknowledge. Expanded screening has led to overdiagnosis and unnecessary biopsies, due to PSA's poor specificity. Some research-including a January 2006 study-has found that early detection of prostate cancer via PSA screening does not improve patients' survival rates.

In fact, in light of a recently published study (also from Hopkins) which found that a blood test for a protein called EPCA-2 may be more accurate than PSA screening, many researchers believe the new test may one day replace PSA for prostate cancer screening. The EPCA-2 test is still in clinical trials, but if those trials confirm its value, the new test could be available to the public as early as 2009. For now, however -- while PSA is still the recommended screening test -- Carroll explains that "tracking PSA changes over time can not only detect cancers earlier [than using an absolute PSA value], but it allows us to distinguish patients who need immediate treatment from those who may be candidates for active surveillance."

When to Test

Given Carter's findings, it’s important for physicians to get a history of a patient's PSA levels, starting at about age 40. At least three screenings over two years are needed to accurately calculate PSA velocity. (See page 2 for simple instructions on calculating PSA velocity.) According to the findings, PSA screening needn't be repeated every year for all men, as this consumes excessive resources without benefiting patients (in fact, it can harm patients, through unnecessary biopsies and treatments). Instead, frequency of testing should depend on each patient's baseline result.

• For a man whose PSA at age 40 is below 0.6 ng/mL (the median value), physicians can wait until age 45 for the next test, according to Carter. If the same man's PSA is still below 0.6 ng/mL at age 45, wait until 50 to test him again. If it's above 0.6 ng/mL at 45, testing every other year would be wise.

• Starting at age 50, men with a PSA below 2.0 ng/mL and stable values should be tested every other year. Those with a PSA above 2.0 ng/mL should be tested yearly.

Testing men with normal PSA results less frequently, and those with higher results more frequently, makes sense financially as well as clinically, Carter notes. A variable screening schedule is more cost-effective than annual screenings for men 50 and older, according to a Hopkins study published in 2000.

Which Patients to Refer

The key question for primary care physicians is which patients warrant referral to a urologist, for biopsy or further monitoring. According to Carter’s findings, men with a PSA velocity of > .35 ng/mL per year-even with a PSA below 4.0 ng/mL-should be monitored carefully or undergo a biopsy, since these men have nearly a 50% risk of dying from prostate cancer over the next two to three decades.

Two Hypothetical Patients

Considering the course of action with two hypothetical patients illustrates the difference between using a single PSA value vs PSA velocity. Suppose a 55-year-old man just had a PSA test, with a result of 4.0. Under the current thinking, "the doctor looks and says, my gosh, we need to do a biopsy!” Carter says. If the patient's 10-year PSA history is available, however, the approach is much different.

If it took the man 10 years for his PSA level to increase from 2 to 4, he has relatively little risk of an aggressive prostate cancer, so a biopsy may not be necessary, Carter says. But consider another hypothetical patient, also age 55, whose PSA level has climbed from 2 to 4 in the last five years. “That’s a whole different situation,” Carter says. “You'd want to do a biopsy, or monitor the patient closely." This scenario shows that "the current approach is a one-size-fits all, which isn't rational. Looking at a patient's PSA history is a much better way to evaluate their risk."

Calculating PSA Velocity

PSA velocity is the annualized rate of change in PSA reported as ng/mL (nanograms per milliliter) per year. An average rate of change is most accurate, and the formula is:

(PSA2 - PSA1/time) + (PSA3 - PSA2/time) / 2

For example: Assume at time 0 the first PSA is 2.0 ng/mL; then 14 months later it is 2.5; then 9 months after that it is 3.2 ng/mL.

To calculate PSA velocity:

• Take the difference between the first 2 measurements (0.5 ng/mL) and then divide it by the time elapsed, to annualize it: 0.5 ng/mL / 1.17 yr = .43 ng/mL per year.

• Then take the difference between the last 2 measurements (0.7 ng/mL) divided by the second time interval: 0.7 ng/mL / 0.75 yr = 0.93 ng/mL per year.

• Then, add the 2 rates of change and divide by 2 to get an average rate of change: (0.43 ng/mL/yr + 0.93 ng/mL/yr) / 2 = 0.68 ng/mL per year.

This patient's PSA velocity would be .68 ng/mL per year. As this is significantly higher than the > .35 ng/mL per year threshold suggested by the latest research, the patient should have a biopsy, despite his PSA being less than 4.0.

RELATED LINKS

PSA screening guidelines from the American Urological Association

Detection of Life-Threatening Prostate Cancer With Prostate-Specific Antigen Velocity During a Window of Curability (Journal of the National Cancer Institute, vol. 98, no. 21, Nov. 1, 2006)

The Effectiveness of Screening for Prostate Cancer: A Nested Case-Control Study (Archives of Internal Medicine, vol. 166, no. 1, Jan. 9, 2006)

Comparative Efficiency of Prostate-Specific Antigen Screening Strategies for Prostate Cancer Detection (Journal of the American Medical Association, vol. 284, no. 11, Sept. 20, 2000)

PSA Screening Rates for Elderly Men Found Too High (ConsultantLive, Nov. 14)