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Early data support tailored prostate cancer screening: low-risk men may need less PSA testing.

WASHINGTON -- Preliminary data from two large prostate cancer screening trials suggest that annual exams may not be necessary for all men.

Early data from the European Randomized Study of Screening for Prostate Cancer (ERSPC) indicate that a screening interval of at least 4 years is probably appropriate for many men.

Similar data from the U.S.-based Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial suggests that it might be possible for men with a baseline prostate-specific antigen (PSA) level of less than 1 ng/mL to undergo repeat screenings every 5 years, while men with an initial PSA of 1-2 ng/mL could undergo repeat screening every other year. The early findings from both trials were presented at the International Union Against Cancer Conference.

Some organizations--including the American Cancer Society--recommend routine screening starting at age 50 for men at average risk. Other organizations, such as the American Medical Association, do not specifically recommend routine prostate cancer screening. In 2002, the U.S. Preventive Services Task Force concluded that the evidence is insufficient to recommend for or against routine screening for prostate cancer using prostate-specific antigen testing or digital rectal examination (DRE). It's hoped that the two large trials will more definitively determine the impact of annual screening on mortality.

The PLCO trial is the smaller of the two trials, with 34,244 men who underwent a PSA test or DRE randomized to the screening arm. These men were predominantly white (86%). About 5% had a prior prostate biopsy and almost a quarter had a history of enlarged prostate or prostate problems, said Dr. Robert L. Grubb III of the division of urologic surgery at Washington University in St. Louis.

A PSA level greater than 4 ng/mL was considered suspicious for cancer, as was a prostate with nodularity or induration on DRE. An examiner could also judge a prostate to be suspicious for cancer on DRE on the basis of other criteria (including asymmetry). For men with an abnormal PSA or DRE, their primary care physician was notified and the men were advised to follow-up with their physician for diagnosis. No follow-up was mandated.

"As you might expect, there's an increase in the incidence of suspicious DRE with increasing age," Dr. Grubb said. (See table.) For all ages combined, 7.5% had a positive DRE and 7.9% had a positive PSA, while 1.2% were positive for both. Of the 4,801 men who had an initial suspicious PSA or DRE, 74% underwent additional diagnostic testing. In years 1-3, another 4,158 men had a suspicious DRE or PSA.

"We found that biopsy rates increased with PSA level and for any PSA level, men with a suspicious DRE had increased biopsy rates," Dr. Grubb said. "This suggests that physicians are using the screening results in a clinically appropriate manner."

A positive DRE increased the risk of biopsy almost twofold. A PSA greater than 10 ng/mL also increased the risk of biopsy (hazard ratio 2.6). Men with a positive confirmatory PSA test had a 52% chance of follow-up biopsy, while those with a positive confirmatory DRE were almost certain to have a follow-up biopsy (90%).

Among the positive screenings, 12% were diagnosed with prostate cancer. Overall, 2% of all men screened were diagnosed with prostate cancer. Of the men with prostate cancer, most (83%) were stage I or II. Of men with a PSA between 4 and 10 ng/mL, 88% were stage I or II.

In a separate analysis, researchers estimated a very low risk of men with a baseline PSA of less than 1 ng/mL converting to a PSA of greater than 4 ng/mL in a 5-year period of subsequent annual screenings (1.5%). Risk increased with increasing baseline PSA--men with a baseline PSA of 3-4 ng/mL had a 79% chance of converting (J. Urol. 2006;175:1286-90).

Given this, the researchers suggested that it might be possible for men with a baseline PSA of less than 1 ng/mL to undergo repeat screenings every 5 years. Likewise, men with an initial PSA of 1-2 ng/mL could undergo repeat screening every other year. This approach could reduce the number of PSA tests by 50%.

There also has been interest in the relationship between the speed at which PSA levels change and subsequent prostate cancer. To address this, the researchers looked at data for 1,295 men diagnosed with prostate cancer who had two PSA tests in the year before diagnosis. The average PSA level at diagnosis was 6.5 ng/mL and the mean change was 1.7 ng/mL in the year before diagnosis.

Almost a quarter of these men had a PSA level change of more than 2 ng/mL in the year before diagnosis. These men were significantly more likely to have a Gleason score--indicating cancer severity--greater than 7 (odds ratio 2.2).

Results from screenings in years 1-3 are expected in 2007.

The ERSPC trial involves men aged 55-64 years at centers in eight European countries. Following an initial PSA test and DRE, rescreening is performed every 4 years (except in one center, which performs rescreening every 2 years). The initial PSA cutoff for referring patients for additional investigation was 4 ng/mL. The primary end point is the difference in mortality between the screening and control arms.

Invitation and randomization occurred in two ways. In some centers, patients were invited to participate, gave informed consent, and then were randomized. In other centers, it was possible to randomize patients first and then invite them to participate in the trial and give consent.

To date, the researchers have recruited 94,831 men to the screening arm and 110,255 men to the control arm (some centers have used greater than one-to-one randomization). Men aged 55-69 years make up 89% of those in the screening arm and 91% of those in the control arm, said Dr. Harry J. de Koning, a professor of epidemiology at Erasmus Medical Centre in Rotterdam, the Netherlands.

Based on a PSA cutoff level of 4 ng/mL, about 10% of men are being referred for additional evaluation. Based on lower PSA cutoff levels or other tests, the referral rate is 6%. Of those referred for biopsy, compliance ranges between 78% and 81%. The positive predictive value of biopsy ranges between 78% and 84%.

"Screening results in these eight countries are reasonably comparable," Dr. de Koning said.

At the largest center with postconsent randomization, 13,320 men underwent a baseline screening. Of these, 12% had PSA levels greater than 4 ng/mL. Another 8% had positive DREs or transrectal ultrasonography. The prostate cancer detection rate at the initial screening was 4.7%.

At the largest center with preconsent randomization, 20,793 men underwent a baseline screening. Of these, 9% had PSA levels greater than 4 ng/mL. Fewer than 1% had positive DREs or transrectal ultrasonography. The prostate cancer detection rate at the initial screening was 2.3%.

Overall, "we have found that up to 50% of screening-detected prostate cancers would never have been diagnosed in the absence of the screening test," Dr. de Koning said.

Based on these data, Dr. de Koning offered several lessons that the researchers have learned from the ERSPC trial:

* DRE is of limited value.

* PSA screening in the general population may reach sensitivities on the order of 75%-95%.

* Screening detects prostate cancer significantly earlier. Earlier detection leads to more favorable Gleason scores in screen-detected cancers, compared with cancers detected without screening.

* A screening interval of at least 4 years is probably appropriate for many men.

"We are advancing the diagnosis about 11-12 years with PSA screening," but there are serious and lasting side effects of treatment to consider, Dr. de Koning said. Both radical prostatectomy and external radiation affect urinary, bowel, and erectile function.

Early detection from screening adds about 10 years of follow-up, distress because of awareness of cancer, and side effects of treatment without clear benefit, Dr. de Koning said.

"Patience, I think, is the key word, because the harm you can do is enormous," he said.

An interim mortality analysis is expected in 2007; additional mortality analyses will follow in 2008 and 2010.


Senior Writer
Baseline Screening Results From PLCO

Age Positive for Positive for Positive for
(years) DRE (%) PSA (%) Both (%)

55-59 4.9 4.1 0.5
60-64 7.2 7.2 1.1
65-69 9.4 10.8 1.8
70-74 11.5 14.0 2.2

Note: Based on 34,244 men who had at least one of the tests.
Source: Dr. Grubb
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Title Annotation:News; prostate-specific antigen
Author:Wachter, Kerri
Publication:Internal Medicine News
Geographic Code:1USA
Date:Aug 15, 2006
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