Medical Device Daily

Even though more annual screenings for prostate cancer lead to more diagnoses of the disease, there are no fewer deaths from the disease, according to a report from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a 17-year project of the National Cancer Institute (NCI).

So does this mean that prostate cancer tests are too little too late? In fact, quite the opposite seems to hold true, according to researchers at the National Cancer Institute.

"I think it's too much too early," Christine Berg MD, NCI leader of the PLCO trial and senior author of the study told Medical Device Daily.

Berg said that by this she means that the report states there may be some men who are diagnosed with prostate cancer and have the side-effects of treatment, which include impotence and incontinence.

She added that there need to be better ways of definitively classifying who needs treatment and which patients can be considered watchful waiting.

"NCI wants to understand why some prostate cancers are lethal even when found early by annual screening, and what approaches can be used to identify these more aggressive cancers when they can be effectively treated," Berg said. "The PLCO biorepository is an invaluable resource for such research, with nearly three million biological samples collected from our participants. Our hope is that through all aspects of the PLCO, we will gather the information that tells us whom to treat aggressively and whom to avoid over treating."

A review of the PLCO shows that nearly 76,700 men took part in the trial that spanned across the country in 10 different centers. About 38,343 were randomly assigned to screening with annual prostate-specific antigen (PSA) tests for six rounds and digital rectal exams (DRE) for four rounds. The remaining men were randomly assigned to usual care, but they received no recommendations for or against annual prostate screening.

About 85% of men had PSA tests and 86% had DRES. The men that were in the usual care arm had these tests as well.

At seven years, 22% more prostate cancers were diagnosed in the screening arm (2,820 men vs. 2,322 in the usual-care group). This excess is continuing to be observed in data collected up to 10 years (currently a 17% excess, 3,452 men vs. 2,974 men in the usual-care group).

Of those men who were screened annually, about 85% were said to have had PSA tests and 86% had DREs. Men in the usual-care arm sometimes had these tests as well, due to the growing public acceptance of such screening. Screening by PSA in this usual-care group increased from 40% at the beginning of the study to 52% of men by the last screening year, and screening with DRE ranged from 41% initially to 46% by the last screening year. Men in the screening arm were referred to their usual healthcare provider for follow-up testing for prostate cancer if their PSA level was greater than 4.0 nanograms per milliliter (ng/mL) or if a DRE found an abnormality.

The vast majority of men in both groups who developed prostate cancer were diagnosed with relatively early stage II (out of IV stages, of which IV is late stage) disease, and the number of later-stage cases was similar in the two groups. However, using the Gleason scoring system, which assesses tumor aggressiveness, men in the usual-care group had more prostate cancers that fell into the Gleason 8 to 10 range, which marks them as more aggressive. The smaller number of men with prostate cancer with a Gleason score of 8 to 10 in the intervention group may eventually lead to a mortality difference between men in the two groups but data analyzed so far have not shown such a difference.

Here are some other key highlights cited from the PLCO.

Men in both groups who were diagnosed with prostate cancer at the same stage received similar treatments for their disease. This reflects the PLCO study design policy of not mandating specific therapies.

At seven years, 50 deaths were attributable to prostate cancer in the screening group and 44 deaths were attributable in the usual-care group.

Through year 10, there were 92 prostate cancer deaths in the screening group and 82 in the usual-care group. The difference between the numbers of deaths in the two groups was not statistically significant. Thus there was no detectable mortality benefit for screening vs. usual-care.

NCI now is focused on looking toward finding new ways of screening for prostate cancer including several sets of biomarkers that are being validated in its Early Detection Research Network (EDRN). Examples of marker tests include using microstrands of RNA to find the disease, examining changes in genes and imaging of proteins in prostate cancer tissue.

A report completed by the European Randomized Study of Screeining for Prostate Cancer (ERSPC) shows that there is a 20% rate of death from the disease but there is a high risk of overdiagnosis. However, in the ERSPC, unlike the PLCO trial, men were referred for follow-up testing if their PSA level was 3.0 ng/mL or higher and were also screened, on average, every four years as opposed to annually in the PLCO.

"Approaches such as lowering the threshold for what is considered an abnormal PSA level to 3.0 ng/mL will diagnose more cases, but it is not at all clear that it will identify the prostate cancers that are more likely to lead to a man's death," said Berg.

The PLCO is a large-scale clinical trial, sponsored and run by NCI's Division of Cancer Prevention, begun in 1992 to determine whether certain cancer screening tests can help reduce deaths from prostate, lung, colorectal and ovarian cancer.

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