PSA Screening Lowers Prostate Cancer Mortality

QUEBEC CITY--For the first time, a randomized clinical trial of screening with prostate-specific antigen (PSA) has been performed and shown to reduce the risk of prostate cancer mortality.

The large Canadian study showed a 69% reduction in mortality in men who participated in screening, as opposed to those who did not. All but one prostate cancer death in the screened group arose from a tumor detected at the initial screening visit.

"This study demonstrates the feasibility and efficacy of early diagnosis and early treatment of prostate cancer," Fernand Labrie, MD, said at the plenary session of the ASCO meeting. "If we take the data as they are, potentially 27,000 of the 39,000 annual prostate cancer deaths in the United States could be prevented by early diagnosis and treatment."

Whether physicians or the public "take the data as they are" remains to be seen. At the plenary session, formal discussion of the results focused on possible methodologic flaws in the study.

In particular, questions were raised about the potential difference in risk of death from prostate cancer between those men who accepted PSA screening and those who did not accept the invitation to be screened.

The study results also raised questions about the use of 4 ng/ml as the upper limit of normal for PSA. Investigators in the trial used 3 ng/ml, which increased the cancer detection rate at the initial and follow-up visits, said Dr. Labrie, director of research at the Laval University Medical Center, Quebec City.

The trial involved more than 46,000 men ages 45 to 80 who were enrolled and followed between January 1, 1989, and December 31, 1996. Dr. Labrie noted that the study began at a time when PSA screening had little support as a means to prevent prostate cancer death.

31,000 Invited to Be Screened

Of the total patient population, almost 31,000 men were contacted and formally invited to be screened for prostate cancer. Ultimately, 23,800 declined the invitation but were included in follow-up with another 15,237 men who were not invited to screening.

In the screened group, the initial evaluation included PSA and digital rectal exam (DRE) in all men. Patients who had abnormal PSA levels or abnormal DRE were also evaluated by transrectal ultrasound. PSA screening and DRE were repeated during early follow-up visits, but DRE was subsequently dropped from later follow-up examinations.

Patients who were not screened had no regularly scheduled clinic visits as part of the study but were followed by usual medical practice.

Mortality Difference

By the end of 1996, five patients in the screened population had died of prostate cancer vs 137 in the control group. Expressed in terms that account for follow-up years, the screened group had a prostate cancer mortality of 15 per 100,000 man-years, compared with 48.7 per 100,000 in the control group.

The investigators separated the patients who declined invitations to screening from those who were never invited, the latter group representing what Dr. Labrie called "the true control group."

The uninvited cohort had a prostate cancer mortality of 41.6 per 100,000 man-years, compared with 53 per 100,000 among the invited-declined group. The difference between the two groups was not statistically significant.

Four of the five prostate cancer deaths in the study group were associated with cancers detected at the initial screening visit. All four of these cancers were metastatic, a finding that Dr. Labrie interpreted as confirming the effectiveness of current therapy for early-stage prostate cancer. Overall, 367 cancers were detected in the screened group, and none were metastatic when detected after the initial screen.

"If we start screening men at age 50, there will be very few cancers that will not be localized; metastatic prostate cancer almost disappears," he said.

An economic analysis of the findings revealed an estimated cost of about $3,000 for diagnosis of a single case of prostate cancer at initial visit. Total cost per each cancer diagnosed at any visit was about $10,000, a figure that compares favorably with costs associated with the diagnosis of breast and cervical cancers, Dr. Labrie said.

The results also show that use of 3 ng/ml as the cutoff for normal PSA has a substantial impact on cancer detection. Dr. Labrie said that a cutoff of 4 ng/ml as the upper limit of normal would have missed 13% of cancers at the initial visit and 21% of cancers at follow-up visits. "It also became clear that only PSA screening should be done at follow-up visits, since approximately 5,000 DREs are required to find one case of prostate cancer if the PSA level is below 3 ng/ml," Dr. Labrie said.

Some Caveats

In a formal discussion of the results, Peter Boyle, MD, focused on the investigators’ decision to combine the uninvited cohort with men who were invited to screening but declined. He argued that the invited-declined group should have been included with men who were screened.

"A randomized clinical screening trial should always be analyzed on an intention-to-screen basis," said Dr. Boyle, director of epidemiology, European Institute of Oncology, Milan, Italy.

Dr. Boyle calculated the death rates from prostate cancer on an intention-to-screen basis, looking at the ratio of death rates in those men who were invited to be screened compared with those men who were not invited to be screened.

Intention-to-Screen Results

With this analysis, the relative risk of prostate cancer death was about 1.1 to 1.16. "This is in tremendous contrast to the 70% reduction in death from screening (relative risk, 3.25) which you get when you look at the particular groups as Dr. La-brie has shown," he said.

However, Dr. Labrie said that the intent-to-screen analysis performed on actual data, even including prevalent cases at time of study initiation, show a relative risk of prostate cancer death of 0.94, a 6% decrease.

When accounting for the compliance rate and years of follow-up, he said, this corresponds to a 63% decrease in prostate cancer death in men actually screened. "This is a figure that confirms the previous analysis and practically eliminates the possibility of selection bias," Dr. Labrie said.

Dr. Boyle, however, said that although the "preliminary findings from this randomized study are of great importance, I think that there needs to be much further analysis of this dataset before final conclusions can be drawn about the study results."

Dr. Boyle cited the large compliance problem in the study: Only about 23% of those men invited to be screened actually complied. "So it is understandable that the authors wish to adjust for this in some way," he said. "Unfortunately, the method presented to take this into account is, I think, strongly susceptible to the possibility of selection bias."

Dr. Boyle also would have liked to have seen information about the total number of prostate cancers detected. "We would like to see increases in prostate cancer incidence along with the decline in mortality," he said.

Finally, Dr. Boyle cited the lack of a "death committee" for the study to allocate deaths to prostate cancer or other causes, rather than relying solely on the death registry for Quebec.

New Statistical Methods

Nonetheless, Dr. Boyle believes that many of the issues raised by the data could be resolved using advanced statistical epidemiology methods.

"There are statistical methodologies available to get a better understanding of the impact of compliance and contamination and the extent of the problem of selection bias and ascertainment bias," he commented.

Dr. Boyle congratulated Dr.Labrie and his group on having the "insight and foresight" to undertake the first randomized trial of prostate screening with PSA, but he emphasized that "no issue, and certainly not an issue as complex as prostate cancer screening, can be resolved by the results from one individual trial."