A Closer Look
PSA Screening and Cancer Mortality: Swedish Study Adds to the Debate
Over the last 2 years, findings from several studies, including two large randomized clinical trials, have fueled debate about the value of screening men for prostate cancer with the prostate-specific antigen (PSA) test. The larger of the two trials, the European Randomized Study for Prostate Cancer (ERSPC), conducted in seven countries, showed a 20 percent reduction in cancer mortality in men who underwent routine screening. But that mortality reduction came at a steep price: many men whose lives would likely never have been threatened by the disease were diagnosed with and treated for cancer.
Now, results from a trial that is part of the larger ERSPC study suggest that PSA screening for prostate cancer may—under certain circumstances, at least—substantially improve cancer-specific survival without the extent of overdiagnosis and overtreatment seen in the ERSPC and the other large prostate cancer screening trial, the NCI-led Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). Unlike the ERSPC, the PLCO reported no mortality benefit, but it also had a significant amount of “contamination,” that is, men in the trial who had already undergone screening with a PSA test, which a number of researchers have said may preclude the trial from ever demonstrating a cancer-specific survival improvement.
After 14 years of follow-up, the study, conducted in Sweden’s second-largest city, Göteborg (pronounced “Yotaborg”), showed an approximate 50-percent reduction in prostate cancer mortality among men age 50 to 64 (at the time of study entry) who were offered routine PSA screening compared with men not offered routine screening. The results were published online July 1 in Lancet Oncology.
—Dr. Jonas Hugosson
The findings, while suggesting promise, also brought calls for caution from researchers in the field, including the team that led the Göteborg trial.
“There are still uncertainties about the risks with PSA screening, especially the risk of overdiagnosis and overtreatment and how many years a man needs to live with possible side effects from treatment before he gains the benefits of screening,” said the trial’s lead investigator, Dr. Jonas Hugosson from Sahlgrenska University Hospital in Göteborg, in an e-mail. “Screening with PSA is an investment in future health, but as with all investments there is a cost.”
Digging into the Discrepant Results
So how are the results of the PLCO, ERSPC, and the Göteborg studies at odds? In the case of ERSPC, for example, the study authors concluded that 1,410 men would need to be screened with a PSA test and 48 cases of prostate cancer treated to prevent a single prostate cancer death. In the Göteborg study, those numbers were much smaller: 293 men screened and 12 diagnosed or treated to prevent one death from prostate cancer.
In an accompanying editorial in Lancet Oncology, Dr. David Neal of the University of Cambridge in the United Kingdom sorted through some of the key differences that could have led to these results, including the Göteborg trial’s much smaller size (20,000 men compared with 77,000 in PLCO and 182,000 in ERSPC), different screening schedules, and longer follow-up (14 years compared with 11 and 9 years, respectively). The median age of the men in the Göteborg trial was also more than 4 years younger (56 compared with over age 60), he wrote, “which is important because younger men are likely to benefit more from early diagnosis than older men.”
More than half of the participants in the Göteborg study are part of the ERSPC trial, which also complicates how the results are interpreted. In effect, the Swedish trial is a subgroup analysis of the larger European trial, explained Dr. Chris Berg of NCI’s Division of Cancer Prevention and the principal investigator of the PLCO trial.
“The Göteborg cohort provided the longest follow-up and the highest mortality benefit from PSA screening in the ERSPC trial. That means that the other groups reported in ERSPC had less than a 20 percent mortality reduction from screening,” Dr. Berg said. So the Göteborg results do not constitute “an independent confirmatory study,” she continued, but instead represent “extended follow-up on an already reported cohort with new information on an additional 8,048 individuals.”
There are other key differences, as well. Few men in the Göteborg trial had ever had a PSA screening test before enrolling in the study, Dr. Neal noted, including men in the control arm, meaning there was very little contamination. This is an important difference compared with the PLCO trial, he pointed out, in which 40 percent of participants had already been screened with a PSA test at study entry.
During the course of the trial, the state of prostate cancer screening in Sweden was “very different from the situation in the United States right now,” explained Dr. Eric Klein, chair of the Glickman Urological and Kidney Institute at the Cleveland Clinic. “It’s comparable to when PSA was introduced in the United States in the late ’80s. Now we have a heavily screened population, which is why it makes sense to build on the results of this trial to further refine our screening efforts to identify men at risk for potentially lethal cancers.”
Dr. Klein pointed, for example, to data suggesting that a baseline PSA in men in their 40s and subsequent PSA velocity (the rate of increase in PSA levels) can predict both lifetime risk of developing cancer and of potentially lethal cancers. Such an approach, he continued, could help identify men at high risk who may benefit from chemoprevention or men diagnosed with biologically significant cancer who would benefit from early intervention.
The substantial mortality reduction in the Göteborg study was achieved even though men in both arms diagnosed with low- to moderate-risk disease received comparable treatments and even though a significant portion of the men in the screening arm who were diagnosed with prostate cancer underwent active surveillance (approximately 40 percent versus approximately 30 percent in the control arm); that is, they chose to forgo definitive treatment, such as surgery or radiation, until there was evidence that their disease was progressing. At the time of the last data analysis, more than one-quarter of those men were still under an active surveillance regimen.
“The weight of the data clearly shows a benefit to screening” in men under 70, Dr. Klein said, “but there are still opportunities to further improve our screening paradigm to focus on identifying men at risk for biologically significant disease.”
While Dr. Berg agrees that screening with PSA likely can reduce prostate cancer mortality, she was less enthusiastic about the state of knowledge surrounding its use and the Göteborg results’ contribution to it.
“I think we still have the same issues, including potential overdiagnosis and overtreatment” she said. “Furthermore, the precise magnitude of the benefit from PSA screening and the precise schedule for screening have not been further defined.”