PSA SCREENING HALVES MORTALITY FROM PROSTATE CANCER?

July 1, 2010 — New data from a Swedish study show that population screening with prostate-specific antigen (PSA) in men between 50 and 69 years of age reduced prostate cancer mortality by almost half during a follow-up period of 14 years. The finding was published online today in Lancet Oncology.

"In this trial, prostate cancer screening was well accepted by the general population and can result in a relevant reduction in cancer mortality, greater than that reported in screening for breast and colorectal cancer," conclude the researchers, headed by Jonas Hugosson, MD, from the Department of Urology at the University of Gotenburg, Sweden.

This is the best mortality result ever seen with PSA screening — even better than the positive results reported from a large European study last year, which found a 20% reduction in prostate cancer deaths after 9 years. Those results came from the European Randomised Trial of Screening for Prostate Cancer (ERSPC) and provided for the first time "proof of the benefits of PSA screening," according to the investigators.

These new findings from Gotenburg provide the second proof after the ERSPC that PSA screening can save lives, David Neal MD, from the Department of Oncology at the University of Cambridge, United Kingdom, commented to Medscape Medical News.

Not Generalizable to the United States

However, there are several important caveats to the Gotenburg study, Dr. Neal writes in an accompanying editorial. It was small (n = 20,000), and more than half of the men were already included in the ERSPC study (n = 162,387, including 11,852 from the Gotenburg study). However, the 2 trials produced different results, probably because of the longer follow-up and younger age at screening in the Gotenburg study, he suggests.

Dr. Neal also emphasizes the context of the new finding. It comes from "a country with low levels of opportunistic PSA testing," which is in direct contrast to the situation in the United States, where there is already widespread PSA testing.

Hence, the results might be generalizable to other countries that have not had prior extensive PSA testing, but not to countries such as the United States, which already have such testing widely available, he said.

This may explain the negative results from the large study from the United States, the Prostate Lung Colorectal and Ovarian (PLCO), which found no reduction in prostate cancer mortality from PSA screening during a follow-up of 11 years. Those results have been discussed in some detail, with a major concern being potential contamination in the control group; the investigators noted that PSA testing had been widespread even before the study began.

The PCLO study is "flawed and will probably never show meaningful results," Dr. Neal commented to Medscape Medical News. "Many of the men were already screened with a PSA test."

The contradictory results from PLCO and ERSPC, which were published together in the New England Journal of Medicine last year, have fueled heated debate and controversy over the benefits vs harms of PSA screening.

However, Dr. Neal told Medscape Medical News that there is growing agreement that PSA screening does save lives from prostate cancer — at a price.

"The consensus is that PSA testing is a 'proof of principle' with a marker that has some defects. We need better biomarkers," he said. In the editorial, he mentions insulin-like growth factor or kallikrein family members, as well as genetic testing.

The new finding from Gotenburg shows that "PSA testing reduces death from prostate cancer in some circumstances," Dr. Neal concludes.

However, it does not imply that PSA screening programs should now be introduced internationally, he adds.

"One important finding in this study is that diagnosis of prostate cancer did not automatically result in men taking up radical treatment," Dr. Neal commented. About 40% of men were placed on active surveillance protocols, and 28% remain on these protocols. Hence, many of the men were managed conservatively, but despite this, there was a survival benefit in the groups that was screened, he pointed out.

Gotenburg Study "Mirrors Population Screening"

The Gotenburg study began in 1994 and enrolled 20,000 men who lived in the city and were older than 50 years (age range, 50 - 64 years; median age, 56 years). They were randomly assigned to either the screening or control group and then invited for screening with the PSA test. The invitations stopped at a median age of 69 years (range, 67 - 71 years).

This design "gives more representative results than does randomisation after informed consent, and mirrors the situation when screening is introduced in the population," the authors explain.

This study shows that a PSA-based screening program is acceptable to men aged 50 years or older, with 76% of men attending at least once, they report.

With such a participation rate, this screening program reduced prostate-cancer specific mortality "by as much as half over 14 years' follow-up."

During the median 14-year follow-up, prostate cancer was diagnosed in 12.7% of men in the screening group and 8.2% in the control group (hazard ratio, 1.64; P < .0001).

Most of the prostate cancer diagnosed in the screening group was early-stage disease, the researchers comment. More patients in the screening group had hormonal therapy, treatment with curative intent, and surveillance, they add.

According to the Cause of Death committee review, there were 44 deaths from prostate cancer in the screening group and 78 in the control group (according to death certificates, these numbers were 45 and 77, respectively).

"Half of the attendees who died from prostate cancer were diagnosed at their first screening visit," the researchers note.

The rate ratio (RR) of dying from prostate cancer was 0.56 in the screening group compared with the control group (P = .002).

The absolute cumulative-risk reduction (Kaplan-Meier estimates) of death from prostate cancer at 14 years was 0.40%, reduced from 0.90% in the control group to 0.50% in the screening group.

Compares Favorably With Other Cancer Screening

At 14 years of follow-up, the number who needed to be invited to screening (NNS) to prevent 1 prostate cancer death was 293, whereas the number needed to be diagnosed (corresponding to number needed to treat, NNT) was 12, the Swedish researchers report.

"These outcomes compare favourably with the well-established screening programs for breast and colorectal cancer," Dr. Neal comments in the editorial.

In their article, the Swedish researchers cite several papers for comparable figures.

Mammography for breast cancer screening has reported a NNS of 377 and an RR of 0.68 for women aged 60 to 69 years, and an NNS of 1339 and RR of 0.86 for women aged 50 to 59 years at 11 to 20 years of follow-up. A separate review reported an NNT for mammography of 10 over 10 years.

Colorectal cancer screening by fecal occult blood test has reported an RR of 0.84 in 2 separate reviews (after 11.7 - 18.4 years and 7.8 - 13 years, respectively), and an NNS of 1173 after 10 years.

Colorectal cancer screening by flexible sigmoidoscopy has reported an RR of 0.69 and an NNS of 489 at median follow-up of 11.2 years. However, as sigmoidoscopy removes any polyps that are found, it is associated with a reduced colorectal cancer incidence, and so an NNT cannot be calculated.

Differences Between Gotenburg and Previous Studies

The Swedish researchers discuss in some detail the discrepancy between their findings and those from the 2 large previous studies of PSA screening — the ERSPC and the PLCO — and offer potential explanations.

"First, the men in our study were younger (median age 56 years at baseline) than in both previous publications (median age>60years)," they point out.

"Younger men are less likely than older men to have incurable prostate cancer at the first screening, and are therefore more likely to gain the full benefit of screening," they comment.

In addition, the PSA threshold for biopsy was lower in the Gothenburg study, and so there was a "much higher rate" of biopsy for men with a positive screening result, the Swedish researchers note. There were also differences in the screening intervals, and the 2 previous studies also included digital rectal examination as a screening tool, whereas the Gotenburg study did not.

Perhaps the most important difference was the length of follow-up — a median of 14 years after randomization in the Gotenburg study compared with 9 years for ERSPC and 11.5 years for PLCO.

Dr. Hugosson and colleagues comment that the results for the first 10 years of follow-up from the Gotenburg study are similar to those from ERSPC, suggesting that most of the benefit from screening occurs after 10 years. "This is to be expected from a disease with a long lead-time and a long natural course," they add.

The NNT of 12 in the Gotenburg study is substantially lower than the NNT of 48 in the ERSPC, which suggests that NNT is very dependent on the length of follow-up, and "it is not easy to predict at which follow-up period the NNT will stabilise," they note.

As the NNT in prostate cancer screening mainly reflects the risk for overdiagnosis, the Swedish researchers suggest that this risk "is probably not as high as some have feared, at least if screening is restricted to the age groups included in this study" (ie, ages 50 - 69 years).

"Inviting men over the age of 70 for PSA screening seems questionable," the researchers comment. The benefit from prostate cancer screening takes a long time to achieve, they point out. Only marginal benefits are gained within the first 10 years, and the risk of overdiagnosis and overtreatment are still the major concerns in this field, so "one should be cautious to recommend that all elderly men have PSA screening."

Dr. Hugosson has received lecture fees from GlaxoSmithKline and Abbott Pharmaceuticals, and coauthor Hans Lilja, MD, has received honoraria from GlaxoSmithKline and holds patents for free PSA and hK2 assays. The other coauthors have disclosed no relevant financial relationships. Dr. Neal is one of the principal investigators on ProtecT, a trial of treatment of localized prostate cancer funded by the National Institute of Health Research.

Approached for independent comment, Philip Kantoff, MD, from the Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, told Medscape Medical News that the new study "does strongly support the position that PSA-based screening reduces prostate cancer specific mortality."

"It also supports the previous findings that prostate cancer mortality in a screened population is low in the first 10 years, and that overtreatment appears to be a significant problem," Dr. Kantoff said. "The issues of refining who should be screened and how frequently — but most importantly, who needs to be treated — needs to be determined," he added.

Lancet Oncol. Published online July 1, 2010.