Update on the Swedish Screening Study

Update by 'The "New" Prostate Cancer InfoLink':

The Göteborg prostate cancer screening trial — now that we’ve read the paper

Posted on July 2, 2010 by Sitemaster

On Thursday we provided an initial summary of media-reported data from the paper just published by Hugosson et al. in Lancet Oncology. Following is a carefully considered analysis after receipt and study of a copy of the full paper and additional information.
The Göteborg study was initiated in 1994, when 20,000 men from the local population were randomly assigned to one or other of two groups of patients: a screening group and a second group who would receive no screening (a control group). The men in this study were all born between 1930 and 1944, and were therefore between 50 and 65 years of age at the start of the study. We should point out immediately that in 1994 the use of PSA testing in Sweden was in comparative infancy, and so almost no one in this cohort of patients would have received any prior prospective testing for PSA at the time this study was started. It is also worth noting that the 20,000 men in this study comprised 61.9 percent of the total male population of Göteborg aged between 50 and 65 years at initiation of the study. It therefore represents a true mass, population-based screening trial and not just early detection.

Analysis of all data in this study is provided for both the entire set of 20,000 men and broken down by three age-related cohorts: men born between 1930 and 1934; men born between 1935 and 1939; and men born between 1940 and 1944.

The patients in the screening group were all invited to receive a PSA test once every 2 years until they reached the upper age limit of the study (which apparently ranged from 69 to 71 years of age, with a median of 69 years). Men in the screening group with elevated PSA levels were offered additional tests (e.g., a digital rectal examination and a prostate biopsy).

The authors have clearly stated that this is only the first report of data from this study. The study is ongoing, because the men who have not reached the upper age limit are still being invited for biannual PSA testing. This report provides cumulative prostate-cancer incidence and mortality data calculated only up through December 31, 2008.

It is important to note the following:

•Extraordinary efforts were made in this study to ensure that deaths from prostate cancer really were deaths that were specifically or highly probably a consequence of the disease, and not some other associated problem.
•Prostate cancer-specific deaths included deaths caused by the disease itself and also deaths resulting from any diagnostic or treatment-related intervention specific to the disease.
So what have Hugosson and his colleagues shown over the first 14 years of their study?

Their findings are reported as follows:

•48 men in the screening group and 48 men in the control group were excluded from the analysis because they died or emigrated before the randomization date, or because they already had been diagnosed with prostate cancer, leaving 9,952 men in each group who were eligible for analysis.
•7,578/9,952 men in the screening group (76 percent) actually received at least one PSA test.
•1,138/9,952 men in the screening group and 718/9,952 men in the control group had been diagnosed with prostate cancer as of the end of 2008.
◦Of the 1,138 men diagnosed with prostate cancer in the screening group, 1,046 (91.9 percent) had actually attended a screening clinic and received at least one PSA test and 92 (8.1 percent) never attended a screening clinic.
•The cumulative incidence of prostate cancer was 12.7 percent in the screening group and 8.2 percent in the control group.
•The total numbers of deaths in the two arms of the study were almost identical, at 1,981 in the screening group compared with 1,982 in the control group.
•44 men died of prostate cancer in the screening group compared to 78 men in the control group.
◦Of the 44 men who died of prostate cancer in the screening group, 27 were men diagnosed after attending a screening clinic and 17 were men who never attended a screening clinic.
◦Half of the men in the screening group who attended a screening clinic and died of prostate cancer (13/27) were diagnosed at their first visit to a screening clinic.
•109/1,138 men (9.6 percent) in the screening group and 54/718 men (7.5 percent) in the control group who were diagnosed with prostate cancer died of other, unrelated causes.
•The absolute cumulative reduction in risk of death from prostate cancer at 14 years was 0.40 percent (down from 0·90 percent in the control group to 0·50 percent in the screening group).
•The ratio of the rate of prostate cancer-specific mortality was 0.56 in the screening group overall (9,952 men) compared with the control group.
•The ratio of the rate of prostate cancer-specific mortality was 0.44 for screening test attendees (7,578 men) compared with the control group.
•Overall, 293 men needed to be invited for screening and 12 needed to be diagnosed to prevent one prostate cancer-specific death.
In their summary interpretation of the data from this study, Hugosson et al. state that, “prostate cancer mortality was reduced almost by half over 14 years. However, the risk of over-diagnosis is substantial.” They further note that the apparent benefit of prostate cancer screening (based on their data) compares favorably to the apparent benefit of other cancer screening programs (such as breast cancer screening).

In his editorial comments about this study, Prof. David Neal of Cambridge University makes a number of careful observations, including the following:

•This is a relatively small study (with only 20,000 men even as originally planned).
•The overall reduction in mortality (at 0.56) is much larger than that seen even in the ERSPC (at 0.8).
•The outcome in the Göteborg study at 9 years was similar to that of the ERSPC study at 9 years.
•In the Göteborg study, the median time since diagnosis is 6.7 years for men in the screened group and 4.3 years for men in the control group — which is much shorter than the equivalent data for the men in the ERSPC study.
•The median age of the men in the Göteborg study was 4 years younger than the median age of men in the ERSPC.
•Only 56 percent of the cancers found in the Göteborg study met the D’Amico criteria for low-risk disease.
•A diagnosis of prostate cancer in the Göteborg study did not necessarily result in radical treatment.
◦About 40 percent of the men diagnosed with prostate cancer in the screening group were placed on active surveillance protocols.
◦About 28 percent of the men diagnosed with prostate cancer in the screening group have remained on active surveillance throughout the study period to date.
Neal concludes that this study does not imply that widespread, population-based prostate cancer screening initiatives should be introduced internationally. His primary reason for this conclusion appears to be that the population that started being screened in 1994 was “screening naïve.” As an inevitable consequence, there was a very high probability of identifying men with relatively high-risk prostate cancer. While that may still be true today in large parts of a country like Nigeria, it would no longer be true in North America or in most Western European nations.

In countries where PSA testing is already widely used, Neal concludes that, until better tests are available, “Men should be aware of the benefits of early detection of prostate cancer,” and goes on to state that, “Current programmes that raise awareness and provide balanced information about the pros and cons of [individual testing] seem to be the right way forward.”

Having been able to review the complete, published article, The “New” Prostate Cancer InfoLink has to say that the degree of detailed information provided in this report is extraordinary, and the authors are to be highly commended for the clarity of the information provided.

Whatever else people may be able to make of this study, we believe that there are some very important facts to be learned:

•This study appears to show clearly that, in a screening-naïve population of men aged between 50 and 70 years of age, biannual PSA testing can lower the risk for prostate cancer-specific mortality by at least 40 percent.
•In addition, the study shows that the proportion of patients diagnosed with prostate cancer and requiring hormone therapy in the screening group (103/1,138 or 9.1 percent) was much less than half that of the patients in the control group (182/718 or 25.3 percent), implying that early detection also reduced the risk for metastatic disease.
•However … the study also shows clearly that (at 14 years of follow-up) biannual PSA screening has no impact whatsoever on the overall mortality rate in the same population.
We are therefore potentially faced with the difficult question of whether mass, population-based screening that does affect disease-specific mortality but does not affect overall mortality is justifiable based on the costs, the effort, and the potential harms to the men who are over-treated.

Please note that we are referring solely to mass, population-based screening — as carefully distinguished from early detection of prostate cancer in individuals who choose (of their own free will) to undergo testing after an appropriate discussion of the risks and benefits of such testing with an appropriately informed health professional. We wish to be very clear that the right of the individual to elect to be tested is — at least in our minds — both sacrosanct and very different from a recommendation to all men who meet certain specific criteria that they should undergo PSA testing.

The single most important fact about this study, as far as The “New” Prostate Cancer InfoLink is concerned, is that it finally has provided us with a highly structured, ongoing assessment of the potential value of mass, population-based screening for prostate cancer in a previously screening-naïve population. The study also includes full treatment information on all men diagnosed with prostate cancer over the course of the study. This means that at last we have a real baseline against which to assess the data from all other screening studies, and we can use this baseline to recognize the inherent problems of the PLCO and ERSPC studies, which include short follow-up (to date) in both studies, variation in protocols (within the ERSPC cohorts), and data adulteration resulting from PSA testing among the “unscreened” patient cohort (in the PLCO study).

The data from the Göteborg study may still not provide a convincing rationale for mass, population-based screening based on use of the PSA test, but it certainly does set the standard for what must be expected from any new test that may come along and show promise as a true screening test for prostate cancer in the future. The one regrettable fact about this study is that if it had included just one additional age cohort (of men born between 1945 and 1950), we might have been able to gain real insight over time into the benefits of even earlier detection for a period of up to 30 years

The Göteborg prostate cancer screening trial — now that we’ve read the paper