No Mortality Benefit Seen from PSA Screening

Risk of prostate cancer in two age groups base...Image via Wikipedia

No Mortality Benefit Seen from PSA Screening

By Charles Bankhead, Staff Writer, MedPage Today
Published: January 06, 2012
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.
Prostate cancer screening with prostate-specific antigen (PSA) afforded no obvious prostate cancer mortality benefit during 13 years of follow-up in a large randomized trial.

In fact, screened patients had a slightly higher prostate cancer mortality: 3.7 per 10,000 person-years, versus 3.4 for unscreened men.

The results emphasize the need to find some means to identify patients who are most likely to benefit from PSA screening, said the first author of a report in the January issue of the Journal of the National Cancer Institute.

“Routine mass screening of the population, purely on the basis of a man’s age, is not going to be an effective way of reducing his chance of dying of prostate cancer,” Gerald Andriole, MD, of Washington University in St. Louis, told MedPage Today.

Action Points  

  • Prostate cancer screening with prostate-specific antigen (PSA) afforded no obvious prostate cancer mortality benefit during 13 years of follow-up in a large randomized trial.
  • The study found that screened patients had a slightly higher prostate cancer mortality: 3.7 per 10,000 person-years, versus 3.4 for unscreened men.
“Having said that, that’s not to say that no man should get PSA testing,” he continued. “There are subsets of men in the population at large who do seem to stand a good chance of benefiting from PSA testing.
“Those are men who are young, with no comorbidities, and generally very healthy. These are men with the longest life expectancy overall. They are men who, even if they harbor a nonaggressive, slow-growing cancer, are nonetheless expected to live long enough to die of prostate cancer in the absence of it being identified and treated.”
Screening also is reasonable for men who have an above-average risk of prostate cancer, such as African Americans and men with a strong family history of the disease, Andriole added.
The data 0ffered nothing to change the conclusions of an earlier analysis of data from the same study, the National Institutes of Health-sponsored Prostate, Lung, Colorectal, and Ovarian (PLCO) screening program. After a median follow-up of seven years (up to as long as 10 years) the screened and unscreened groups had a similar prostate cancer mortality.
The prostate cancer portion of PLCO involved 76,685 men who were ages 55 to 74 and cancer-free at enrollment. Study participants were randomized to annual PSA screening for six years or to usual care, which sometimes included “opportunistic” PSA screening.
The initial report from the study showed a prostate cancer rate of 116 per 10,000 in the screened group compared with 95 per 10,000 in the control group. Prostate cancer mortality was 2 per 10,000 with screening and 1.7 per 10,000 in the control group.
The current report showed that after a median follow-up of 13 years, cancer incidence was 108.4 and 97.1 per 10,000 in the screened and unscreened groups, respectively. The difference represented a statistically significant 12% increase in cancer incidence in the screened group (RR 1.12, 95% CI 1.07 to 1.17).
Mortality was 3.7 and 3.4 per 10,000 with and without screening, respectively, a nonsignificant difference.
“This article updates with more person-years of follow-up our previously reported finding of no reduction in mortality from prostate cancer in the intervention arm compared with the control arm to 10 years, with no indication of a reduction in prostate cancer mortality to 13 years,” the authors wrote of their findings.
Responding to the study, Otis W. Brawley, MD, chief medical officer of the American Cancer Society, acknowledged that the results are consistent with other studies that have pointed to a potential harm from overscreening and unnecessary treatment of indolent prostate cancer.
“This trial does suggest that if there is truly an advantage to mass [PSA] screening it is small,” Brawley said in a statement.
Even so, the results do not rule out the possibility of a benefit in some high-risk men or the value of PSA screening in men who want the test, he added.
“I truly believe that a man who is concerned about prostate cancer and understands that experts are not certain that screening saves lives, but it definitely causes anxiety and needless treatment, can reasonably choose to be screened,” said Brawley.
“A man who is more concerned with unnecessary diagnosis and treatment might reasonably choose not to be screened. It is an area that needs to be left to an informed patient.”
The PLCO trial is sponsored by the National Institutes of Health.
Andriole disclosed relationships with Amgen, Augmenix, Bayer, Cambridge Endo, Caris, France Foundation, GenProbe, GlaxoSmithKline, Myriad Genetics, Steba Biotech, Ortho Clinical Diagnostics, and Viking Medical. Co-authors disclosed relationships with GlaxoSmithKline and Human Genome Sciences.

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Cribado de cancer de prostata – Screening of prostaste cancer

Prostate and bladder, sagittal section.Image via Wikipedia

Editorial del NEJM 26 de Marzo 2009

In the United States, most men over the age of 50 years have had a prostate-specific–antigen (PSA) test,1 despite the absence of evidence from large, randomized trials of a net benefit. Moreover, about 95% of male urologists and 78% of primary care physicians who are 50 years of age or older report that they have had a PSA test themselves,2 a finding that suggests they are practicing what they preach. And indeed, U.S. death rates from prostate cancer have fallen about 4% per year since 1992, five years after the introduction of PSA testing.3 Perhaps the answer to the PSA controversy is already staring us in the face. At the same time, practice guidelines cite the unproven benefit of PSA screening, as well as the known side effects,4,5 which largely reflect the high risks of overdiagnosis and overtreatment that PSA-based screening engenders.6
The first reports from two large, randomized trials that many observers hoped would settle the controversy appear in this issue of the Journal. In the U.S. Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Andriole et al.7 report no mortality benefit from combined screening with PSA testing and digital rectal examination during a median follow-up of 11 years.8 In the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial, Schröder et al.8 report that PSA screening without digital rectal examination was associated with a 20% relative reduction in the death rate from prostate cancer at a median follow-up of 9 years, with an absolute reduction of about 7 prostate cancer deaths per 10,000 men screened.8 The designs of the two trials are different and provide complementary insights.
First, one must ask, “Why were these results published now?” Neither set of findings seems definitive; that is, there was neither a clear declaration of futility in the PLCO trial nor an unambiguous net benefit in the ERSPC trial. Both studies are ongoing, with future updates promised. The report on the ERSPC trial follows a third planned interim analysis, which found a marginally significant decrease in prostate-cancer mortality after adjustment of the P value for the two previous looks in an attempt to avoid a false positive conclusion (yet apparently preserving no alpha for the planned final analysis). On the other hand, the investigators in the PLCO trial made the decision to publish their results now because of concern about the emerging evidence of net harm compared with potential benefits associated with PSA screening. Both decisions to publish now can be criticized as premature, leaving clinicians and patients to deal with the ambiguity.
The ERSPC trial is actually a collection of trials in different countries with different eligibility criteria, randomization schemes, and strategies for screening and follow-up. The report by Schröder et al. is based on a predefined core group of men between 55 and 69 years of age at study entry. Subjects were generally screened every 4 years, and 82% were screened at least once. Contamination of the control group with screening as part of usual care is not described. Biopsies were generally recommended for subjects with PSA levels of more than 3.0 ng per milliliter. It is unclear whether the clinicians and hospitals treating patients with prostate cancer differed between the two study groups.
Adjudications of causes of death were made by committees whose members were unaware of study-group assignments, though not of treatments. This point is important, since previous research has suggested that the cause of death is less likely to be attributed to prostate cancer among men receiving attempted curative treatment.9 Misattribution might then create a bias toward screening, since the diagnosis of more early-stage cancers in the ERSPC trial led to substantially more attempted curative treatments.
The ERSPC interim analysis revealed a 20% reduction in prostate-cancer mortality; the adjusted P value was 0.04. The estimated absolute reduction in prostate-cancer mortality of about 7 deaths per 10,000 men after 9 years of follow-up, if real and not the result of chance or bias, must be weighed against the additional interventions and burdens. The 73,000 men in the screening group underwent more than 17,000 biopsies, undoubtedly many more than did men in the control group, though the latter is not reported. Men had a substantially higher cumulative risk of receiving the diagnosis of prostate cancer in the screening group than in the control group (820 vs. 480 per 10,000 men). Diagnosis led to more treatment, with 277 versus 100 per 10,000 men undergoing radical prostatectomy and 220 versus 123 per 10,000 undergoing radiation therapy with or without hormones, respectively (tentative estimates given the unknown treatments in both groups).
Although estimates of the benefit of screening were somewhat greater for men who actually underwent testing (taking into account noncompliance) than for those who were not tested, the side effects would be proportionately higher as well. Given these trade-offs, the promise of future ERSPC analyses addressing quality of life and cost-effectiveness is welcome indeed. The ERSPC results also reemphasize the need for caution in screening men over the age of 69 years, given an early trend toward higher prostate-cancer mortality with screening in this age subgroup, although this finding may well be due to chance alone.
A final point to make about the ERSPC trial is that to the extent that the diagnosis and treatment of prostate cancer in the screening group differed from those in the control group, it becomes difficult to dissect out the benefit attributable to screening versus improved treatment once prostate cancer was suspected or diagnosed. A similar distribution of treatments among seemingly similar patients with cancer is only partially reassuring in this regard.
Despite a longer median follow-up, the PLCO trial was smaller and therefore less mature than the ERSPC trial, with 174 prostate-cancer deaths driving the power of the study, as compared with 540 such deaths in the ERSPC trial. The screening protocol was homogeneous across sites with an enrollment age of 55 to 74 years and annual PSA tests for 6 years and digital rectal examinations for 4 years, with about 85% compliance. Subjects in the screening group who had a suspicious digital rectal examination or a PSA level of more than 4.0 ng per milliliter received a recommendation for further evaluation. This strategy helped to ensure that any difference in outcome was attributable to screening, rather than downstream management. The effectiveness of screening, of course, will be determined by the effectiveness of subsequent “usual care,” but this is the same usual care that many practitioners assume has been responsible for the falling U.S. death rate from prostate cancer. Adjudication of causes of death was similar to that in the ERSPC trial.
Though the PLCO trial has shown no significant effect on prostate-cancer mortality to date, the relatively low number of end points begets a wide confidence interval, which includes at its lower margin the point estimate of effect from the ERSPC trial. Other likely explanations for the negative findings are high levels of prescreening in the PLCO population and contamination of the control group. Contamination was assessed by periodic cross-sectional surveys, with about half the subjects in the control group undergoing PSA testing by year 5. It is unclear whether these estimates reflect testing that year or since trial inception; if the former, the cumulative incidence may be even higher. The smaller difference in screening intensity between the two study groups in the PLCO trial, as compared with the ERSPC trial, is reflected in a smaller risk of overdiagnosis (23% vs. more than 70%) and a less impressive shift in cancer stage and grade distributions. Given that study-group contamination from the use of digital rectal examination was less problematic (only about 25%), ongoing results from both of these trials may necessitate rethinking the role of digital rectal examination in cancer screening.
After digesting these reports, where do we stand regarding the PSA controversy? Serial PSA screening has at best a modest effect on prostate-cancer mortality during the first decade of follow-up. This benefit comes at the cost of substantial overdiagnosis and overtreatment. It is important to remember that the key question is not whether PSA screening is effective but whether it does more good than harm. For this reason, comparisons of the ERSPC estimates of the effectiveness of PSA screening with, for example, the similarly modest effectiveness of breast-cancer screening cannot be made without simultaneously appreciating the much higher risks of overdiagnosis and overtreatment associated with PSA screening.
The report on the ERSPC trial appropriately notes that 1410 men would need to be offered screening and an additional 48 would need to be treated to prevent one prostate-cancer death during a 10-year period, assuming the point estimate is correct. And although the PLCO trial may not have the power as yet to detect a similarly modest benefit of screening, its power is already more than adequate to detect important harm through overdiagnosis. However, the implications of the trade-offs reflected in these data, like beauty, will be in the eye of the beholder. Some well-informed clinicians and patients will still see these trade-offs as favorable; others will see them as unfavorable. As a result, a shared decision-making approach to PSA screening, as recommended by most guidelines, seems more appropriate than ever.
Finally, despite these critiques, both groups of investigators deserve high praise for their persistence and perseverance: to manage such monstrous trials is a herculean task, made no easier when so many observers think the results are self-evident. Further analyses will be needed from these trials, as well as from others — such as the Prostate Cancer Intervention Versus Observation Trial (PIVOT) in the United States ( number, NCT00007644 [] )10 and the Prostate Testing for Cancer and Treatment (PROTECT) trial in the United Kingdom (Current Controlled Trials number, ISRCTN20141297 [] )11 — if the PSA controversy is finally to sleep the big sleep.
No potential conflict of interest relevant to this article was reported.

Source Information

From Massachusetts General Hospital and Harvard Medical School, Boston.

This article (10.1056/NEJMe0901166) was published at on March 18, 2009.

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