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PSA screening not recommended

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Population studies show that PSA testing is not worth the expense and hazard which includes impotency (the needle used in the biopsy can damage the nerve going to the penis). Moreover the PSA followed by biopsy leads to treating low-grade tumor that pose no risk.  Around 44% to 66% of those treated for prostate cancer shouldn’t have been treated.  The bottom study concludes that for each life extended by treatment for prostate cancer more than 20 had to be treated.  A more recent study put the number at 90 treated for to save 1 life—at that ratio the results are statistically insignificant.  In other words, PSA testing does not extend life, AND THUS NOT RECOMMENDED

 

BMJ 2010; 341:c4538 doi: 10.1136/bmj.c4538 (Published 14 September 2010)

Cite this as: BMJ 2010; 341:c4538

  • Editorial

Screening for prostate cancer

  1. Gerald L Andriole Jr, chief of urologic surgery

+ Author Affiliations

  1. 1Washington University School of Medicine, 4960 Children’s Place, Campus Box 8242, St Louis, MO 63110, USA
  1. andrioleg@wustl.edu

PSA testing should be tailored to individual risk

Screening based on prostate specific antigen (PSA) measurement has contributed to a dramatic increase in the number of prostate cancer cases diagnosed. In addition, most tumours are now smaller and clinically localised at diagnosis, whereas before the introduction of screening, tumours were often clinically advanced or overtly metastatic at diagnosis. However, the effects of screening on overall mortality and mortality from prostate cancer were unclear and variable in two large randomised trials.1 2 The American PLCO study found no benefit on mortality, whereas the European ERSPC trial showed a 20% reduction in prostate cancer specific mortality after 10 years in men who underwent PSA based screening.

In the linked systematic review and meta-analysis (doi:10.1136/bmj.c4543), Djulbegovic and colleagues comprehensively assessed the effects of screening for prostate cancer. The analysis of six randomised controlled trials, including the PLCO and ERSPC studies, found that screening increased the probability of being diagnosed with prostate cancer (relative risk 1.46, 95% confidence interval 1.21 to 1.77) but had no significant effect on mortality from prostate cancer (0.88, 0.71 to 1.09) or overall mortality (0.99, 0.97 to 1.01). The authors concluded that insufficient evidence is available to support the routine use of prostate cancer screening.3

In addition to the uncertain benefit on mortality, the human and economic costs associated with PSA based screening are substantial, mainly as a result of “overdiagnosis” and “overtreatment.”4 5 This occurs because repetitive PSA based screening detects all types of prostate cancer—indolent small volume tumours as well as aggressive lesions that have a high potential to cause harm. To date, methods of reducing overdiagnosis and overtreatment of indolent tumours have included the use of 5α reductase inhibitors6 7 as an adjunct to PSA testing and “active surveillance”8 programmes for small “low risk” tumours. By eliminating dihydrotesterone, 5α reductase inhibitors reduce the development or growth (or both) of low grade prostate tumours. In clinical trials, about 25% fewer cases of low grade prostate cancers were seen in treated men who were followed for four to seven years. Active surveillance requires close follow-up of men with low grade tumours, with frequent PSA testing and biopsy every year or so. In well selected patients, often elderly men or those with an anticipated short overall survival, this strategy has helped avert aggressive treatment in those who are likely to die of other conditions. Neither of these strategies is widely practised at the moment.

A second linked study by Vickers and colleagues assessed the potential of another strategy to improve the efficacy and reduce the costs of PSA based screening.9 They correlated PSA concentration at age 60 to the lifetime risk of a clinical diagnosis of prostate cancer, prostate cancer metastasis, and death from prostate cancer. PSA concentration at age 60 was strongly associated with prostate cancer and death from prostate cancer. Men with a PSA concentration below 1 ng/ml (about half of the population studied) had negligible rates of metastasis or death. Although only a minority of men with a PSA concentration greater than 2 ng/ml developed fatal prostate cancer, 90% (78% to 100%) of deaths from prostate cancer occurred in these men. Thus, men with a PSA less than 1 ng/ml could be exempted from repetitive testing, which would reduce overdiagnosis and overtreatment. Conversely, men with higher PSA concentrations at age 60, who have the highest risk for prostate cancer metastases or death, could be followed more intensively and might be more compliant with screening and treatment recommendations and with risk reduction strategies, such as drugs and lifestyle adjustments.

These findings need to be validated in additional studies. Studies should also look at different racial and ethnic groups, in whom the risk of prostate cancer may correlate with different PSA thresholds, and investigate whether a similar risk stratification can be carried out in a younger cohort—for example, men in their late 40s and early 50s. However, ultimately, early detection of prostate cancer relies on finding more specific biomarkers. Sadly, none has yet emerged, although recently there have been some promising developments.10 11 Identification of cancer specific genes in cells sloughed into the urine after prostatic examination, which is now feasible with the commercially available PCA3 test, may reduce the number of benign biopsies in men whose increased PSA concentration is caused by benign prostatic hyperplasia, and identification of aggressive prostate cancer by its molecular signature should help clinicians decide which prostate cancers need aggressive treatment.

For now, clinicians are best advised to individualise their approach to PSA based screening. Young men at high risk of prostate cancer, such as those with a strong family history and higher baseline PSA concentrations, should be followed closely and could also be considered for “risk reduction” approaches with 5α reductase inhibitors or dietary and lifestyle modifications (or both). Conversely, elderly men and those with a low risk of disease could be tested less often, if at all. Approaches such as these will hopefully make the next 20 years of PSA based screening better than the first 20.12

Notes

Cite this as: BMJ 2010;341:c4538

Footnotes

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Lead Time and Overdiagnosis in Prostate-Specific Antigen Screening: Importance of Methods and Context

  1. Gerrit Draisma, Ruth Etzioni, Alex Tsodikov, Angela Mariotto, Elisabeth Wever, Roman Gulati, Eric Feuer and Harry de Koning

+ Author Affiliations

  1. Affiliations of authors: Department of Public Health, Erasmus MC, University Medical Center, Rotterdam, the Netherlands (GD, EW, HdK); Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (RE, RG); Department of Biostatistics, University of Michigan, Ann Arbor, MI (AT); Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD (AM, EF)
  1. Correspondence to:
    Gerrit Draisma, PhD, Department of Public Health, Erasmus MC, University Medical Center, PO Box 2040 3000 CA, Rotterdam, the Netherlands (e-mail: g.draisma@erasmusmc.nl).
  • Received July 18, 2008. Revision received December 9, 2008. Accepted December 31, 2008.

Abstract

Background The time by which prostate-specific antigen (PSA) screening advances prostate cancer diagnosis, called the lead time, has been reported by several studies, but results have varied widely, with mean lead times ranging from 3 to 12 years. A quantity that is closely linked with the lead time is the overdiagnosis frequency, which is the fraction of screen-detected cancers that would not have been diagnosed in the absence of screening. Reported overdiagnosis estimates have also been variable, ranging from 25% to greater than 80% of screen-detected cancers.

Methods We used three independently developed mathematical models of prostate cancer progression and detection that were calibrated to incidence data from the Surveillance, Epidemiology, and End Results program to estimate lead times and the fraction of overdiagnosed cancers due to PSA screening among US men aged 54–80 years in 1985–2000. Lead times were estimated by use of three definitions. We also compared US and earlier estimates from the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) that were calculated by use of a microsimulation screening analysis (MISCAN) model.

Results The models yielded similar estimates for each definition of lead time, but estimates differed across definitions. Among screen-detected cancers that would have been diagnosed in the patients’ lifetimes, the estimated mean lead time ranged from 5.4 to 6.9 years across models, and overdiagnosis ranged from 23% to 42% of all screen-detected cancers. The original MISCAN model fitted to ERSPC Rotterdam data predicted a mean lead time of 7.9 years and an overdiagnosis estimate of 66%; in the model that was calibrated to the US data, these were 6.9 years and 42%, respectively.

Conclusion The precise definition and the population used to estimate lead time and overdiagnosis can be important drivers of study results and should be clearly specified.

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Prostate Cancer Diagnosis and Treatment After the Introduction of Prostate-Specific Antigen Screening: 1986–2005

  1. H. Gilbert Welch and  Peter C. Albertsen

+ Author Affiliations

  1. Affiliations of authors: VA Outcomes Group, Department of Veterans Affairs Medical Center, White River Junction, VT (HGW); Dartmouth Institute for Health Policy and Clinical Practice, Department of Medicine, Dartmouth Medical School, Hanover, NH (HGW); Department of Surgery, University of Connecticut School of Medicine, Farmington, CT (PCA)
  1. Correspondence to:
    H. Gilbert Welch, MD, MPH, VA Outcomes Group (111B), Department of Veterans Affairs Medical Center, White River Junction, VT 05009 (e-mail: h.gilbert.welch@dartmouth.edu).
  • Received February 4, 2009. Revision received June 17, 2009. Accepted July 23, 2009.

Abstract

Background Although there is uncertainty about the effect of prostate-specific antigen (PSA) screening on the rate of prostate cancer death, there is little uncertainty about its effect on the rate of prostate cancer diagnosis. Systematic estimates of the number of men affected, however, to our knowledge, do not exist.

Methods We obtained data on age-specific incidence and initial course of therapy from the National Cancer Institute's Surveillance, Epidemiology, and End Results program. We then used age-specific male population estimates from the US Census to determine the excess (or deficit) in the number of men diagnosed and treated in each year after 1986—the year before PSA screening was introduced.

Results Overall incidence of prostate cancer rose rapidly after 1986, peaked in 1992, and then declined, albeit to levels considerably higher than those in 1986. Overall incidence, however, obscured distinct age-specific patterns: The relative incidence rate (2005 relative to 1986) was 0.56 in men aged 80 years and older, 1.09 in men aged 70–79 years, 1.91 in men aged 60–69 years, 3.64 in men aged 50–59 years, and 7.23 in men younger than 50 years. Since 1986, an estimated additional 1 305 600 men were diagnosed with prostate cancer, 1 004 800 of whom were definitively treated for the disease. Using the most optimistic assumption about the benefit of screening—that the entire decline in prostate cancer mortality observed during this period is attributable to this additional diagnosis—we estimated that, for each man who experienced the presumed benefit, more than 20 had to be diagnosed with prostate cancer.

Conclusions The introduction of PSA screening has resulted in more than 1 million additional men being diagnosed and treated for prostate cancer in the United States. The growth is particularly dramatic for younger men. Given the considerable time that has passed since PSA screening began, most of this excess incidence must represent overdiagnosis.

  • Published by Oxford University Press 2009.

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Wikipedia at http://en.wikipedia.org/wiki/Prostate-specific_antigen

 

PSA is false positive-prone (7 out of 10 men in this category will still not have prostate cancer) and false negative-prone (2.5 out of 10 men with prostate cancer have no elevation in PSA).[35]  {These figures are not adjusted for those whose treatment of indolent cancer has no effect upon mortality, which the first study estimates to be about 90%.} 

Risk stratification and staging

Patients with localized (non-metastatic) prostate cancer have traditionally been characterized as low-, intermediate-, or high-risk for failure of curative treatment and prostate cancer mortality. PSA level is one of three variables on which the risk-stratification is based; the others are the grade of prostate cancer (Gleason score) and the stage of cancer based on clinical investigations (as opposed to examination of surgical pathology). Criteria for each risk category are as follows:

Low-risk: PSA < 10, Gleason score ≤ 6, AND clinical stage ≤ T2a

Intermediate-risk: PSA 10-20, Gleason score 7, OR clinical stage T2b/c

High-risk: PSA > 20, Gleason score ≥ 8, OR clinical stage ≥ T3

Free PSA

Most PSA in the blood is bound to serum proteins. A small amount is not protein bound and is called 'free PSA'. In men with prostate cancer the ratio of free (unbound) PSA to total PSA is decreased. The risk of cancer increases if the free to total ratio is less than 25%. (See graph at right.) The lower the ratio the greater the probability of prostate cancer. Measuring the ratio of free to total PSA appears to be particularly promising for eliminating unnecessary biopsies in men with PSA levels between 4 and 10 ng/mL.[27] However, both total and free PSA increase immediately after ejaculation, returning slowly to baseline levels within 24 hours

NIH division National Cancer Institute

http://www.cancer.gov/newscenter/pressreleases/2009/plcoprostateresults

U.S. Cancer Screening Trial Shows No Early Mortality Benefit from Annual Prostate Cancer Screening

Six annual screenings for prostate cancer led to more diagnoses of the disease, but no fewer prostate cancer deaths, according to a major new report from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a 17-year project of the National Cancer Institute (NCI), part of the National Institutes of Health. The PLCO was designed to provide answers about the effectiveness of prostate cancer screening.

"What this report tells us is that there may be some men who are diagnosed with prostate cancer and have the side-effects of treatment, such as impotence and incontinence, with little chance of benefit," said John E. Niederhuber, M.D., director of the NCI. "Clearly, we need a better way of detecting prostate cancer at its earliest stages and as importantly, a method of determining which tumors will progress. Many of the molecular studies we're currently sponsoring will hopefully yield new, better ways of definitively classifying which men need treatment and which can consider watchful waiting. Until we have developed and verified a new test's benefits and harms, as we have done with the PLCO, regular visits to your doctor to monitor your health are still strongly recommended."

Results appear online March 18, 2009, in the New England Journal of Medicine, to coincide with presentation of the data at the European Association of Urology meeting in Stockholm, Sweden. The print version of the results will appear in the March 26, 2009 issue.

NCI does not have a recommendation about prostate cancer screening. The U.S. Preventive Services Task Force, whose recommendations are considered the gold standard for clinical preventive services, recently concluded that there is insufficient evidence to assess the balance of benefits and harms of prostate cancer screening in men younger than age 75 and recommended against prostate cancer screening in men age 75 and older.

Digital Prostate Examination (DRE)There were 76,693 men in the PLCO trial that was conducted at 10 centers around the United States. Of the men in the trial, 38,343 were randomly assigned to screening with annual prostate-specific antigen (PSA) tests for six rounds and digital rectal exams (DRE) for four rounds. A DRE is an exam whereby a doctor inserts a lubricated, gloved finger into the rectum and feels for anything that is not normal. The other 38,350 men were randomly assigned to usual care, but received no recommendations for or against annual prostate cancer screening.

Of those men who were screened annually, 85 percent had PSA tests and 86 percent had DREs. Men in the usual-care arm sometimes had these tests as well, due to the growing public acceptance of such screening. Screening by PSA in this usual-care group increased from 40 percent at the beginning of the study to 52 percent of men by the last screening year, and screening with DRE ranged from 41 percent initially to 46 percent by the last screening year. Men in the screening arm were referred to their usual health care provider for follow-up testing for prostate cancer if their PSA level was greater than 4.0 nanograms per milliliter (ng/mL) or if a DRE found an abnormality.

This report includes data for all participants at seven years after they joined the trial and for 67 percent of participants at 10 years after they joined the trial. Other important findings include:

  • At seven years, 22 percent more prostate cancers were diagnosed in the screening arm (2,820 men vs. 2,322 in the usual-care group). This excess is continuing to be observed in data collected up to 10 years (currently a 17 percent excess, 3,452 men vs. 2,974 men).
  • The vast majority of men in both groups who developed prostate cancer were diagnosed with relatively early stage II (out of IV stages, of which IV is late stage) disease, and the number of later-stage cases was similar in the two groups. However, using the Gleason scoring system, which assesses tumor aggressiveness, men in the usual-care group had more prostate cancers that fell into the Gleason 8 to10 range, which marks them as more aggressive. The smaller number of men with prostate cancer with a Gleason score of 8 to10 in the intervention group may eventually lead to a mortality difference between men in the two groups but data analyzed so far have not shown such a difference.
  • Men in both groups who were diagnosed with prostate cancer at the same stage received similar treatments for their disease. This reflects the PLCO study design policy of not mandating specific therapies.
  • At seven years, 50 deaths were attributable to prostate cancer in the screening group and 44 deaths were attributable in the usual-care group. Through year 10, there were 92 prostate cancer deaths in the screening group and 82 in the usual-care group. The difference between the numbers of deaths in the two groups was not statistically significant. Thus there was no detectable mortality benefit for screening vs. usual-care.

Given the uncertainties about the mortality benefits of PSA testing, NCI has been pursuing many avenues to find new ways of screening for prostate cancer, including several sets of biomarkers that are being validated in its Early Detection Research Network (EDRN), some using specimens from PLCO's biorepository of tissue and blood. Some examples of the marker tests include using microstrands of RNA to detect disease, examining changes in genes such as GSTP1, and imaging of proteins in prostate cancer tissue.

"NCI wants to understand why some prostate cancers are lethal even when found early by annual screening, and what approaches can be used to identify these more aggressive cancers when they can be effectively treated," said Christine Berg, M.D., NCI leader of the PLCO trial and senior author of the study. "The PLCO biorepository is an invaluable resource for such research, with nearly three million biological samples collected from our participants. Our hope is that through all aspects of the PLCO, we will gather the information that tells us whom to treat aggressively and whom to avoid overtreating."

Another report in this same online publication of the NEJM is from the large European Randomized Study of Screening for Prostate Cancer (ERSPC), which shows a 20 percent reduction in the rate of death from prostate cancer but with a high risk of overdiagnosis. In the ERSPC, unlike the PLCO trial, men were referred for follow-up testing if their PSA level was 3.0 ng/mL or higher and were also screened, on average, every four years as opposed to annually in the PLCO.

"Approaches such as lowering the threshold for what is considered an abnormal PSA level to 3.0 ng/mL will diagnose more cases, but it is not at all clear that it will identify the prostate cancers that are more likely to lead to a man's death," said Berg.

The PLCO data are being made public now because the study's Data and Safety Monitoring Board (DSMB), an independent review committee that meets every six months, saw a continuing lack of evidence that screening reduces death due to prostate cancer as well as the suggestion that screening may cause men to be treated unnecessarily. The DSMB also supports continued follow up of all participants so that every participant is tracked for at least 13 years from entry onto the trial.

The PLCO is a large-scale clinical trial, sponsored and run by NCI's Division of Cancer Prevention, begun in 1992 to determine whether certain cancer screening tests can help reduce deaths from prostate, lung, colorectal and ovarian cancer. The underlying rationale for the trial is that screening for cancer may enable doctors to discover and treat the disease earlier.

Nearly 155,000 women and men between the ages of 55 and 74 have joined the PLCO trial. At entry, participants were assigned at random to one of two study groups: One group received routine health care from their health providers. The other received a series of exams to screen for prostate, lung, colorectal, and ovarian cancers. Screening of participants ended in late 2006. Follow-up of participants is anticipated to continue for several more years.

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A call-in teleconference was held on Tuesday, March 17, 2009 at 12:00 p.m. (noon) EDT to discuss the implications of this finding and to answer reporter questions about these results. This teleconference is now available via MP3 playback. For a copy of the audio file, please contact a NCI press officer at either (301) 496-6641 or ncipressofficers@mail.nih.gov.

A Q&A on the prostate screening results from the PLCO is available at http://www.cancer.gov/newscenter/pressreleases/PLCOprostateResultsQandA.

A Spanish version of this document is available at http://www.cancer.gov/espanol/noticias/PLCOprostateResultsSpanish

A new issue of NCI's BenchMarks, related to cutting-edge prostate cancer treatment issues, is available at http://www.cancer.gov/newscenter/benchmarks-vol8-issue1.

Andriole GL, Grubb RL, Buys SS, Chia D, Church TR, Fouad MN, Gelmann EP, Kvale PA, Reding DJ, Weissfeld JL, Yokochi LA, Crawford ED, O'Brien B, Clapp JD, Rathmell JM, Riley TL, Hayes RB, Kramer BS, Izmirlian G, Miller AB, Pinsky PF, Prorok PC, Gohagan JK, and Berg CD. Mortality Results from a Prostate-Cancer Screening Trial. Online March 18, 2009. In print, March 26, 2009. Vol. 360, No. 13. NEJM.

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

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