Prostate cancer screening

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Prostate cancer screening is an attempt to identify individuals with prostate cancer in a broad segment of the population—those for whom there is no reason to suspect prostate cancer. There are currently two methods used: One is the digital rectal examination (DRE), in which the examiner inserts a gloved, lubricated finger into the rectum to examine the adjoining prostate. The other is the prostate-specific antigen (PSA) blood test, which measures the concentration of this molecule in the blood.

The United States Preventive Services Task Force (USPSTF) recommended against PSA screening in healthy men finding that the potential risks outweigh the potential benefits.[1] Guidelines from the American Urological Association,[2] and the American Cancer Society[3] recommend that men be informed of the risks and benefits of screening. The American Society of Clinical Oncology recommends screening be discouraged in those who are expected to live less than ten years, while in those with a life expectancy of greater than ten years a decision should be made by the person in question based on the potential risks and benefits. In general, they conclude that based on recent research, "it is uncertain whether the benefits associated with PSA testing for prostate cancer screening are worth the harms associated with screening and subsequent unnecessary treatment." [4]

Interpretation[edit]

Two clinical prediction rules help predict the probability of cancer based on the level of the prostate-specific antigen and other clinical findings.[5][6]

Digital rectal examination[edit]

Digital rectal examination (DRE) is a procedure where the examiner inserts a gloved, lubricated finger into the rectum to check the size, shape, and texture of the prostate. Areas that are irregular, hard, or lumpy need further evaluation, since they may contain cancer. Although the DRE evaluates only the back of the prostate, 85% of prostate cancers arise in this part of the prostate. Prostate cancer that can be felt on DRE is, in general, more advanced.[7] The use of DRE has never been shown to prevent prostate cancer deaths when used as the only screening test.[8]

Prostate specific antigen[edit]

The PSA test measures the blood level of prostate-specific antigen, an enzyme produced by the prostate. To be specific, PSA is a serine protease similar to kallikrein. Its normal function is to liquify gelatinous semen after ejaculation, allowing spermatozoa to more easily navigate through the uterine cervix.

PSA testing is controversial and may lead to unnecessary, even harmful, consequences in some patients.[9] Since the test was introduced in the U.S., more than 1 million additional men there have been diagnosed and treated for prostate cancer, but it has been estimated that the vast majority (more than 95%) of these men receive no benefit from their positive diagnosis. Even if one makes the most optimistic assumption about the benefit of screening (i.e. that the entire decline in prostate cancer mortality observed since the introduction of PSA testing is due to introduction of the test) less than 5% (or one in twenty) of those getting a positive diganosis received any benefit at all from it.[10] [11]

Other research studies, however, point to the success of the PSA test in reducing death due to prostate cancer. The European Randomized Study of Screening for Prostate Cancer (ERSPC) study, published in the New England Journal of Medicine (March 2009), documented that screening resulted in a 20 percent reduction in prostate cancer mortality.[12]

More recent studies have shown greater effectiveness in how screening has reduced the prostate cancer death rate. A study published in the European Journal of Cancer (October 2009) documented that prostate cancer screening reduced prostate cancer mortality by 37 percent. By utilizing a control group of men from Northern Ireland, where PSA screening is infrequent, the research showed this substantial reduction in prostate cancer deaths when compared to men who were PSA tested as part of the ERSPC study.[13]

The risk of prostate cancer increases with increasing PSA levels.[14] 4 ng/mL was chosen arbitrarily as a decision level for biopsies in the clinical trial upon which the U.S. Food and Drug Administration (FDA) in 1994 based adding prostate cancer detection in men age 50 and over as an approved indication for the first commercially available PSA test.[15] 4 ng/mL was used as the biopsy decision level in the PLCO trial, 3 ng/mL was used in the ERSPC and ProtecT trials, and 2.5 ng/mL is used in the 2007 NCCN guideline.

PSA levels can change for many reasons other than cancer. Two common causes of high PSA levels are enlargement of the prostate (benign prostatic hypertrophy (BPH)) and infection in the prostate (prostatitis). It can also be raised for 24 hours after ejaculation and several days after catheterization.

PSA levels are lowered in men that use finasteride (Proscar or Propecia) or dutasteride (Avodart) to treat BPH. After a year, finasteride was shown to lower PSA levels by 50% or more. Finasteride is also marketed as Propecia (1 mg.) for baldness, and the lower dose was shown in a further clinical trial to also lower PSA readings by 50% after a year. As a result, reference ranges and calculations of the rate of change in PSA levels per year must be adjusted accordingly in men taking such drugs.

Several other ways of evaluating the PSA have been developed to avoid the shortcomings of simple PSA screening. The use of age-specific reference ranges improves the sensitivity and specificity of the test. The rate of rise of the PSA over time, called the PSA velocity, has been used to evaluate men with PSA levels between 4 and 10 ng/ml, but it has not proven to be an effective screening test.[16] Comparing the PSA level with the size of the prostate, as measured by ultrasound or magnetic resonance imaging, has also been studied. This comparison, called PSA density, is both costly and As of 1994 is not considered to be an effective screening test.[17] but does have prognostic value.[18] PSA in the blood may either be free or bound to other proteins. Measuring the amount of PSA which is free or bound may provide additional screening information, but questions regarding the usefulness of these measurements limit their widespread use As of 2000.[19][20]

Controversy about screening[edit]

Prostate cancer can develop into a fatal, painful disease, but it can also develop so slowly that it will never cause problems during the man's lifetime. It is difficult for a physician to determine how the cancer will proceed based on screening tests currently available alone.[citation needed]

The United States Preventive Services Task Force (USPSTF) recommended against PSA screening in healthy men finding that the potential risks outweigh the potential benefits.[1] This recommendation, released in October 2011, is based on a review of evidence and concludes that "prostate-specific antigen–based screening results in small or no reduction in prostate cancer–specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary."[21]

Hal Arkes, a psychologist, presents the statistical case as follows:

If there were two auditoriums each filled with 1,000 men, one filled with men who had taken PSA screening tests and the other with men who didn't take the test, there would be just as many men (8) "who died of prostate cancer in each auditorium, which leads us to think in the aggregate it didn't do any good." Among those who took the test there would also be 20 men who were treated for prostate cancers which never would have caused symptoms. Five of these men would have lifelong complications, including impotence and incontinence.[22][23]

This recommendation has been criticized by many prostate cancer experts for an over-reliance on findings of the U.S. Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.[24] This trial intended to randomize men between screening and no screening. However, because the study was initiated during a time when PSA screening was already becoming widely adopted, there were high rates of PSA testing among men who were in the control arm. This rate of "contamination" was very high: acknowledged by the authors to be 44% before the study started and 52% during the course of study. In fact, the rate was likely much higher, since over 90% of the prostate cancers found in the "control" arm were stage T1 or T2, which by definition can only be detected with screening.[25] The PLCO authors stated in a later publication that the PLCO should not be interpreted as a trial of screening vs. no screening, but rather as a trial of annual screening vs. so-called opportunistic or ad-hoc screening.[26] The USPSTF also based their assessment of the "harms" of screening and treatment based on a biased and out-dated literature review. For just one example, their statement cited a 1:200 risk of dying within 30 days of radical prostatectomy. This number comes from men over the age of 65 treated in the early 1990s; the actual number in contemporary practice is closer to 1:10,000.[27]

PSA testing of men in their mid-70s and older, is discouraged as most people at this age diagnosed with prostate cancer detected by a PSA test would die of other causes before the cancer caused problems.[28] On the other hand, up to 25% of men diagnosed in their 70s or even 80s die of prostate cancer, if they have high-grade (i.e., aggressive) prostate cancer.[29] Conversely, some argue against PSA testing for men who are too young, because too many men would have to be screened to find one cancer, and too many men would have treatment for cancer that would not progress. This argument again ignores the fact that low-risk prostate cancer does not require immediate treatment, but may be amenable to active surveillance.[30]

Prostate cancer is both common (by far the most common solid-organ cancer diagnosed among men and surpassed only by lung cancer as a source of cancer mortality[31] ). Prostate cancer is also extremely heterogeneous: many, perhaps most, prostate cancers are indolent and would never progress to a clinically meaningful stage if left undiagnosed and untreated during a man's lifetime. On the other hand, a subset are potentially lethal, and screening can identify some of these within a window of opportunity for cure[32] Thus the concept of PSA screening is advocated by some[33] as a means of detecting high-risk, potentially lethal prostate cancer, with the understanding that lower-risk disease, if discovered, often does not need treatment and may be amenable to active surveillance.[34]

Screening for prostate cancer is controversial because of cost and uncertain long-term benefits to patients.[9][35] Testing may lead to overdiagnosis and unnecessary treatment. Follow-up tests can include painful biopsies which can result in excessive bleeding and infection. The discoverer of PSA, Dr. Richard J. Ablin, concludes that the test's popularity "has led to a hugely expensive public health disaster," as only 16 percent of men will ever receive a diagnosis of prostate cancer, but only a 3 percent chance of dying from it. He states that "the test is hardly more effective than a coin toss."[36] Dr. Horan echos that sentiment in his book.[37]

According to the American Urological Association, the controversy over prostate cancer should not surround the test, but rather how test results influence the decision to treat:

"The decision to proceed to prostate biopsy should be based not only on elevated PSA and/or abnormal DRE results, but should take into account multiple factors including free and total PSA, patient age, PSA velocity, PSA density, family history, ethnicity, prior biopsy history and comorbidities.
"A cancer cannot be treated if it is not detected. Not all prostate cancers require immediate treatment; active surveillance, in lieu of immediate treatment, is an option that should be considered for some men. Testing empowers patients and their urologists with the information to make an informed decision."[38]

Private medical institutes, such as the Mayo Clinic, likewise acknowledge that "organizations vary in their recommendations about who should — and who shouldn't — get a PSA screening test." They conclude: "Ultimately, whether you should have a PSA test is something you'll have to decide after discussing it with your doctor, considering your risk factors and weighing your personal preferences."[39]

A study in Europe resulted in only a small decline in death rates and concluded that 48 men would need to be treated to save one life. But of the 47 men who were treated, most would be unable to ever again function sexually and require more frequent trips to the bathroom.[36][37]

A study by the New England Journal of Medicine found that over a 7 to 10 year period, "screening did not reduce the death rate in men 55 and over."[36][37] Former screening proponents, including some from Stanford University, have come out against routine testing. In February 2010, the American Cancer Society urged "more caution in using the test." And the American College of Preventive Medicine concluded that "there was insufficient evidence to recommend routine screening."[36][37]

Expense[edit]

The annual cost of PSA screening in the U.S. totals at least $3 billion, with much of it paid for by Medicare and the Veterans Administration.

According to Ablin, "testing should absolutely not be deployed to screen the entire population of men over the age of 50 . . ." He concludes that the primary promoters of tests are drug companies, which "continue peddling the tests," along with advocacy groups including the American Urological Association, all of which "stand to profit" by pushing continual tests. He states:

"I never dreamed that my discovery four decades ago would lead to such a profit-driven public health disaster. The medical community must confront reality and stop the inappropriate use of P.S.A. screening. Doing so would save billions of dollars and rescue millions of men from unnecessary, debilitating treatments."[36][37]

Clinical practice guidelines[edit]

Clinical practice guidelines for prostate cancer screening are controversial because the benefits of screening may not outweigh the risks of follow-up diagnostic tests and cancer treatments:[40]

  • The United States Preventive Services Task Force (USPSTF) recommended against PSA screening in healthy men in October 2011 finding that the potential risks outweigh the potential benefits.[1] This recommendation, released in October 2011, is based on a review of evidence and concludes that "prostate-specific antigen–based screening results in small or no reduction in prostate cancer–specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary."[21]
  • American Cancer Society, in its cancer screening guidelines says that it does not support routine screening for prostate cancer.[41] This is because the benefits are unclear or unproven.[42] Instead it recommends that doctors discuss the pros and cons of testing and that men should be offered the possibility of a DRE and a PSA test if they are over 50 with a life expectancy of more than 10 years (or over 40 if they are in a high-risk group). It recommends that men should sit down with their physician and weigh the benefits and risks of the test before a decision is made.[41] Men at high risk for prostate cancer such as African-American men should discuss this with their doctor at age 45. Men who have a first-degree relative (father, brother, or son) diagnosed with prostate cancer at an early age (younger than age 65) and men with several first-degree relatives diagnosed at an early age should begin the discussion at age 40.[43]

In the European Randomized Study of Screening for Prostate Cancer (ERSPC) initiated in the early 1990s, the intention was to evaluate the effect of screening with prostate-specific antigen (PSA) testing on death rates from prostate cancer. The trial involved 182,000 men between the ages of 50 and 74 years in seven European countries randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. During a median follow-up of almost 9 years, the cumulative detected incidence of prostate cancer was 820 per 10,000 in the screening group and 480 per 10,000 in the control group. Deaths from these cancers in this time was much lower. There were 214 prostate cancer deaths in the screening group and 326 in the control group, a difference of 7.1 men per 10,000 in the tested group compared to the control. The researchers concluded that PSA-based screening did reduce the rate of death from prostate cancer by 20%, but that this was associated with a high risk of overdiagnosis, which means that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent just one death from prostate cancer within 9 years. However, the number needed to treat to prevent one progression to metastatic disease was only 24, and both numbers are expected to fall as patients in the study are followed for longer periods of time.[44] Furthermore, the benefit for screening was greater (30% rather than 20%) with adjustment for noncompliance and contamination (i.e., men who were randomized to get PSA tests but did not, and those who were in the control arm but actually received PSA tests during the study period).[45] One recent analysis of the ERSPC data suggested that projecting over a 25-year time horizon, which is more appropriate for a man in his 50s than the 9 years reported to date from the trial, the number needed to screen falls to 186-220, and the number needed to treat to prevent a death falls to between 2 and 5 men.[46]

In addition to the 20 percent reduction in prostate cancer mortality shown by the ERSPC study, a more recent study has shown greater effectiveness in how screening has reduced the prostate cancer death rate. A study published in the European Journal of Cancer (October 2009) documented that prostate cancer screening reduced prostate cancer mortality by 37 percent. By utilizing a control group of men from Northern Ireland, where PSA screening is infrequent, the research showed this substantial reduction in prostate cancer deaths when compared to men who were PSA tested as part of the ERSPC study.[13]

The American Urological Association said in early 2009 that "The decision to screen is one that a man should make in conjunction with his physician, and should incorporate known prostate cancer risk factors, such as family history of prostate cancer, age, ethnicity/race, and whether or not a man has had a previous negative prostate biopsy. These factors are different for every man and, therefore, the benefits of screening should be considered in the broader perspective."[47] The organization will review its best practice guidelines later in 2009.

  • The 2008 recommendations of the U.S. Preventive Services Task Force (USPSTF) concluded that routine screening for prostate cancer using PSA testing or digital rectal examination (DRE) was not recommended for men over 75 and that the evidence was insufficient to recommend for or against screening for men under 75 years old.[48] The previous 1995 USPSTF recommendation was against routine screening.
  • The American Cancer Society (ACS) has recently updated its guidelines making clear that it does not recommend routine prostate cancer screening for all men.[49] It recommends that the risks and benefits of screening need to be weighed, and discussions should start early for those in high-risk groups. Screening should take place only wíth informed consent of the patient in full knowledge of both benefits and risks. The revised guidelines reflect the concerns about the potentially down-played risks and over-blown claims for the success of prostate cancer screening.[50][51]
The American Cancer Society (ACS) does not support routine testing for prostate cancer at this time. ACS does believe that health care professionals should discuss the potential benefits and limitations of prostate cancer early detection testing with men before any testing begins. This discussion should include an offer for testing with the prostate-specific antigen (PSA) blood test and digital rectal exam (DRE) yearly, beginning at age 50, to men who are at average risk of prostate cancer and have at least a 10-year life expectancy. Following this discussion, those men who favor testing should be tested. Men should actively take part in this decision by learning about prostate cancer and the pros and cons of early detection and treatment of prostate cancer. This discussion should take place starting at age 45 for men at high risk of developing prostate cancer. This includes African American men and men who have a first-degree relative (father, brother, or son) diagnosed with prostate cancer at an early age (younger than age 65). This discussion should take place at age 40 for men at even higher risk (those with several first-degree relatives who had prostate cancer at an early age). If, after this discussion, a man asks his health care professional to make the decision for him, he should be tested (unless there is a specific reason not to test). [49]
  • Some U.S. radiation oncologists and medical oncologists who specialize in treating prostate cancer recommend obtaining a baseline PSA in all men at age 35[52] or beginning annual PSA testing in high risk men at age 35.[53]
  • The American Urological Association Patient Guide to Prostate Cancer.[54]

Since there is no general agreement that the benefits of PSA screening outweigh the harms, the consensus is that clinicians use a process of shared decision-making that includes discussing with patients the risks of prostate cancer, the potential benefits and harms of screening, and involving the patients in the decision.[55]

Research[edit]

The results from two of the largest randomized trials have now been published.[56]

In the European Randomized Study of Screening for Prostate Cancer (ERSPC) study initiated in the early 1990s, the intention was to evaluate the effect of screening with prostate-specific antigen (PSA) testing on death rates from prostate cancer. The trial involved 182,000 men between the ages of 50 and 74 years in seven European countries randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. During a median follow-up of almost 9 years, the cumulative detected incidence of prostate cancer was 820 per 10,000 in the screening group and 480 per 10,000 in the control group. Deaths from these cancers in this time was much lower. There were 214 prostate cancer deaths in the screening group and 326 in the control group, a difference of 7.1 men per 10,000 in the tested group compared to the control. The researchers concluded that PSA-based screening did reduce the rate of death from prostate cancer by 20% but that this was associated with a high risk of overdiagnosis. Statistically, it means that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent just one death from prostate cancer.[44]

In addition to the 20 percent reduction in prostate cancer mortality shown by the ERSPC study, a more recent study has shown greater effectiveness in how screening has reduced the prostate cancer death rate. A study published in the European Journal of Cancer (October 2009) documented that prostate cancer screening reduced prostate cancer mortality by 37 percent. By utilizing a control group of men from Northern Ireland, where PSA screening is infrequent, the research showed this substantial reduction in prostate cancer deaths when compared to men who were PSA tested as part of the ERSPC study.[13]

A US study, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial,[57] looked at the general effectiveness of a screening program involving both PSA and DRE methods. This was conducted between 1993 thu 2001, in which 76,693 men at 10 U.S. study centers 38,343 subjects received screening (an annual PSA testing for 6 years and DRE for 4 years) and a control group of 38,350 subjects received 'usual care' with subjects and health care providers receiving the results and deciding on the type of follow-up evaluation. 'Usual care' means that some in this group would have received some screening, as some organizations have recommended. After 7 years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 (2,820 cancers) in the screening group and 95 (2,322 cancers) in the control group. The incidence of death attributed to prostate cancer per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95% CI, 0.75 to 1.70). The data at 10 years were 67% complete and consistent with these overall findings. The researchers concluded that after 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups.[57]

Commenting on the findings, the Chief Medical Officer of the American Cancer Society, Otis W. Brawley, MD, said

many experts had anticipated these studies would show a small number of men will benefit from prostate screening, but a large number of men will be treated unnecessarily. And that's what these studies show. However, the question is not as simple as: 'does prostate cancer screening work?' What we need to know is: what are benefits of prostate cancer screening and are they large enough to outweigh the harms associated with it? And despite the release of this early data, we still cannot say whether the benefits outweigh the risk.[43]"

His Deputy chief medical officer, Len Lichtenfeld, MD, MACP said

"When one considers all of the problems associated with treatment for prostate cancer -- urine incontinence, impotence, pain and bleeding among others -- that is a lot of men left with a lot of symptoms to save one life."

A further study, the NHS Comparison Arm for ProtecT (CAP) and Prostate testing for cancer and Treatment (ProtecT) studies randomized GP practices with 460,000 men aged 50–69 at centers in 9 cities in Britain from 2001-2005 to usual care or prostate cancer screening with PSA (biopsy if PSA ≥ 3),[58] has yet to report.

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