Screening for prostate cancer

Early screening is key to the diagnoses of many diseases. In the case of prostate cancer, however, the prostate specific antigen (PSA) test does have its drawbacks.

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By  Harvard Medical School Published  March 15, 2006

|~||~||~|Early diagnosis is important for the successful treatment of many diseases. When it comes to cancer, early detection seems especially urgent. In some cases, however, screening is not effective, either because there are no good tests (brain cancer is an example) or because early treatment usually doesn’t affect the outcome (pancreatic cancer). In other cases, some screening methods have failed, but others are on the horizon (lung cancer). And in some diseases, screening has proved its value and should be part of everyone’s preventive maintenance (colon cancer). The value of a screening test depends, not on its ability to detect disease, but on its ability to improve a person’s outcome, considering both the duration and quality of life. To decide if a test is right for an individual patient, it’s important to balance the risks and side effects of testing and treatment against the benefits they can expect from early treatment. For women, routine Pap smears have dramatically reduced deaths from cancer of the cervix, and research has validated the long-held belief that mammograms reduce the risk of dying from breast cancer. For men, self-screening for testicular cancer is easy and logical, if unproven, while testing for prostate cancer is much more important but much less clear-cut. Let’s look at the screening issues that apply strictly to men. Prostate cancer At first glance, screening for prostate cancer looks like a sure winner. The disease is common — worldwide, it ranks third in cancer incidence and sixth in cancer mortality among men. It can be treated and cured; less than 15% of all men with prostate cancer die from the disease, and logic says early treatment should improve survival. And an inexpensive, safe blood test, the prostate specific antigen (PSA) test, has made early diagnosis much easier than ever before. The PSA test seems like a no-brainer, but it’s not. That’s because the test has weaknesses as well as strengths, the disease has a variable and unusual course, and treatment has potentially troublesome side effects as well as potentially major benefits. Every man above the age of 50 has to decide about PSA screening each year. It’s a yes-or-no answer, but it’s by no means simple. Since there is no right or wrong answer, a man can go with his instincts (or take the advice of your relatives and friends) and simply say yes or no. But they should understand why some authorities say that the PSA is a lifesaver while others caution that it may do more harm than good. What is PSA? At the centre of the controversy is a simple protein produced by the epithelial cells of every prostate gland, benign or malignant. The prostate secretes PSA in the ejaculate, where its job is to liquefy semen, allowing sperm to swim toward their target. But although PSA is intended for the semen, some of it spills into the blood, where it can be measured by a simple blood test. Blood tests can also measure how much of the PSA is bound to other proteins and how much is unbound, or free. “Normal” values For a test to be useful, doctors should be able to tell whether the result is normal. Most tests have a well-established range of normal values, but for the PSA, even this apparently simple issue is controversial. Most doctors use 4.0 ng/ml (nanograms per millilitre) as a cutoff, considering results below that as normal and higher values as abnormal. But since PSA values tend to rise with age, even in healthy men, other authorities have proposed a range of reference values adjusted for age. Unfortunately, however, there is no clear cut threshold for “normal” at any age. The likelihood that a man has prostate cancer increases as PSA levels rise, but even men with low PSAs face some risk. An important 2004 study shows how the risk rises as the PSA increases, even within the normal range. At higher PSA levels, the risk is even greater; according to some estimates, it may exceed 50% at PSAs above 10. Interpreting the number The real question is not whether a number is normal but what it means. And when it comes to interpreting results, the PSA’s strengths and weaknesses become clear. The test’s strength is its ability to detect prostate cancer in its earliest, most curable form. In round numbers, PSA testing has the potential to detect about 80% of prostate cancers. Still, a normal or low reading does not rule out the disease; about 20% of men with prostate cancer have normal PSA results. A false negative result provides false reassurance, but it’s less of a problem than a false positive, which often causes great anxiety and usually leads to a prostate biopsy. In all, about 70% of men with high PSA results do not have cancer. New horizons Researchers are working hard to improve the accuracy of the PSA test. Two of the refinements are becoming popular, though neither is of proven value. The first depends on serial measurements of the PSA, typically at yearly intervals. The PSA velocity reflects the rate of change; researchers suggest that a rise of more than 0.75 ng/ml over the course of a year increases the likelihood of cancer. The second approach relies on measurements of both the total and the free PSA. Cancer is more likely when the free PSA constitutes less than 25% of the total PSA; the lower the percentage of free PSA, the more likely the diagnosis of cancer. These experimental refinements may help interpret a PSA result, but it’s also important to consider other details that can affect the test. Finasteride (Proscar) and dutasteride (Avodart), drugs used for benign prostatic hyperplasia (BPH), will reduce the PSA by about half. On the other hand, BPH itself will raise the PSA, and prostatitis, an inflammation of the gland, can send it soaring. Even ejaculation may produce a temporary mild bump in the PSA, so men should refrain from ejaculation for 48 hours before the test, particularly if they are being retested to check an abnormal result. Although research has cast doubt on the old theory that a digital rectal exam can boost the PSA, many doctors prefer to have the blood test done before they do the exam. Finally, the PSA test can vary up or down without apparent cause; in one major study, about half of men with an abnormal PSA had a normal result on retesting. As a rule, the first response to an abnormal result should usually be a second test. Does the PSA predict survival? Prostate cancer is a highly variable disease. Many prostate cancers grow slowly, and some are so indolent as to be harmless. On the other hand, some are aggressive and lethal. If doctors could predict a cancer’s behaviour, they would be able to leave the indolent cases alone and hit the bad actors with everything in the arsenal. A single PSA can’t discriminate between indolent and aggressive cancers, but a rapid rise in the PSA before a diagnosis of cancer is worrisome. In fact, there is no entirely accurate way to tell the difference between the good actors and the bad. Researchers are developing genetic tests that may help, but the best method available depends on a pathologist’s evaluation of a biopsy specimen using the Gleason scoring system. PSAs for suspected and proven cancer There is no debate about the value of the PSA in these circumstances. Every man with clinically suspected prostate cancer should have a PSA test. Most often, suspicion arises because of abnormal findings on digital rectal exams, but symptoms such as rapidly progressive bladder obstruction, impotence, bone pain, and weight loss also raise a concern about cancer. And every man with diagnosed prostate cancer should have his PSA measured at regular intervals because serial PSA measurements are the best way to monitor the course of the disease and the efficacy of treatment. Does PSA testing save lives? It’s the $64,000 question, but nobody can answer it, at least not yet. Proponents of the PSA point out that, in the U.S., deaths from prostate cancer have declined since the test became popular in the early 1990s. But opponents counter that the death rate has declined at a similar pace (though to a lesser degree) in England and Wales, where testing is uncommon. Advocates point out that prostate cancer deaths have declined in the Tyrol region of Austria, where testing is widespread, but not in other areas of the country where testing is less common. Sceptics answer that widespread PSA testing in Seattle and Quebec does not appear to have produced a fall in the prostate cancer death rate. Randomised clinical trials are the only way to find out if testing saves lives. Large studies are under way in Europe (the ERSPC trial) and the U.S. (the PLCO and PIVOT trials), but they will take years to complete. Until then, the only honest answer to the big question is “maybe.” Can a PSA test do any harm? It’s a simple blood test that’s entirely safe. But an abnormal test usually leads to a prostate biopsy. Although biopsies are frightening and uncomfortable, serious side effects are uncommon. But if a biopsy reveals cancer, it usually leads to treatments that often produce impotence, sometimes cause urinary incontinence, and may have other physical and psychological side effects. Most men would gladly trade potency and even continence for life, but it’s not that simple. If treatment saves lives, the PSA test has done much more good than harm, but if men would live as long with no treatment or late treatment, the simple blood test will have done more harm than good. It’s intuitively obvious that early cancer treatment can save lives, but since the average prostate cancer grows slowly, it’s not necessarily so. Table 3 summarizes the estimated impact of untreated prostate cancer on life expectancy; it suggests that low-grade cancers do little harm, even in young men, and that moderately large cancers may have surprisingly little impact on the life expectancy of men 75 and older. It’s why some younger men decline PSA testing and why some older men with low-grade prostate cancers quite reasonably choose careful observation rather than active treatment. And the rather poky growth of many prostate cancers is also the reason that even the most passionate advocates of the PSA do not recommend the test for men older than 75 or for men of any age with medical problems that limit their life expectancy to 10 years or less. With all this uncertainty, it’s no surprise that even the experts are divided about the value of routine PSA testing. Here is a summary of the major viewpoints. The case for PSA screening The American Cancer Society (ACS) and the American Urological Association (AUA) recommend that doctors discuss the PSA and offer annual testing to every man above the age of 50; they also call for the yearly discussions to start at the age of 40 (AUA) or 45 (ACS) for men at increased risk, including African Americans and men with family histories of prostate cancer. The ACS says that if a man cannot decide, his doctor should recommend testing. They have a point. Requiring only a single blood sample, PSA testing is quick, easy, and safe. With a typical cost of about $40, it is inexpensive, and technical improvements have made it reliable in most labs. The accuracy of PSA testing is more controversial. In the most favorable studies, PSA screening has a sensitivity of about 80%; that is, it succeeds in detecting cancer in 8 of every 10 men with the disease. Without screening, about 40% of prostate cancers are not diagnosed until they have spread too far to be curable. Early detection is surely the best hope for curing prostate cancer, and PSA screening is the best way to find early disease. The case against PSA screening The Canadian Task Force on the Periodic Health Examination and the Canadian Urological Association recommend against PSA testing in men who seem healthy. The U.S. Preventive Services Task Force concludes: “Although potential harms of screening for prostate cancer can be established, the presence or magnitude of potential benefits cannot.” The American College of Physicians and American Academy of Family Physicians agree that men should be counselled about “the known risks and uncertain benefits of screening for prostate cancer” before they undergo any testing. They, too, have a point. Even at an average cost of $40, the annual testing of all 28 million American men over 50 would cost billions of dollars. Still, it might save money if early diagnosis could reduce the need for even more expensive treatment of advanced cancer. But critics go beyond economics to consider the drawbacks of the test itself. The PSA stormMedical controversies should be resolved through calm consideration, not emotional confrontation. But when the editors of the respected Western Journal of Medicine published an op-ed commentary questioning routine PSA screening, they were instantly barraged by angry e-mails, phone calls, and letters. Some were abusive, others called on the University of California to “fire those impostors,” and still others expressed the hope that the physicians who wrote the article would themselves develop the disease. Medical decisions should never be based on dogma. Nor should they be motivated by financial gain. As it turns out, the “grassroots” organization that led the attack got funding from drug companies. They call it “cause-related marketing” or “passion branding.” Indeed. First, they consider sensitivity. Even if PSA screening were 80% sensitive, it would fail to detect 2 of every 10 prostate cancers — and some studies suggest a higher failure rate. Still, if men with early disease benefited from the test, their gain would outweigh the false reassurance given the men whose disease had been missed. But what about the test’s specificity? What about the men who have high PSA results but do not have cancer? In some studies, at least two of every three men with elevated PSAs turn out not to have cancer. That means they worry about a possible cancer diagnosis and endure the discomfort of a prostate biopsy without needing any of it. Most men would gladly trade two false alarms for one life-saving early diagnosis. But here’s where the debate really heats up. The value of an early diagnosis of many cancers seems indisputable, but prostate cancer may be different. Unlike many other malignancies, prostate cancer can have a long latent phase. Cancer cells can exist in the prostate gland for years, even decades, without causing harm. As many as two of every three prostate cancers are harmless, even if untreated. All cancers are caused by genetic abnormalities; some are inherited, others develop because of environmental influences, and most result from a combination of the two. Doctors are able to diagnose a variety of cancers by detecting DNA abnormalities, and they can also tell if people are at high risk for certain cancers by testing DNA samples. People with very strong family histories of colon, breast, and ovarian cancers can request genetic testing at many medical centres, but they should always have counselling first. Although scientists have discovered several prostate cancer genes, genetic testing for men is not available clinically and is not recommended. Should Patients have a PSA test? The U.S. Office of Technology Assessment said it best: “An informed and reasonable patient could equally well decide to have screening or forgo it.” He is the only one who can decide if it is right for him. Here is a summary of the four main facts patients need to make a decision. 1. Prostate cancer is common. Unlike most malignancies, its growth pattern and natural history are highly variable; it may be aggressive and lethal, but it is more likely to be indolent. 2. The PSA is the best way to detect prostate cancer in its early, potentially curable stages. 3. PSA testing has many false-negative and false-positive results. There is a substantial probability that annual testing will lead to invasive testing that will not detect cancer. 4. The early diagnosis and aggressive treatment of prostate cancer may save lives but can also have substantial adverse side effects. The benefits of PSA screening and aggressive treatment have not been proven. If screening has value, it is likely to diminish after age 70–75 and is less likely to help men with serious medical conditions. Other screening tests Before the PSA came into use, the digital rectal exam (DRE) was the only way doctors could screen men for early prostate cancer. The PSA is a much better screening test, and the DRE does not help at all in screening for colorectal cancer. Most men would rather roll up their sleeves for a PSA blood test than drop their pants for a DRE. But since a DRE can occasionally detect an abnormality when the PSA does not, men who choose to be screened for prostate cancer should have both. Doctors can use ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) to look at the prostate. Unfortunately, none of these tests can screen for early prostate cancer, although ultrasound is essential for a prostate biopsy, and CT and MRI can be important for staging the disease. The paradox of screening Despite enormous progress over the past 30 years, scientists still have a lot to learn about the prevention, diagnosis, and treatment of cancer. When it comes to early diagnosis, technology often delivers screening techniques to doctors before outcome studies show how best to use them. At present, it’s clear that everyone over 50 should be screened for colon cancer. Women are sure to benefit from Pap smears for cervical cancer and mammograms for breast cancer. Everyone is likely to benefit from simple self-examinations for melanomas and other skin cancers, and young men will probably benefit from testicular self-exams. But it’s not clear if PSA testing will live up to its promise, and studies of spiral CTs for lung cancer are just getting under way. In a sense, these tests are a paradigm for much of modern medicine: technology has provided knowledge about what is possible before science has produced the wisdom about how to use it. This article is provided courtesy of Harvard Medical International. © 2006 President and Fellows of Harvard College||**||

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