PSA, Screening, prostate cancer, USPSTF, PLCO, ERSPC, draft statement, prostate specific antigen, US preventive services task force

PSA Screening: Opening Pandora's Box

PSA Screening: Opening Pandora's Box

© 2011 Dr. Dale Peterson &

In one of Greek mythology’s more familiar stories Zeus presents the first woman, Pandora, with a beautiful jar and cautions her to never open its lid. Over time, curiosity prevails and Pandora opens the jar releasing all sorts of evil into the world. She attempts to prevent the rest of the jar’s contents from escaping by quickly closing the lid, but only one item remains – hope. Today, the phrase “opening Pandora’s Box” refers to releasing evil that cannot be undone.

Prostate cancer screening is a modern day example of opening Pandora’s Box – at least this is the conclusion of a committee known as the United States Preventive Services Task Force (USPSTF). On October 7, 2011 they released a drafted statement, which concluded that using levels of prostate specific antigen (PSA) to screen for prostate cancer in healthy men is of no net value or causes greater harm than benefit.

The USPSTF is an independent panel of experts in preventive medicine. It is made up of primary physicians (internists, family physicians, pediatricians, and obstetricians), nurses, behavioral specialist and epidemiologists (specialists in understanding the distribution and frequency of disease among populations). Members of the task force are appointed by the Agency for Healthcare Research and Quality, which is a division of the United States Department of Health and Human Services, but they are not Federal employees.

The USPSTF is charged with reviewing the scientific evidence regarding preventive health care services and making recommendations based upon that evidence. It is important to recognize that the USPSTF’s primary focus is not on the ability to identify a particular disease, but on the maintenance of health and quality of life. A procedure will not be recommended if its potential to harm quality of life exceeds its potential benefits.

The USPSTF draft statement is generating a great deal of controversy, and one thing is abundantly clear. The science of screening is quite different from, and often takes a back seat to, the politics of screening. While there is no evidence that external forces had an impact on the contents of the statement, they have exerted tremendous influence over the release of the statement.

It has been reported that the USPSTF first voted to recommend against the use of PSA testing in November 2009, but no statement was issued at that time. The USPSTF was scheduled to meet and vote again on the recommendation in November 2010, just before the mid-term elections. That meeting was cancelled amid rumors that if the vote were to take place the agency’s funding would be in jeopardy. The second vote finally took place in March 2011. The committee’s recommendation was not released to the public, but it was sent to the editors of a medical journal, The Annals of Internal Medicine for review. The public release of the draft statement in October came only after The Cancer Letter obtained a copy of the paper and posted it online.

By issuing the statement as a “draft” the USPSTF is able to measure public reaction to the proposed recommendation and retain the ability to save face by retracting the guideline if the response is too great to withstand. Retraction under political pressure, however, should not be interpreted as sound scientific judgment.

A case in point is the committee’s 2009 guideline on the use of mammography in screening for breast cancer. After a thorough review of the available literature the committee voted to recommend against screening of women under the age of fifty. They did so because the evidence shows that women under the age of fifty who obtain screening mammograms are more likely to die than those who are not screened. (This is believed to be due to the awakening of a pre-cancerous condition called ductal carcinoma in situ, which, if left undisturbed might resolve and never present a challenge.) Furthermore, 20 out of every 10,000 women starting mammograms at age 35 and 13 of every 10,000 women beginning annual screening at age 40 will develop cancer as a direct result of exposure to radiation from the x-ray.

When the mammography guideline was released, several professional societies and patient advocacy organizations accused the Obama administration of attempting to ration healthcare. Health and Human Services Secretary Kathleen Sibelius quickly distanced herself and the administration from the USPSTF recommendations. Congress also stepped in and passed legislation requiring insurance companies to continue to provide co-pay free screening mammograms annually to women beginning at age forty.

It is quite likely that the PSA screening recommendation will generate a similar response. The American Urological Association, whose members stand to lose hundreds of millions of dollars in surgical fees each year if routine PSA screening is discontinued, issued a statement immediately upon learning of the USPSTF recommendation:

“. . . we are concerned that the Task Force’s recommendations will ultimately do more harm than good to the many men at risk for prostate cancer both here in the United States and around the world. The AUA’s current clinical recommendations support the use of the PSA test, and it is our feeling that, when interpreted appropriately, the PSA test provides important information in the diagnosis, pre-treatment staging or risk assessment and monitoring of prostate cancer patients.”

The AUA has also initiated a letter-writing campaign urging Secretary Sibelius to reject the recommendation and congress to enact legislation similar to that passed in response to the mammography guidelines.

Why is PSA screening a “Pandora’s Box” and why did the USPSTF vote to recommend against its use? To answer these questions it is necessary to understand what is meant by screening, the natural history of prostate cancer, and what experience tells us about the results of PSA screening.

A screening test is something that is done to look for the presence of a condition when there is no reason to suspect that it exists. By definition, screening tests are done on individuals who feel well and are asymptomatic. If a symptom exists, the test is no longer a “screening test”; it is a study done to determine why the symptom is present.

A basic assumption underlying all health care screening is that early detection and treatment of a disease always results in a better outcome that if the condition is discovered at a later time. Lives should be saved and quality of life should be maintained. Therein lies the challenge of PSA screening for prostate cancer. (Remember that the USPSTF’s chief focus is not upon the ability to detect a disease, but rather upon how a procedure affects one’s health and quality of life.)

The natural history of prostate cancer does not make it a good candidate for screening. This is because while prostate cancer is extremely common, its presence does not automatically mean that a man will die from the disease or that he will even become aware of its existence. In most instances, prostate cancer is a disease that progresses very slowly. Autopsy studies have shown that prostate cancer starts to develop as early as a man’s twenties. Its incidence then parallels the decade of life. 29 % of men in their thirties, 32 % in their forties, 55 % in their fifties, and 64 % of men in their sixties dying of random causes have been found to have prostate cancer. One study found that while 86 % of men over eighty years of age at the time of their death had prostate cancer, few of them had known of its presence while they were still living.

It has been stated that every man will develop prostate cancer if he lives long enough. I am not that pessimistic, but it is clear that prostate cancer is an extremely common condition. Fortunately, in most men prostate cancer is indolent, a condition that develops slowly and causes no symptoms. We do not see thirty percent of men in their thirties and forties dying of prostate cancer even though it is present. Neither do we see over eighty percent of old men dying of the disease. The actual lifetime chance of dying of prostate cancer is three percent, and the median age of death from prostate cancer is eighty.

I am not trying to downplay the tragedy of dying of prostate cancer. I personally had a friend die of prostate cancer in his early forties and I recently saw another friend die in his eighties. I have been involved in the care of other men who were found to have prostate cancer, some of whom died of the disease. The question is not whether it is desirable to have men die of prostate cancer. Clearly it is not. The question is whether early detection and treatment prevents prostate cancer deaths and, if so, at what cost.

The USPSTF reviewed five published studies on the effectiveness of PSA testing in the detection and management of prostate cancer. Two of the largest were the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC). The PLCO study was done under the auspices of the U.S. National Cancer Institute. 154,942 men and women between the ages of 55 and 74 were enrolled between 1993 and 2001. The study is ongoing and continues to look at the outcome of screening tests conducted on the participants. The ERSPC study involved 182,000 men between the ages of 50 and 74. It was begun in the early 1990s and concluded in 2006.

The PLCO data failed to demonstrate any change in the death rate from prostate cancer due to screening by means of PSA testing and digital rectal prostate examinations. The study was not perfect as it was impossible to deny screening to men who were not enrolled in the study. Nevertheless, a substantially higher percentage of men in the study group received screening compared to those in the control group. The difference should have been large enough to detect a benefit if one were present. Critics suggest that the follow-up time was not long enough to show the benefits of screening. This may be true, but it only serves to emphasize how many men will be treated for a disease that they would never have become aware of had they not undergone PSA screening.

The ERSPC trial showed a twenty percent decrease in deaths in the screened group. This was obtained at a high cost, however. The study revealed that fifty men must be aggressively treated for prostate cancer to potentially save one from dying of the disease. Put another way, 98 % of men treated for prostate cancer detected by PSA screening will not benefit from the treatment. Most would have died of a different cause blissfully unaware that they had prostate cancer and some will die of the disease in spite of the early detection and treatment. Screening lowers an individual man’s chances of dying from prostate cancer by less than one percent – from 3 % to 2.19 %.

A risk reduction of 0.81 % might be considered worthwhile if a completely safe and effective treatment for prostate cancer existed. Scanning internet sites promoting various treatments would lead one to believe that success rates are high and that complications rarely occur. Unfortunately, that is not the case. Despite early detection and treatment up to 40 % of men who undergo surgery or radiation will have the cancer reappear. Complications are much more common than treating physicians and institutions are generally willing to admit.

When a PSA screening test suggests that cancer may be present biopsies of the prostate gland are often performed. Seven percent of prostate biopsies result in a complication serious enough to require hospitalization. The most common adverse event is a serious infection, but bleeding can also occur. An unanswered question is whether or not the act of taking a biopsy increases the risk of turning an indolent growth into an aggressive tumor or causes spread of the disease from the prostate gland to bone or other sites. The studies I have seen suggest that this is not the case, that a prostate biopsy does not change the course of the disease. This is not terribly reassuring in the light of what is known about biopsies of other cancers. One study found that women who underwent a breast biopsy prior to surgical removal of their tumor were 50 % more likely to have breast cancer found in lymph nodes. Others have reported spread of tumors along the tracks of biopsy needles.

Perhaps the most concerning aspect of biopsies is the effect of inflammation on tumor growth and spread. Inflammation is known to increase the virulence of cancerous tumors, including those of the prostate. The act of puncturing the prostate and removing tissue creates inflammation in the gland, and this may have a bearing on the ultimate course of the disease.

When the diagnosis of prostate cancer is confirmed a man should be given several options including “watchful waiting”, monitoring the prostate cancer over time and intervening only if it appears to be progressing at a rate that is likely to cause symptoms or death in the future. While this sounds reasonable in theory, in my experience it is rarely possible for a man to accept this option. The words, “You have CANCER!” are too emotionally charged to allow one to go on with one’s life as though they had never been spoken.

If a man opts for surgery he has a 0.5 % chance of dying from the surgery itself. He has a 30 % chance of experiencing long-term impotence and a 20 % risk of having to deal with urinary incontinence. It is possible that risks may be reduced somewhat by the use of robot to assist the surgeon in the removal of the prostate, but the procedure appears to have a steep learning curve. One study reported that a surgeon does not achieve optimum proficiency in complete tumor removal until he or she has performed in excess of 1600 operations. This is of particular concern because the average urologist performs less than 100 such procedures each year.

A man opting for radiation faces similar challenges. A 15 % rate of erectile dysfunction has been reported and there is a significant risk of developing ongoing uncontrollable diarrhea as a result of damage to the rectum from the radiation. Having worked with several men who experienced this complication I can testify that it lowers a man’s quality of life in a devastating way.

Hormonal blockade to shut down the effects of testosterone and shrink the size of the tumor prior to surgery or radiation provides the greatest chance for successful treatment, but the side effects associated with this approach are not pleasant. They include hot flashes, loss of sex drive, erectile dysfunction, fatigue, weight gain, loss of muscle mass, anemia, and memory loss. Hormonal treatment also increases a man’s risk of developing osteoporosis and diabetes or of having a heart attack or a stroke.

Faced with a lack of evidence that early diagnosis and treatment has a significant positive effect on the outcome of prostate cancer and learning that 49 out of 50 men who undergo treatment will face risks of loss of sexual function, urinary incontinence, or diarrhea the USPSTF had little choice but to recommend that healthy men not undergo PSA screening. It is unlikely that the recommendation will have much impact, however. The fear of dying of cancer is simply too strong. Most men will continue to seek early detection and treatment hoping that they will be one of the 2 % who benefit.

Should you (or, if you are a woman, should the men in your life) undergo PSA screening for prostate cancer. I recommend it if dying of prostate cancer is one of your greatest fears. If you are able to say, “I’m willing give up sexual activity and wear a diaper the rest of my life if it means that I can lessen my risk of dying of prostate cancer by even one percentage point,” you are a good candidate for PSA screening. One always hopes for a good outcome - that the test will be negative and you will be reassured that your prostate cancer risk is low or if treatment is required no adverse consequences will occur – but in the case of PSA screening it is important to consider a worst case scenario as well.

I do believe that there is a place for PSA screening, but it is in younger rather than older men. Research at Johns Hopkins University has shown that a PSA of 1.0 or greater indicates inflammation in the prostate gland 100 % of the time. Instead of screening men annually over the age of fifty and using a cut-off of 4.0 we should be screening men between the ages of 25 and 50 at five year intervals using a cut off of 1.0. If above 1.0, the man could be counseled in ways to reverse the inflammation before it triggered changes leading to prostate cancer. If the PSA was found to be greater than 2.0 it could be followed more closely and intervention taken if it appeared that an aggressive prostate cancer was present.

This will only happen, however, if American medicine embraces prevention as ardently as it pursues early detection. Unfortunately, the financial rewards of practicing prevention pale in comparison to those of treating an existing disease. PSA tests will remain available to men who choose to have them. I encourage you to choose wisely.

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