Prostate cancer and PSA Screening:
A Personal Perspective
Prostate cancer is common, and 2-3% of men die from prostate cancer. The primary risk factor for death from prostate cancer is age. Since everyone dies from something, delaying death from other causes increases the probability that prostate cancer will be the cause of death.
In undeveloped countries, few men live long enough to die from prostate cancer. In developed countries, cardiovascular disease is the most common cause of death. Anything that delays death from cardiovascular disease increases the risk that prostate cancer will be the cause of death. Conversely, anything that accelerates death from cardiovascular disease will decrease the risk of death from prostate cancer.
The probability that a man will be diagnosed with prostate cancer depends primarily on how hard we look for prostate cancer. The incidence of prostate cancer diagnosis has increased due to increased detection rather than increased risk. It has been known for about 50 years that most men over 50 years old without known prostate cancer harbor prostate cancer cells if carefully examined at autopsy. With perfect detection tools, all these men could potentially receive a diagnosis of prostate cancer.
Current 12-core biopsy techniques will detect prostate cancer in about 15% of men at age 50 who have a normal PSA and a normal digital rectal exam. The probability increases with age. We know this from the control group of a study that was designed to see if the drug Proscar influenced the diagnosis of prostate cancer. All the normal control patients (not taking Proscar) were biopsied. In my experience using a PSA value of about 4 as a cut-off, the probability of a biopsy diagnosing prostate cancer in a man with an elevated PSA is about 30%. With better tools and techniques, this could increase.
To understand the risks and benefits of prostate cancer detection, the concept of “quality-adjusted years of life” (QAYL) is important. A year of enjoyable life without impairment is considered 1 QAYL. A year of life with a degree of impairment is assigned a value below 1 year based on what that individual would be willing to trade for a year without impairment. For example, a year of moderate pain or blindness may be only as valuable as half of a year with no impairment. The same impairment may have a different value for different individuals.
Prostate cancer screening and diagnosis contribute to patient stress regardless of the physical consequences to the patient. Patients react differently to stress, and education from the physician influences the degree of stress. One patient may feel re-assurance by a normal PSA while a different patient may sense anxiety every time that he is tested regardless of the result. A diagnosis of “elevated PSA” alone will cause stress and have some effect on the quality of life for some patients. A diagnosis of prostate cancer, even if considered “clinically insignificant” lowers the quality of life for most patients.
One study demonstrated a doubling of the probability of heart attack or stroke in the 5 years following a diagnosis of prostate cancer, even if the cancer was considered insignificant. By shortening life expectancy through accelerating cardiovascular death, a diagnosis of prostate cancer, even without treatment, will decrease the risk of death from prostate cancer. Stress is harmful. Both the quality of life and the length of life are lowered by a simple diagnosis.
Next, I’ll discuss my experience with prostate cancer with almost 50 years of taking care of patients. I began medical school in 1970, and my experience working with patients began in 1972. By 1973, I decided to become a urologist. Since 1973 and for nearly 50 years, I have read nearly every Journal of Urology, Yearbook of Urology, and Quarterly Review of Urology. I have been a Board-Certified Urologist since 1982 and a member of the American Urological Association (AUA) since 1984. I have some experience.
In 1974, only 5% of patients diagnosed with prostate cancer were candidates for curative attempt. We were aware that clinically insignificant prostate cancer was common. Autopsy series showed small amounts of prostate cancer in most older men. About 10% of specimens from transurethral resection of the prostate for seemingly benign disease had small areas of prostate cancer. Studies showed that these patients had similar life expectancies to the general population whether treated or left alone, so the finding was considered harmless.
The definitive diagnosis of prostate cancer was by prostate biopsy. At first, open prostate biopsy was performed through a perineal incision. This was generally done when a palpable prostate nodule was detected. Later, trans-perineal needle biopsy became more common. This was usually performed blindly, using a finger in the rectum for guidance. If cancer was detected, a perineal prostatectomy could be performed. Postoperative incontinence and impotence were expected. Retropubic prostatectomy in those days was a bloody and morbid procedure. Radiation therapy was used, but benefits were fewer and side effects greater than modern radiation therapy.
We also managed patients with advanced prostate cancer. Most of these patients had cancer that had spread to the bones at the time of diagnosis. PSA had not been discovered. Serum acid phosphatase was used as an indicator of prostate cancer, and this marker was used to follow the progress of prostate cancer. Acid phosphatase was elevated only when the cancer had spread to the bones. Advanced prostate cancer was treated with either castration or estrogen therapy. Diethylstilbestrol (DES) 3 mg daily was as effective as castration. Breast enlargement or tenderness, which could be managed with radiation therapy or breast removal, was the only important side effect of DES. The treatment was inexpensive.
I have always believed that DES fell out of favor for economic reasons. DES provided no significant profit for the medical industry. A report of increased risk of blood clots caused physicians to avoid DES. Liability was prominent in the decision. Lupron injections became the “standard of care”. These injections were priced at about $8000 yearly, and the pharmaceutical industry developed a cleaver program to share these profits with the prescribing physicians, all paid by insurance and Medicare. Naturally an injection was more popular with patients than castration. DES would have avoided hot flashes, osteoporosis, and substantial side effects of Lupron. And a lower dose of DES correlated with a reasonably low risk of blood clots. But a new “standard of care” was established, and the legal risk of prescribing DES was too great. Why fight windfall profits?
Radiation therapy to painful areas of bone was used for hormone failure. Chemotherapy offered no benefit. High dose estrogen was sometimes used. Adrenalectomy sometimes helped. Eventually, only morphine offered relief until the patient died.
In the 1980s, I hade a very busy urology practice in Ohio. Every year, a few of my patients died from advanced prostate cancer. Another group of patients was managed for advanced prostate cancer until they died, often from unrelated causes. Radical prostatectomy to cure early prostate cancer was uncommon.
In the 1990s, three separate developments changed everything. These were (1) PSA screening, (2) easy prostate ultrasound with biopsy, and (3) safer and less challenging radical retropubic prostatectomy.
PSA became popular in the 1990s. This test could be used to follow the extent of prostate cancer and the response to treatment. Eventually PSA was used to screen for prostate cancer and to decide if prostate biopsy was appropriate. A value of 4 was set as a standard upper limit of normal. In fact, the values of PSA were a continuum with most mild elevations due simply to benign prostate enlargement. PSA screening became a “standard of care”, and the failure to screen became a medical malpractice risk even though there was no good evidence to support this practice. Screening was performed by primary care physicians, and patients with abnormal results were referred for further evaluation.
Trans-rectal ultrasound of the prostate reliably imaged the prostate. Originally, it was thought that prostate cancer had a characteristic appearance on ultrasound, but this proved to be incorrect. Specialized biopsy needles using a spring-loaded biopsy gun could easily be placed through the rectal wall to biopsy areas of the prostate under ultrasound guidance. A template grouping of biopsies could be obtained in the office under local or no anesthesia, and the procedure could be completed in a matter of minutes. Biopsy of all healthy men with a PSA greater than 4 became the “standard of care” even without good evidence to support this standard. To meet the demand, my office of 9 urologists was performing several ultrasonically guided biopsies daily, and about 30% were positive for prostate cancer. The incidence of prostate cancer skyrocketed.
The nerve-sparing radical retropubic prostatectomy became a common procedure. Using the modified technique, this was a 1-hour procedure in experienced hands. The need for transfusion was almost non-existent, persistent incontinence was infrequent, and many patients retained some level of sexual function. Consistent with the “standard of care”, I did many of these operations. Radiation therapy improved, and radioactive seed implants also evolved. These were alternate forms of treatment.
By 2000, my office was diagnosing and “curing” prostate cancer in about 10 times as many as patients as we ever had die from this illness. I had to wonder who these patients were that we were “curing”, and what would have been their fate if they had never been diagnosed with cancer. I had always been skeptical about our practices, but I was now certain that something was wrong with our standards and practices. For medico-legal reasons, I was required to follow prevailing standards for my patients. Yet for myself, I have never checked a PSA.
Other urologists were also recognizing that we were diagnosing and treating many patients that did not need to be treated. But the prostate cancer business was thriving. Hospitals were offering free prostate screening events. Hospital systems and physician groups were investing in prostate treatment “institutions”. Prostate cancer treatment became a $10 billion a year business.
The next game-changer came from the United States Preventative Services Task Force (USPSTF). After analyzing years of data, the USPSTF gave PSA screening a “D” rating. This meant that PSA screening caused more harm than good. The USPSTF advised against PSA screening at any age and in any population. The American Academy of Family Physicians and the American College of Physicians followed suit and agreed. The “standard of care” was changed in an instant.
It's important to distinguish between using PSA for screening or testing. Screening involves periodic testing of men without symptoms with the goal of detecting early disease. Testing involves using PSA to diagnose a man with symptoms that could be from prostate cancer or to follow the course of disease in a man with known prostate cancer. The controversy applies only to screening.
I was delighted. The USPSTF determination meant that I no longer needed to practice against my honest opinion for fear of legal consequences. I would not be sued for advising against PSA screening.
Those with substantial investment in prostate cancer treatment pushed back. This included the American Urological Association (AUA) and hospital organizations. Claims were made that the data was flawed and that conclusions were drawn without the best expert opinions. After substantial lobbying, the outcome was more political than scientific. The USPSTF changed the grade from D to C and conceded that PSA screening between the ages of 55 and 70 could be justified following a comprehensive discussion with the patient of the risks and benefits.
The AUA responded by claiming victory and continuing to advise PSA screening for most patients. Some “experts” doubled down by advising a first PSA at age 40 and by considering anything over 2.5 to be good reason for a prostate biopsy. Other “experts” acknowledged that prior overtreatment was an error, but that PSA screening and prostate biopsy were appropriate. “Active surveillance" without definitive treatment was advised for patients with earlier and less aggressive disease. I recall that an honest, but probably not very ethical, urologist explained to the audience at a urology conference that active surveillance could be even more profitable than definitive treatment of prostate cancer.
Hospital systems continued sponsoring free PSA screening clinics where men of all ages were welcome and where there was no real opportunity for discussing the potential risks. I recall that an administrator of a well-recognized hospital system claimed that a “free screening PSA” was worth about $5000 to the healthcare system on average. This considered the value of subsequent prostate biopsy, surgery, radiation therapy, and management of the complications of treatment, for those with abnormal results along the cascade of events.
Actual informed consent related to PSA screening is a logistic impossibility considering the time constraints of a physician office visit. Most primarily care physicians probably had inadequate knowledge to adequately inform patients about the risks and benefits of PSA screening, and most patients lack the ability to truly understand anyway. Even with the ability to educate, physicians don’t have enough time in a routine visit. Patients generally do whatever their physician advises. Most patients that are referred to me with an elevated PSA don’t even understand that a screening PSA was performed or what it means.
Next, I’ll discuss the risks and benefits of PSA screening that caused the USPSTF to develop their conclusions.
The desired benefit of PSA screening would be to prevent death from prostate cancer, thereby delaying the time of death. Conceivably, there could also be an improved quality of life following treatment, but that wouldn’t occur soon for a patient with no symptoms before treatment. The USPSTF calculated that death from prostate cancer was prevented in only 2-6% of patients who were treated for early prostate cancer with the intent to cure the cancer. And this cancer death would occur, on the average, about 5 years earlier than had the cancer not been treated. A substantial majority of treated patients would not have died from the prostate cancer had they not been diagnosed or treated.
Another large group of patients that were treated with intent to cure developed recurrent cancer. The probability of recurrent cancer following surgery is as high as 30%. Some of these patients died from the cancer, but most probably died from other causes before the prostate cancer became fatal. One large study calculated that the time from postoperative recurrence of the cancer until death from that cancer was about 13 years. And this was before modern treatments that delay death from advanced prostate cancer for even a few more years.
The harm from PSA screening depends on how far a patient falls along the cascade of diagnoses and treatments. A simple PSA blood test to screen for prostate cancer seems harmless. That is, of course, unless the patient is unfortunate enough to have an elevated level. An elevated PSA will lead to a urology referral. The urologist is likely to advise a prostate biopsy.
Prostate biopsy is simple for the urologist, but it is uncomfortable and somewhat risky for the patient. Death from biopsy has occurred, but it is rare. Infection and sepsis following prostate biopsy have become increasingly common with reports of 1-5%. Most of these patients are ill enough to require hospitalization. Bleeding and urinary retention requiring a urethral catheter can occur. Even an incidence of erectile dysfunction has been reported to occur from biopsy alone. The risk has been greatly understated in the past.
Patients with a negative biopsy are usually followed and frequently re-biopsied. About 30% of biopsied patients are diagnosed with prostate cancer. Their situation is much worse than those with a negative biopsy. The emotional stress from a diagnosis of prostate cancer varies among patients, but it is always substantial. The diagnosis alone detracts from a patient’s quality of life, even if the cancer would never have become significant. Arguably, this stress may also decrease the length of life by accelerating cardiovascular disease.
In the past, almost all patients with a positive biopsy were advised to have treatment. Recently, patients with “low-risk” cancer are offered “active surveillance”. Active surveillance programs vary, but all entail risk, stress, and discomfort. Periodic repeat prostate biopsies are part of every protocol. However, studies have demonstrated that active surveillance is a safe strategy for avoiding or delaying active treatment while not increasing the risk of dying from prostate cancer.
The greatest risks are due to active treatment of screen-detected prostate cancer with the intent to cure the disease. Treatment is generally surgical removal, external radiation therapy, radiation seed implants, or combinations of these treatments. Sometimes hormonal treatments or chemotherapy are added. Each has a side-effect and complication profile.
Beyond the immediate surgical complications, radical prostatectomy frequently causes erectile dysfunction and often leads to incontinence. These disorders reduce the quality of life. Additional corrective surgery is often performed.
Radiation therapy, whether external or by implantation, may cause a variety of long-term complications including hematuria, rectal problems, secondary malignancy, and a variety of other problems.
I have seen many lives ruined by the complications of treatment for prostate cancer that almost certainly would have never caused problems had it not been treated. The results of treatment would need to be very effective to justify these risks. But treatment is not particularly effective. Risk of recurrence following treatment, based on a rising PSA, is as high as 30%. It is likely that the 70% that do not recur are mostly the same patients that would have been fine had the cancer never been detected or treated.
The important improvements in treatment relate to a decrease in complications. Robotic radical prostatectomy, particularly when performed by a limited number of experts with high-volume experience, has greatly decreased the complications from this surgery. Radiation therapy has been refined to decrease some of the problems. But the risk of recurrent cancer has not significantly declined. And there is no good evidence to prove that early but unsuccessful attempts to cure improve the eventual outcome of the disease. However, these treatments definitely detract from the quality of life, and they also may decrease the average length of life.
So, what are the important trends today. First, many urologists are attempting to be more selective in choosing which patients need to be treated. There are even initiatives the limit who needs a prostate biopsy. Next there are great advances in the treatment of advanced and incurable prostate cancer.
Some urologists are becoming more selective in choosing patients for prostate biopsy. Newer blood and urine markers, beyond PSA, are used to identify patients considered to be at a lower risk. This trend is offset by a group of urologists who are screening by age 40, lowering the upper limit of PSA to 2.5, and biopsying almost everyone who has an abnormal result. Prostate MRI may also select a patient for deferred biopsy.
The new advisable standard is to avoid or delay attempted curative treatment for patients considered to be “low-risk” or “very low-risk” for life-threatening prostate cancer. Standard pathology is often combined with risk profile analysis, genomic testing, and prostate MRI to determine the risk of progression. These patients are assigned to “active surveillance”. Although there is no standardized protocol for active surveillance, a combination of PSA testing, serial prostate biopsy, and sometimes prostate MRI is used to determine who should be treated. I am unaware of any definitive data to prove that this approach is better than simply following the PSA or even ignoring the cancer in these patients if judged by an improvement in quality adjusted years of life. Clearly active surveillance is preferred over aggressively treating everyone, but the stress and harmful effects of this approach have not been calculated into the risk/benefit equation.
It has been stated that PSA screening has decreased the number of patients who are found to have advanced disease at the time of diagnosis. This is certainly correct, but it does not mean that these same patients don’t progress to develop advanced disease at the same age that would have occurred without treatment. They may be diagnosed many years sooner, but the progress of the disease may not be different.
The most important tends in the past 20 years involve improved treatments for patients with incurable or advanced prostate cancer. It is uncertain whether screening, early diagnosis, and aggressive treatment intended to cure prostate cancer have resulted in any real benefit. But, it is clear that advances in the treatment of advanced prostate cancer have improved and extended lives. This is probably the most important reason that prostate cancer mortality has improved.
Since everyone dies from something, it is unfortunate that the other reason for a decrease in prostate cancer mortality is that many patients succumb from other disease at a younger age due to the treatment of their cancer. Of course, when patients are screened for cancer, total prostate cancer diagnoses increase, including patients with insignificant disease. This always decreases the percentage of patients with known prostate cancer that die from that cancer.
In this essay, I will not discuss the many improvements in the treatment of advanced prostate cancer. New treatments become available frequently. This discussion will be left for the experts, modern urology oncologists. One thing that all the new treatments have in common: they are very expensive. The cost of caring for prostate cancer, and therefore someone’s profits, has skyrocketed. And perhaps, that is the most obvious message from this discussion.