Now the prostate specific antigen (PSA) blood test has become the primary marker for measuring the potential and/or presence of prostate cancer (Pca). We are advised to begin regular PSA testing somewhere between the ages of 40 to 50, dependent upon our race, ethnicity, family medical history, symptomatic conditions, etc. (See ACS Reference here)
We have also been conditioned to view the test as a monitor of the relative possibility for contracting Pca as well as a measure, post-primary therapy, of the "cure" or failure of our particular cancer. In both instances an increase in the PSA level or the velocity of change will generate significant anxiety or cause for concern, whether it is warranted or not. (Click here for reference info)
But where is the reality in the rising PSA test results that mandate an agenda for action? Does the increase in PSA dictate a death sentence; does it mean that further treatment is required; or do we continue to monitor it and hope for the best? In the words of Dr. Willet Whitmore: "Is cure possible for men in whom it is necessary? Is cure necessary for men in whom it is possible?"
Dr. Alexis Te, Assistant Professor of Urology and Director of the Incontinence Care Center of New York Presbyterian Medical Center will attempt to provide a framework of understanding that will enable you to make the appropriate diagnostic and/or treatment decisions for your situation.
Before we talk about a rising PSA, Dr. Te, help us to understand the mechanism of prostate specific antigens, why the test itself is important and how should the patient view all of this in the context of certain institutional concerns over "mass" screenings and aggressive (unnecessary?) medical intervention.
AT: PSA is a protein produced specifically by prostate cells that is a component of semen. As such it is an organ specific marker. It is contained within the prostate and is usually detected in small amounts in the blood stream under normal conditions. However, many conditions can cause it to "leak " into the blood stream; such as inflammation or cancer that break down the barriers that contain the PSA will cause it to leak into the blood and therefore increase its blood level. PSA has been a useful marker to help screen for prostate cancer. While it is an important tool to follow the progress of patients with prostate cancer, its greater use has been to determine whether a biopsy of the prostate is indicated in order to evaluate the presence of cancer. If a PSA is elevated, it may be due to prostate cancer. As such, a biopsy is indicated to further investigate whether a cancer is present.
In the context of institutional concerns over mass screening, several issues come to light that are the basis of a complex controversy to screen, diagnose and treat prostate cancer. First, prostate cancer is generally a slow growing tumor, and if detected late in life, its presence may not impact on a patient's longevity or quality of life. However, as the average male lifespan increases, the issue to treat/cure prostate cancer becomes a significant factor affecting the mortality and quality of life of that man. Add to this the potential risk and side effects of various treatments for prostate cancer such as death, incontinence, impotence and other effects, the situation becomes an even more complex public health issue. At base level is whether the treatment can be worse than the disease. This is further complicated by the economics of cost effective delivery of such care.
In the context of the individual, it is a little simpler. The questions posed by men, who elect to be screened for prostate cancer are, "Am I old enough and healthy enough to outlive prostate cancer if I have it". And "If I have prostate cancer, am I willing to aggressively pursue appropriate treatment as well as accept the potential risk of side effects of the various treatments in order to be cured." Equally important regardless if one decides to be treated or not be treated is the need to know if one has it and the potential impact on one's life plans. Thus, choices in being screened, biopsied, diagnosed and treated are as individual, and as personal, an issue for each patient as much as it is a public health issue. Each individual's care needs to be personalized to their needs.
VS: Looking at the undiagnosed patient, what are some of the factors that can cause a rise in the PSA level, related to Pca versus other medical conditions, e.g. benign prostatic hyperplasia (BPH), hypertension, etc.? Are there other environmental factors (food, air, water, sex) that can also elevate the PSA level?
AT: PSA is an organ specific marker and not a cancer specific marker. Thus, many conditions can be responsible for a PSA level that is higher than what is considered normal. When evaluating an elevated PSA level, distinctions must be made over a PSA level that stays elevated above normal and one that rises and falls back to normal. In the former, the issue is whether the elevated level is due to a large prostate (BPH) producing more PSA or a cancer producing more PSA. Only a biopsy can reliably differentiate between the two. Situations that cause a rise of a PSA from normal and a fall back to normal are often benign in nature. These are often conditions that cause inflammation of the prostate such as infection, trauma and injury. A vigorous rectal exam, prostate surgery, urinary retention, urinary tract infections, prostatitis are just a few conditions responsible for a temporary rise in PSA. One of the most difficult situations to evaluate is an inflammatory state that can cause a fluctuating rise and fall in PSA levels but at its lowest level still is above normal. One common condition is chronic prostatitis. In this situation, only a systematic and thorough biopsy can reliably determine whether a cancer is present. Editors note: see article on social factors affecting PSA levels here.
VS: Conversely, Dr. Te, are their foods, medications, etc. that can mask the true level?
AT: Yes. PSA is produced by the prostate gland and this production is dependent on the presence of male hormones such as testosterone and more specifically dihydrotestoterone. Any drug that affects the metabolism of male hormones can affect PSA production and levels. Many medications that decrease or block certain aspects of male hormone metabolism will lower PSA levels. One example is finasteride, which is marketed as Proscar. Certain Chinese herbs that have antiandrogen effects have the potential to lower PSA levels as well. Additionally, medications that affect organs such as the liver, adrenal glands, pituitary glands could also have an indirect effect on androgen metabolism. Converse to a rise in PSA, a disease state that decreases androgen metabolism or favors estrogen metabolism, such as liver cirrhosis or obesity, may have a propensity to lower PSA.
VS: There is continuing discussion over the use, and interpretation of the results, of more advanced diagnostic tests - free vs. bound PSA, complexed PSA (cPSA), RT-PCR – which claim to be better predictors of prostate cancer incidence and morbidity. Please comment on your experience with these procedures. (See links here)
AT: These variation of what I call "PSA derivatives" such as the free PSA/ total PSA, PSA density, PSA velocity and many others were designed with the intention of creating a better/ more sensitive screening tools to distinguish which patients would have a higher likelihood of having prostate cancer and thus require a biopsy. More importantly, it was hoped that one could also identify patients who, despite a relatively elevated PSA, could avoid a biopsy. Overall goal of these derivatives was to provide a more sensitive predictor of which patient population would best be a candidate for prostate biopsy. The present PSA level test as it stands today is not as sufficiently accurate a screening tool in the 4-10 PSA range to be considered a good screening test. This is because in this range about half of the patients biopsied could have an elevated PSA due to prostatitis, or more commonly, BPH. These derivatives, in my opinion, should not be the final guide to not performing a prostate biopsy in patients with an elevated PSA level. Rather they are more useful in the context of following patients with an elevated PSA level, with a previously negative biopsy, and deciding if another biopsy in warranted. This tool might help to identify cancers that were initially missed because of their small volume and are now growing to become more clinically significant and would have a better chance of being discovered on a follow-up biopsy.
The RT-PCR PSA test is a special test that was designed to look for prostate cancer cells in the blood. Specifically, it was designed to identify patients with prostate cancers that had spread outside the prostate. At present, there are no noninvasive methods that can accurately identify micrometastasis of prostate cancer. With this technique, if a prostate cancer cell even in it most minute amount were traveling in the blood stream, it could potentially be collected with a simple blood sample. PCR technology would then amplify the DNA of the cancer cell, which could then be identified by looking for the DNA footprint of DNA codes for PSA. This would in effect identify micrometastatic prostate cancer cells. It is thought that most failure of local therapy is due to undetected micrometastatic disease at the time of treatment for prostate cancer. RT PCR could be the tool to therefore identify these patients and possibly avoid unnecessary invasive local treatment for this group of patients. Present data concerning this technology have not so far demonstrated this tool as an effective and sensitive diagnostic tool. The technology is still being investigated and refined.
VS: The generally accepted range for "normal" PSA levels, based on the standard developed by Dr. Osterling, is between 0.0 and 4.0. At what absolute number, or change in the velocity of increase, would you move to get further diagnostic testing? And, how would this action differ based on age, race, environment, etc.?
AT: The accepted range of normal for current standard of practice is between 0.0 and 4.0. However, this is a range developed from data on a population of white males in Omstead County. Several studies have shown that "normal PSA values" can be different according to age, ethnicity, environment and geography. For practical clinical purposes, 0.0 to 4.0 is a range accepted and applied by most urologist in the setting of a normal rectal exam. However, certain clinical situation could warrant a biopsy despite a normal PSA and a normal rectal exam. For example, a PSA rise of 1.0 to 3.5 could justify a biopsy because it has exceeded a PSA velocity of 1 per year. This could suggest a small but rapidly growing cancer. Other situations that could justify a biopsy are a PSA of 4.0 in a relatively young male such as a 45-year-old male or a male with a small prostate. Finally, any non-tender prostate nodule warrants a biopsy regardless of its PSA level.
VS: Given the fact that there are variables in the type of test used, the lab protocols for processing and/or measurement, range of acceptability, etc. How would you counsel a patient on the results noted, establishing a framework for monitoring continuity or initiating a plan for primary therapy?
AT: This is not a simple question nor is there a truly simple answer. However, it is generally accepted and recommended by the AUA and the American Cancer Society that a PSA and DRE be performed biannually after the age of 50. This can be moved to an earlier age if risk factors such as a positive family history or being in an at-risk population such as black males are identified. Thereafter, every person's strategy is tailored to their expectations based on age, medical condition, life expectancy, desired to be treated etc. As I have alluded above, every clinical scenario needs to be assessed in the context of a patients needs and quality of life expectations.
VS: When the PSA results are outside the desired range, other diagnostic procedures (CT scan, bone scan, biopsy) are traditionally utilized to confirm or negate the presence of Pca. Given the innovations in medical technology – Color Doppler Ultrasound, endo-rectal MRI, Prostascint scan, etc. – as well as improvements in procedural evaluations – Partin Tables, Dr. Ron Ennis' work to eliminate the need for CT scans, etc. – what would you recommend as a diagnostic pathway to minimize unnecessary testing, decrease medical expense and enhance patient decision-making?
AT: In any setting, the first priority is to decide the need to know whether a diagnosis is necessary. In a perfect example, a 90-year-old male may not want a biopsy despite a PSA level of 10 because his cancer in all likelihood will not have a significant impact on his life expectancy or even his quality of life if left untreated. The situation is quite different in a healthy 55-year-old male where aggressive curative therapy is pursued to increase life expectancy past 15 years. In any context, once a decision is made towards making a diagnosis, a prostate biopsy is the very next step. All other remaining diagnostic test become pertinent only in the context of a positive biopsy result and the ultimate therapeutic goals of the patient. Let me describe some of the purposes of the tests you have mentioned:
An endorectal MRI is useful in evaluating gross extension of prostate cancer past the surgical capsule or seminal vesicles. Pelvic CT scans, Pelvic MRI scans, Nuclear Bone Scans and the Prostascint Scans are used to assess if cancer spread into the lymph nodes or bones. Partin Tables are basically utilized to estimate the probability of pathology associated with poor prognosis because it may influence the choice of therapy for the patient.
When the biopsy is positive, the use of the above mentioned tests is to determine the presence of extraprostatic disease. The educated decision of which test to use and when depends on the PSA, Gleason score and DRE, as well as the potential choices of preferred therapy.
VS: If at this point it appears that the patient is a candidate for a primary therapy, how should the process of decision-making evolve so that doctor and patient become "partners" in making the appropriate treatment selection and quest for a "cure"?
AT: As I have stated before, the answer to this question depends on the goals of patients and his understanding of the risk and benefits of undertaking a cure. However, I have a few biases that I will relate. Present data concerning definitive therapy for the cure of localized prostate cancer appears to demonstrate that 3D conformational external beam radiation therapy and radical retropubic prostatectomy appear to be very good choices with demonstrated cure rates. Radioactive Seed Implants are also a good option. However, conceptually, I believe that a radical prostatectomy holds the best hope for definitive cure because the offending pathology is completely removed from the patient. Failure, to my understanding occurs, because micrometastatic disease has occurred at the time of therapy. With the other modalities, local failure is a possibility because the cancer is not removed. In fact, local failure has occurred with tumors that were aggressive and resistant to radiation therapy. 15 year data has suggested that radical retropubic prostatectomy is superior to radiation therapy. However, the driving force of these alternative therapies is their relatively minimally invasive nature. At most major academic institutions, the complication rate of surgery is comparable to radiation therapy. However, in the community, this may not be true with incontinence rates for example being reported as high as 40% compared to the less than 5% at major academic centers. This, however, is changing as surgeons are becoming more aware and better trained to the improved techniques in achieving lower complication rates. With regards to the other technologies such as external beam radiation and seed implants, the same can also be said. Higher complications exist with older technology and less experience. The therapy is only as good as the therapist and his tools. With that stated, I always highly recommend a radical retropubic prostatectomy as the best option for cure. However, the other alternatives are also discussed in the context of a patient being able to tolerate and survive the therapy, and their long-term expectations of therapy. Please note that I have only discussed definitive curative therapy for localized disease.
VS: Until now we've focused on the individual's initial pathway from screening to diagnosis to treatment; we now need to address the person who has had primary therapy – be it surgery, radiation or chemotherapeutic – and is faced with a rising PSA. A rising PSA is perceived as a "failure" of the primary therapy and evidence that the cancer has recurred. How should the patient process this information and determine if, and when, further treatment is required?
AT: Virgil…this is not a good question because each situation, a rising PSA after surgery, radiation, chemotherapy can mean nothing therapeutically or failure of therapy or poor control of disease by therapy. However, I will try to simplify each situation with regards to a rising PSA level and its interpretation. After a radical prostatectomy, a nondetectable PSA is the benchmark for determining cure. Any rise of PSA from 0, signifies recurrent disease. When this occurs, the question is where is the rise from and where is the prostate tissue. If the recurrence is due to failure of local therapy to remove the disease, then additional therapy such as radiation therapy can be directed to bring the PSA back to zero. However, if the PSA rise is due to metatstatic disease, then a discussion of a treatment involving hormonal therapy will take place. If the PSA rise occurs after radiation therapy, the issue first is the timing of the rise and the significance of the rise. If it occurs just after treatment, this is due to a post inflammatory reaction to the radiation and will therefore "bounce up" and then down. The PSA will then nadir and stay at that level. In the optimal setting, the PSA would be also 0.0. However, it is also acceptable to see a PSA nadir down to a low level such as 1.0 and failure would be a rise from this bottom number. Since prostate tissue is not removed physically, it is thought that this residual PSA is from remaining normal prostate tissue. Treatment after radiation therapy is a difficult decision because any procedure to salvage for a cure is often fraught with a high complication rate such as incontinence and impotence. Salvage therapy could be a salvage radical prostatectomy or cryosurgery. A rise in PSA for a patient on hormonal therapy (usually a patient who has metastatic prostate cancer) suggests either that the patient is not compliant with his medication or that the cancer is becoming hormonally resistant and at this point, chemotherapy therapy is an option for further therapy. As you can see, the issues of a PSA rise after therapy can be quite complex.
VS: Outside of the major teaching medical centers there has been noted a "disconnect" between urologists and medical oncologists over how to treat the patient with post-primary failure. How would you counsel the patient on when, and how, to seek another opinion?
AT: It has been always my philosophy that patients educate themselves as much as possible to feel comfortable with their choices. Currently, there are many therapies for the same disease with different side effects. Therefore, a decision about which is best for them is a personal matter that involves the interaction of a physician to help guide them to a plan that is best suited for them. It has been always my practice to encourage another opinion to develop a level of comfort with the choices that are offered and the decisions that will be made. Good care always has a consensus, and when it does not, it becomes more important to educate oneself about care or therapy that, while is not commonplace, may be best suited to their needs.
VS: In the instance of primary failure, and when further treatment is indicated, some studies have suggested that early intervention with hormonal therapy at low PSA levels have better effectiveness for long term survival than waiting until the PSA, and the advance of the recurrence, is at a higher level. Do you have any opinions as to a recommended course of action?
AT: No and that is because the issue is more complicated and involves the acceptance of the patient to accept one of the common side effects of hormonal therapy, impotence, balanced against the true need for therapy at an early stage.
VS: All of us – patients, survivors, the undiagnosed and the unaware – have our lives and emotions wrapped up in the results from that syringe of blood. Supposedly 23,000,000 PSA tests are done annually, from which we see approximately 300,000 diagnoses for Pca and roughly 40,000 deaths. Coupled with this is a building controversy over whether or not our screening efforts actually decrease mortality or merely promote needless, aggressive treatment.
What can you suggest to us to help make more informed decisions and are there other tools on the horizon that will provide a better standard of detection and maintenance?
AT: Only more research will answer this question. However, new developments are always on the horizon and we need to be vigilant about supporting these efforts to cure prostate cancer.
VS: We want to thank you, Dr. Te, for your time and insights as well as your contribution to the body of patient knowledge as Webmaster for the New York Presbyterian Department of Urology’s Website. Should anyone want to contact you for more information, how can you be reached?
AT: The URL is http://www.ccc.columbia.edu/ and you can also direct general
questions to the appropriate doctors on that website. Finally, they can always
call my office for a consultation at 212 305-0136. In July of 2000, I will become
the new director of the Brady Prostate Center at New York Hospital in the Department
of Urology of the Weill Medical College of Cornell University.