PSA – A Barometer to Prostate Health or a License to Biopsy?
by: Dr. Ronald E. Wheeler, M.D.
Prostate Cancer is the most common malignancy among men and the second leading cause of death. It is estimated that 1 in every 5 to 6 men will get Prostate Cancer in their lifetime. Statistically, if men live long enough virtually every male will get Prostate Cancer. Clearly, Prostate Cancer is of epidemic proportion.
The PSA (Prostate Specific Antigen) blood test, available commercially since 1988, has revolutionized our ability to detect Prostate Cancer. Originally approved in the United States for the monitoring of men with established malignancy, the most important indication now is for use in early detection and screening for prostate carcinoma. [i]The widespread use of serum PSA testing for early Prostate Cancer detection has increased the proportion of early stage cancers detected and is at least partially responsible for the recent decrease in Prostate Cancer mortality rates in the United States. [ii]Thus, the clinical timeline to diagnosis and treatment has been enhanced favoring the patient versus the disease.
Despite these factors, many men choose to ignore the availability of a proven biologic marker. This speaks to their lack of understanding that PSA diagnoses Prostate Cancer. Men who choose to avoid the PSA blood test endorse the argument that needless testing is performed on the majority of the patients tested. Their argument is strengthened by biologic variability of Prostate Cancer, known non-Prostate Cancer diseases that stimulate serum PSA elevations, inconsistent application of the PSA test and the lack of a completed randomized, controlled trial that proves the benefit of early detection. [iii]The controversy, notwithstanding, the plain and simple fact remains that early detection allows opportunity to make informed decisions based upon facts. Everything that you live for is reason enough to track your PSA result and begin PSA testing by age 40. Quality of life issues and the “American Dream” mean little without a health status report that indicates there is more life to live. Ignorance in regard to healthcare issues and specifically healthcare markers should be discouraged. Rhetorically speaking, people who argue that something else will get them first, may be right, but what if they are wrong? PSA blood testing yields a lead-time bias to the prostate health problems, principally Prostate Cancer, that they may develop in 8-10 years. Thus, the understanding of the PSA value is as germane to your health status as your bank account is to your financial well being. To avoid this test is tantamount to reckless and irresponsible behavior.
Recently I met a 50-year-old male from Michigan, at The Diagnostic Center for Disease, in Sarasota Florida. His primary care physician was at a loss for how to explain why his patient had developed bilateral leg weakness. Considerations included some rare neurological disease such as ALS (Lou Gehrig’s Disease) or other equally baffling disease like MS. Leg weakness is not common in an otherwise “normal, healthy male”. His union shop insurance did not support PSA testing prior to age 50 based in part on the American Cancer Society guidelines. When the patient’s PSA was ultimately tested, the result was 150 ng/ml. His bone scan was positive for disease metastasis throughout his skeleton. He was given 2-4 years to live by his oncologist, with or without therapy. While his wife sits with their 2 year old, we have to ask the question – Why did this need to happen? Clearly, if we became more proactive and encouraged screening at an earlier age, the devastation to one man’s life may have been averted.
The educational process suggesting earlier detection via PSA must be enhanced if we hope to give health choices rather than ultimatums. Thus, we need to identify prostate disease earlier. The established absolute cut-off value commonly used to differentiate the risk between cancer and no cancer is 4.0 ng/ml. [iv] Fred Lee, M.D. commonly states that “a PSA of greater than 2 ng/ml indicates a high probability that one’s clinical course will be associated with Prostate Cancer”. The limitations of this marker, specifically its false negative and false positive rates are well known. Numerous investigators have attempted to enhance the sensitivity and improve specificity of the PSA assay through enhancements including: prostate volume, density index, velocity change, percent free PSA, and age specific indices. [v][vi][vii]These modifications have added little to the decision armamentarium. Some investigators have suggested lowering the diagnostic threshold to increase the sensitivity in detecting cancer. [viii][ix]However, a lower threshold would significantly increase the number of men who would be candidates for biopsy. [x]Nationally, the gold standard for Prostate Cancer detection using the economically burdensome ultrasound and biopsy process is well known at about 30%. To translate further, 10 men with suspicion for Prostate Cancer would yield 3 prostate cancers only. Thus, 70% of biopsies are negative or not indicated. Academically, for the most part, we lack the ability to judge which patients are truly at risk and which ones are not. My belief is that there is a means to differentiate patients at risk with an elevated PSA from the group that has little or no risk. Recognition that PSA is driven primarily by Prostatitis (inflammation/infection) will allow for a more conservative approach. Prostatitis is also an epidemic disease and associated with virtually all cases of Prostate Cancer. To state further, we must recognize that antibiotics have limitations and work minimally to ameliorate chronic Prostatitis as noted in Campbell’s Urology, the reference text.
Additionally, physicians must be willing to do the all important EPS (expressed prostatic secretion) in an effort to improve the diagnostic awareness for the disease itself. Physicians must also be willing to decrease the number of prescriptions written for antibiotics, thereby, providing impetus for the use of non-traditional, complimentary alternative treatment methodologies.
In an effort to decrease needless prostate biopsies, three large centers of academic interest and clinical practice are trying to determine the ability of a prostate nutritional formula to alter an otherwise expected path to prostate biopsy. Many men who have had one negative biopsy will require another within 6-12 months. Some men have 6-8 biopsy procedures before cancer is detected. In this prospective trial, men who have had a negative biopsy in the face of an elevated PSA and a non-cancerous digital exam will be randomized to either a placebo or the PEENUTS prostate formula in a double blind format. This product is a combination of antioxidants, immune boosters, anti-inflammatories, and beta sitosterols. PEENUTS has recently received Patent recognition nationally and internationally, based upon its ability to lower biologic markers commonly associated with Prostatitis, including PSA. Patients on the study protocol will repeat a PSA at 3 and 6-month intervals. The findings should be available within a year.
Dennis Gibson of the Chicago Chapter of Us Too, suggests that patients at risk of Prostatitis (virtually all adult males) who exhibit an elevated PSA without digital findings to support Prostate Cancer, “may one day try this product as their first option”. We expect the study protocol, previously noted, to provide support for this innovative thinking process. The ability to lower the PSA based upon improvement of Prostatitis will reserve the biopsy procedure for those who fail to respond. This process is expected to increase the sensitivity for the prostate biopsy procedure to detect Prostate Cancer and save significant health care dollars.
Notwithstanding the above, many physicians continue to suggest that the PSA be lowered in an effort to increase sensitivity, thereby, finding Prostate Cancer earlier. Richard Babaian, M.D., William Catalona, M.D. and others have suggested that men who have a PSA of 2.5 to 4 ng/ml should undergo prostate biopsy earlier. If one accepts the premise that detection of clinically important cancer can be enhanced by lowering the PSA cut offs, the challenge becomes the task of reducing the false positive results in the lower PSA ranges.
Unnecessary biopsies can be reduced by restricting the biopsy recommendation to men at relatively higher risk in this generally low-risk population. Risk stratification can be achieved by combining risk factors (such as age, race, family history, biopsy history, and prostate volume), biochemical markers (such as free PSA and human kallikrein 2 (hK2), and statistical methods (such as artificial neural networks and regression analysis) to provide better discrimination of men more likely to have Prostate Cancer. [xi]
Approximately 12% of all men have PSA in the range of 2.5 to 4 ng/ml. [xii]In independent studies, Catalona and Babaian showed an incidence of Prostate Cancer between 20% to 25%, respectively, when the PSA of 2.5 to 4.0 ng/ml was used. Gann et al, reported that, compared with men whose PSA levels were less than 1 ng/ml, those with PSA levels of 2.01 to 4.0 ng/ml were 5.5 to 8.6 times more likely to develop aggressive Prostate Cancer within 10 years. [xiii]Clearly, the lower the PSA the further from Prostate Cancer one will be. Dr. Catalona’s work further suggested that a 2.6 ng/ml PSA cut-off detects more potentially curable cancers without over detecting harmless ones. In their study, 676 consecutive patients were treated with radical prostatectomy only. The rates of organ confined cancer were 81% for the PSA range of 2.6 to 4.0 ng/ml, 70% for the range of 4.1 to 10 ng/ml, and 53% for the range 10 ng/ml or higher. [xiv]With all due respect, the percentage of extra capsular disease, commonly associated with treatment failure, suggests a less than favorable decision process for an unpredictable disease. The random chance to eradicate Prostate Cancer, associated with the indignity of impotency and incontinence, is an unacceptable validation for the need to perform the therapy. These findings underscore further the need to look beyond the “one size fits all” mentality that traditional therapy speaks to. To state further, our collective failure to satisfactorily conquer Prostate Cancer speaks to a more basic void in pathophysiology and healthcare comprehension. The emphasis should not be on earlier detection to find Prostate Cancer but rather earlier detection to prove prostate diseases like Prostatitis. If men feel the need to make an effort to cure Prostate Cancer, Brachytherapy and Cryosurgery may represent a less incapacitating disease resolution, highlighting the preservation of quality of life issues. Suffice it to say, our collective inability to judge which patient will benefit from which form of therapy, may suggest a moratorium on definitive therapy until an improved understanding of the disease treated is known.
At The Diagnostic Center for Disease, we subscribe to the proven theory that, a PSA of greater than or equal to 1 is abnormal and unhealthy. This is in concert with the identification of Prostatitis and based largely on a review of 177 patients, whereby, PSA and EPS were among markers studied. Our data showed unequivocally and convincingly that a PSA of greater than or equal to 1 translates 100% of the time to Prostatitis. Prostatitis was verified by the use of the EPS, noting that greater than or equal to 10 WBC’s (white blood cells)/400x validates the presence of disease. This data was presented at the NIH in November 2000 (unpublished).
Clearly, Prostate Cancer does not just happen! PSA, therefore represents a marker that will guide a patient’s clinical course. Cellular oxidative changes and free radical formation result from chronic inflammatory states. It is well known, that chronic disease such as colitis, cervicitis, gastritis, and esophagitis lead to cancers of their respective organs. The inability of epidemiologists to establish a cause and effect from a correlation, noted with large numbers of patients with Prostatitis and Prostate Cancer, does not mitigate against that relationship. The association of Prostatitis to Prostate Cancer is highly suspected by David Bostwick, M.D., Tim Moon, M.D. and others. Factors that may influence the likelihood for a cause and effect phenomenon may include, but are not limited to, prostatic intraepithelial neoplasia (PIN), zinc levels, the presence or absence of glutathione-s-transferase at the basal cell layer, and/or altered endorphin activity.
I believe that in order to have an opportunity to defend patients against Prostate Cancer, we must recognize the need to advise patients of a new application to an old concept; that is, a PSA of greater than or equal to 1 minimally indicates a less than healthy prostate. Therefore, in this regard, PSA now serves as a barometer to prostate health. In this capacity PSA is a more meaningful marker. Our data would suggest that a new normal for PSA testing be recognized as less than one.
In the future, statistical methods may be used to more accurately estimate a man’s risk of Prostate Cancer. One may enter data concerning age, race, family history, history of Prostatitis, previous biopsy history, total PSA, free PSA, and any other markers and/or risk factors identified, and the risk of having a prostate biopsy will be computed. Then the patient and the Doctor can decide whether the risk justifies a biopsy. [xv]This sounds like common medical sense, but without implementing an improved thought paradigm for treatment, all that we propose will be doomed to failure or minimally a trade off; exchanging a disease for a new set of disease complications including the possible return of the disease itself. Should this happen, maybe we would all be better off with a watch and wait approach as a lesser of the two evils.
[i] Brawer, M.K.: PSA: An Update. 11th International Prostate Cancer Update: Page 40, 2001
[ii] Hankey, B.F. Feuer EJ, Clegg LX, et al: Cancer Surveillance Series: Interpreting Trends in Prostate Cancer. J Nat’l Cancer Inst.91; 1017-1024, 1999
[iii] Woolf, S.H.: Screening for Prostate Cancer With Prostate Specific Antigen: An Examination of the Evidence. N Engl. J Med 333(21): 1401-1405, 1995
[iv] Benson, M.C., Whang. I.S., Pantuck, A. et al: Prostate Specific Antigen Density: A Means of Distinguishing Benign Prostatic Hypertrophy and Prostate Cancer. J Urol, 147:815, 1992
[v]Babian, RJ and Camps, J.L.: The Role of Prostate Specific Antigen as Part of the Diagnostic Triad and as a Guide When to Perform a Biopsy. Cancer, 68:2060, 1991
[vi] Oesterling, J.E. Jacobsen S.J., Chute, C.G. et al: Serum Prostate Specific Antigen in a Community Based Population of Healthy Men. Establishment of Age-specific Reference Ranges. JAMA, 270:860, 1993
[vii] Babaian, R.J. Kojima, M. et al: Comparative Analysis of Prostate Specific Antigen and its Indexes in the Detection of Prostate Cancer. J Urol, 156:432, 1996
[viii] Catalona, W.J., Smith, D.S. et al: Prostate Cancer Detection in Men with Serum PSA Concentrations of 2.6 to 4.0 ng/ml and Benign Prostate Examination. JAMA 277:1452, 1997
[ix] Schroder, F.H., van der Cruijsen-Koeter, I., de Koning, H.J. et al: Prostate Cancer Detection at Low Prostate Specific Antigen. J Urol, 163:806,2000
[x] Babaian, R.J., Johnston, D.A. et al: The Incidence of Prostate Cancer in a Screening Population with a Serum Prostate Specific Antigen between 2.5 and 4.0 ng/ml.: Relation to Biopsy Strategy. Jurol, 165, 757-760, 2001
[xi] Catalona, W.J. Ramos, C.G. et al: Lowering PSA Cut Offs to Enhance Detection of Curable Prostate Cancer. Urol. 55:791-795, 2000
[xii] Kane, R.A., Littrup, P.J. et al: Prostate Specific Antigen Levels in 1695 Men Without Evidence of Prostate Cancer. Findings of the American Cancer Society National Prostate Cancer Detection Project. Cancer, 69:1201, 1992
[xiii] Gann, P.H. Hennekens, C.H. et al: A Prospective Evaluation of Plasma Prostate Specific Antigen for Detection of Prostate Cancer. JAMA 273:289-294, 1995
[xiv]Catalona, W.J. Ramos, C.G. et al: Lowering PSA Cut Offs to Enhance Detection of Curable Prostate Cancer. Urol. 55:791-795, 2000