|Who Should Be Treated?|
|Thomas A. Stamey, M.D.|
|Professor and Chairman of Urology Stanford University School of Medicine|
| Last Modified: November 1, 2001
IntroductionProstate cancer is now the most commonly diagnosed cancer among men in the United States and is the second most common cause of all cancer deaths in men. Thirteen percent of all deaths in men in the U.S. in 1994 will be from some form of cancer. There will be 200,000 new cases of prostate cancer diagnosed in the U.S. in 1994 and about 38,000 deaths. When we consider that the incidence of prostate cancer increases with advancing age and that life expectancy among most populations continues to improve, this cancer, more than any other, presents the individual patient, his physician and the overall health care system with a serious dilemma--i.e., how to identify those who should be definitively treated with the intent to cure their cancer or to achieve long-term control with an excellent quality of life.
The Dilemma of 40, 8, and 3 PercentThere are some serious dilemmas as to the appropriate management of prostate cancer. One dilemma derives from the fact that in autopsies on men over 50 years of age, microscopic examination of the prostate gland demonstrates the presence of invasive cancer in 40%. This surprisingly high incidence of invasive histologic cancer occurs in men of all nationalities and increases with advancing age. In contrast, however, based on the National Cancer Institute's annual surveys (Surveillance, Epidemiology and End Results, or SEER), we have recently published that only 8% of men in the U.S. will present with clinically significant disease in their lifetime affecting their quality of life (1). Furthermore, only 3% of all men in the U.S. die of prostate cancer (2). In no other human cancer is there such an enormous disparity between the very high incidence of malignancy microscopically and relatively low death rate.
Growth Rate and Cancer VolumeWe reported in the journal Cancer last year that prostate cancer has an astonishingly slow growth rate, with half of all cancers requiring over five years to double their size (3); breast cancer, in contrast, doubles its size every three months. This observation, in part, explains the enormous discrepancy between the 40% presence of prostate cancer in the general population and the 3% death rate. The primary reason that only 8% of all men are ever bothered by this cancer is that the remaining 32% have tumors that are too small (less than 0.5cm3) to become clinically significant in view of the slow growth rate of four to five years. [A 1 cm cube (cm3) is about the size of a sugar cube.]
Starting with a tumor smaller than 0.5cm3 (80% of all prostate cancers are less than 0.5cm3 and 50% are less are less than 0.05cm3), and doubling the volume of the cancer every five years, most men over 50 do not live long enough for the cancer to reach a size that will become a significant problem to them. Thus, estimates of the size of the cancer at the time of diagnosis are critically important. Unfortunately, estimates based on rectal examination of the prostate are not nearly as accurate as information that can be obtained from carefully performed biopsies of the prostate. For example, we have recently shown that if men have six "systematic" spatially separated core biopsies of the prostate, a core cancer length of more than 2mm(one-fifth of a cm) is always associated with at least 0.5cm3 of cancer or more (4).
Increasing Cancer Detection RatesThe recent introduction of rapid, safe and reliable techniques for obtaining biopsies under ultrasound guidance in ambulatory patients, combined with the availability of a blood test for prostate cancer called "prostate specific antigen" (PSA), greatly enhances our diagnostic capability even in the presence of a normal digital rectal examination of the prostate. The combination of the traditional rectal examination, the PSA blood test and the ease with which multiple biopsies can be obtained has resulted in a greatly increased rate of detection of this extraordinarily common cancer. It is imperative that we develop reliable guidelines as to who should and who should not be treated. Indeed, the estimated detection rate of prostate cancer among U.S. men rose 21% from 1993 to 1994, the largest jump in a cancer in a single year since the start of the National Cancer Institute's SEER Program in 1973. The increase in detection rate of smaller prostate cancers is analogous to the 33% increase in breast cancer from 1980 to 1987, which paralleled the increase in the use of mammography.
Depending on a patient's age, the size of his cancer, the rate of cancer growth (the doubling time of his PSA), and the presence of other potential life-limiting diseases, earlier detection is in general a good thing. The window of curability is not large--somewhere between 0.5cm3 to 6cm3 of cancer. We can cure most cancers surgically if they are less than 6 cm3, but we cure no one with over 12cm3 of cancer and cure only a few between 6 to 12cm3 (the "normal" prostate averages 38cm3 in size in men 50 to 59 years old). However, if an annual PSA is obtained from men over 50 years old, the time that it takes for a prostate cancer to increase from 0.5cm3 to 6cm3 in size is about 14 years at an average doubling time of 4 years. Annual PSA determinations should detect this cancer long before it becomes incurable at the size of 6 sugar cubes. Men with a strong family history of prostate cancer, such as a brother or father who died of prostate cancer under the age of 70, should probably have an annual PSA starting at age 40 rather than 50. Their risk of developing clinically important prostate cancer is about twice (16%) that of a man without a family history (8%). Black men, since their cancer reaches clinical significance five years earlier than in white men, should have their annual PSA determinations starting at 45 years of age.
There should be one word of caution when the growth rate of prostate cancer is followed by serial changes in serum PSA. Benign prostatic hyperplasia (BPH)--the benign growth of prostatic tissue that most men develop over the age of 50--also increases serum PSA (albeit one-tenth as much as the same volume of cancer). Some men grow very large amounts of BPH. In those with over 50cm3 of BPH, the total amount of PSA produced can cause such an elevation of serum PSA that it may mask the rise in PSA caused by cancer, especially a smaller cancer of 1 to 2cm3. Complicating the problem imposed by very large benign prostates is another observation we have recently made. In a small subset of men with very large prostates the BPH tissue grows so rapidly that it can approach the doubling time of PSA in prostate cancer. Recognition of these important limitations can lead to the correct diagnosis by
Age-Adjusted Levels for Interpretation of PSA testsPSA remains the most important marker for both diagnosing and monitoring prostate cancer; indeed, it is unique among all cancer blood markers. An annual PSA in men over 50 is a good recommendation as long as the PSA is done by the same assay and in the same laboratory. Recent automation of some assays avoids random technical errors and adds greater confidence to changes in PSA values obtained annually. Prostate cancer will be associated with a steady but slow rise of PSA which should usually require about four to five years to double its value. Because this rate of rise is so slow, a PSA once a year is often enough and there is no excuse for obtaining PSAs more often than annually, unless under extraordinary circumstances. We now know that in men without prostate cancer there is a slow rise in PSA (much slower than in the presence of prostate cancer) due to a small increase in size of the prostate with aging. This has changed the classic 0.004.0 ng/ml "normal" limits of PSA to "age-adjusted levels" that reflect this slow rise in PSA in normal prostates. Thus, 95% of all men without cancer should have the following upper limits of PSA values for each decade(5,6):
These age-related, normal PSA values will increase the chances of detecting an early cancer in men under 60 (where the upper limit used to 4.0 ng/ml), and will decrease the chance of "over diagnosis" in men over 60 years of age which so often leads to unnecessary biopsies. The above values are based on "monoclonal-monoclonal" assays which in the U.S. are either the Hybritech assay or the automated Tosoh assay. Other assays available in the U.S. may have different values. There is an urgent need to internationally standardize PSA assays so that all assays will give equivalent results. Stanford has played the major role in efforts to achieve an international agreement; our second and hopefully final international conference on PSA will be held at Stanford on September 1 and 2, 1994.
I have emphasized the importance of both the "normal" slow increase in PSA caused by the expected increase in prostate size with aging and the much more rapid rise of PSA in men with prostate cancer (and in a very small subset of men with benign enlargement of their prostate--BPH). It is important to recognize that there is a "physiological" or normal variation of PSA in men that is poorly understood. One-third of healthy male volunteers presumably without prostate cancer can have as much as a 20% variation in their PSA between two consecutive specimens a few weeks apart, especially when PSA levels are less than 4.0 ng/ml. When PSA is greater than 4.0 ng/ml, only 17% will show a 20% variation PSA values between two consecutive specimens. These studies at Stanford in the Department of Urology utilized an automated assay with great precision which is why we know there variations are physiological within the man himself rather than technical variations within the assay.
How Does Prostate Cancer Escape from the Prostate?We began removing prostates surgically at Stanford in November 1984 in a carefully designed protocol. Before admission to the hospital, all patients had preoperative blood samples drawn and stored at -70 degrees C. for further analysis. Immediately after surgery, each prostate was taken directly to the Department of Urology Laboratories where small samples were removed for tissue culture and other basic molecular investigations prior to formalin fixation. After fixation, each specimen was outlined with ink to identify cancer cells potentially present at the margin of the excision and then serially sectioned at 3-mm intervals. The area of cancer in each step-section was precisely quantified by means of digital computer techniques that allowed us to calculate the volume of cancer. Spatially correct maps of the whole prostate were then produced. In addition to the volume of the cancer (the number of "square sugar cubes"), every morphological evidence of tumor aggressiveness was quantified, including the different grades of the cancer*, the amount of perforation of the tumor through the capsule, the degree of invasion into the sperm sacs (seminal vesicles) attached to the prostate (usually a hallmark of incurability), the presence of ink resting on cancer cells (positive surgical margins which can indicate that some cancer has been left in the patient), the spatial location of each cancer and the direction of its spread. These, and other measurements, were carefully documented on cards and all information was transferred to a computer database. Since November 1984 each of the 800 prostates removed at Stanford have been subjected to these exacting quantitative studies. These studies have led us to a greater understanding of how prostate cancer escapes from the gland, an understanding that has led to a much better and wider excision of the gland at critical points where the cancer may have started its escape from an otherwise confining capsule.
-- [*There are 5 different Gleason grades or architectural patterns of prostate cancer. As the cancer increases in size, the grade changes from 3 to 4 to 5. The absence of grade 4 or 5 is a good sign. For example, we believe that approximately 3cm3 of grade 4 cancer is required for the cancer to reach the lymph nodes. Because most cancers contain more than one grade, in biopsies the Gleason "score" is used rather than the grade. The score is the sum of the two most common grades. Thus, grades 4 and 3 would give a score of 7. In general, scores of 6 or less are good news (they contain no grade 4) while 7 or more indicates a higher grade tumor (some grade 4). However, many patients are cured by radical prostatectomy in the presence of some grade 4.]
Importantly for our analysis of these specimens, we have developed an assay for PSA at Stanford that increases the sensitivity of the detection of residual cancer cells by 10-fold (5). Since there should be no detectable PSA if all prostate cells have been removed surgically, a three-year follow-up with our PSA assay after surgery has better than a 95% chance of indicating precisely which of the histologic measurements of cancer progression in our surgical specimens determine incurability. We have already compiled preliminary findings on this series, and they show that our morphometric measurements on these prostate specimens can yield a high level of predictability for progression. Cancer volume is the most important index of cancer behavior and histologic grade is an important modifier. For example, an early analysis of the first 102 radical prostatectomy specimens indicated that almost all cancers greater than 12cm3 in volume ultimately developed a detectable PSA after surgery even if the tumors were organ-confined at the time of surgery.
International Differences in How to Treat Prostate CancerTherapeutic approaches to prostate cancer have differed widely from one country to another. For example, urologists in the Scandinavian countries have avoided definitive treatment, relying upon hormonal therapy (inhibition of androgens--male hormones--by estrogen therapy or by removal of the testes) for temporary control of the later clinical stages of cancer progression. Clinicians in the U.S., taking advantage of the effectiveness of our new diagnostic capabilities, have been much more aggressive in treating the early stages of prostate cancer. Utilizing either surgical removal or super-voltage irradiation of the prostate, there has been a veritable explosion in the number of prostates removed for cancer or irradiated in the past five years. About 50,000 radical prostatectomies were done in the U.S. in 1991 and 100,000 in 1993. To the extent that perhaps as many as 50% of these procedures are either unnecessary (the cancer is too small) or ineffective (surgical excision of the prostate fails to cure the patient of his cancer), they represent an enormous cost to an already overburdened health care system.
AgeAnother important consideration is the age of each patient when the cancer is discovered. Prostate cancer is more common in men over 70 years of age. But life expectancy becomes progressively more limited in men over 70 because of cardiovascular disease and causes of death other than prostate cancer; only 50% of all men will live into their early eighties. Thus, few men, if any, over 70 years of age should have aggressive treatment for their prostate cancer because 50% of them will die of other natural causes before they reach 82 years of age; the average life expectancy in 1992 for a 70-year-old man was 12 years. Moreover, the size of prostate cancers in men over 70 years old tends to be larger and much more difficult to cure by surgery than in younger men, all of which argues for a very conservative approach to this age group.
Available Treatment Options
Concluding RemarksBecause prostate cancer constitutes one-third of all cancers diagnosed in men as well as 13% of all cancer deaths(17), it is no wonder that prostate cancer has received such extraordinary coverage in the national and local press. The advent of PSA and the ease with which multiple biopsies can be taken of the prostate in a relatively painless and highly accurate way (using transrectal ultrasound guidance), have changed our traditional approach to this cancer. More importantly, we now understand this cancer probably better than any other human tumor.
Because so many men have prostate cancer and so few die from it, there is and will continue to be substantial controversy as to who should be treated, and with what method. I have written these comments with the firm belief that men need to know that this cancer is unique among all human cancers. I believe they can make a better and wiser decision if they understand the reasons for the controversy surrounding prostate cancer.
I have another reason for trying to present this controversy in a way that will help patients make a choice. I learned 25 years ago from Professor Paul Beeson when he was in Oxford, England that each of us, when faced with a serious illness beyond our comprehension, unknowingly becomes childlike, afraid and looking for someone to tell us what to do. It is an awesome responsibility for the surgeon to present the options to a patient with prostate cancer in such a way that he does not impose his prejudices which may or may not be based on the best objective information. I have prepared these comments with the hope that my own patients will find it easier to make the right decision as to how their prostate cancer should be treated, regardless of what I tell them. --April, 1994
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