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Who Should Be Treated?

Thomas A. Stamey, M.D.
Professor and Chairman of Urology Stanford University School of Medicine
Last Modified: November 1, 2001

Introduction

Prostate 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 Percent

There 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 Volume

We 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 Rates

The 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

  1. determining the true size of the prostate with ultrasound and

  2. biopsying the anterior BPH area, in addition to the standard 6 posterior biopsies already described, if the prostate is larger than 50 to 60 grams.

Age-Adjusted Levels for Interpretation of PSA tests

PSA 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):

40 to 49 = 2.5 ng/ml
50 to 59 = 3.5 ng/ml
60 to 69 = 5.0 ng/ml
70 to 79 = 6.5 ng/ml

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 Cancer

Therapeutic 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.

Age

Another 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

  1. Radical Prostatectomy (Surgical Removal of the Prostate)

    • a. Volume and grade as a determinant of success or failure. Provided the cancer volume is somewhere between 0.5cm3-6cm3 in size, radical prostatectomy offers the best opportunity for a permanent cure; alternative therapies are substantially less certain. However, in the U.S. today, about half of all men who have had a radical prostatectomy are showing recurrence of their cancer as measured by a detectable and rising serum PSA, even though 95% fall to undetectable levels immediately after surgery. The failure of radical prostatectomy to cure the patient is caused largely by operating on men who have a cancer too large to be cured by surgery (greater than 6.0cm3). It is important to appreciate the fact that even small cancers palpable on rectal examination and considered to be "confined" to the prostate and therefore "curable" have an enormous variation in cancer volume. For example, cancers thought be confined to one-half of the prostate on digital rectal examination vary in volume between 0.2cm3 and 19cm3(8); the 0.2cm3 cancer is clinically too small to treat and the 19cm3 is too large to cure. For this reason, six systematic, spatially separated biopsies under ultrasound guidance are more reliable than rectal examination in separating large cancers from small ones; when the cancer area is seen on ultrasound as a dark area of circumscribed tissue, and proven to be cancer by direct biopsy, the size of the "hypoechoic area" is also useful in estimating the volume of the cancer. Unfortunately, both the finger and the ultrasound are subjective examinations. The level of the serum PSA, when corrected for age or size of an enlarged prostate due to benign growth of the gland, combined with the amount and spatial separation of the cancer in the six systematic biopsies, is the most objective and best measurement to estimate the size of the cancer. The Gleason grade (the architectural pattern of the cancer in the tissue) is also important in estimating the size of the prostate; there is a strong correlation between higher grades (Gleason grade 4 and 5) and larger cancer volumes.

    • b. Positive surgical margins as a determinant of success or failure. The second cause of failure of radical prostatectomy to cure the patient (other than underestimating the volume and grade of the cancer) occurs when the surgeon cuts into the cancer of an otherwise curable tumor during surgical excision of the prostate. This can be determined a few days after the operation by careful examination of the excised prostate by the pathologist for areas where surgical ink applied to the outside of the prostate is found microscopically to rest on cancer cells within or just outside the capsule of the gland. This finding is referred to as a positive surgical margin, as discussed earlier.

      Performing the "nerve-sparing" operation to preserve erectile function postoperatively, increases the chances of cutting into cancer cells (9). Most patients are unaware that the nerves for erection are not separate from the prostate in that they are enclosed in a sheath that surrounds and is closely adherent to the capsule of the gland. To preserve the nerves, this sheath, called the lateral periprostatic fascia, must be incised and the nerve dissected away from the gland. Half of all cancers that escape from the prostate follow the spaces that surround these nerves (10). Our group at Stanford, based on exacting detailed study of hundreds of radical prostatectomy specimens, has argued since 1988 that the nerve-sparing operation exposes the patient to a serious risk of leaving cancer cells in the patient because the fascia closely surrounding the prostate must be removed in efforts to preserve these nerves (8). Reports on the incidence of positive surgical margins vary widely, but the Johns Hopkins' group who is aggressive at sparing the nerves for erections, has published the highest rate of positive surgical margins--48% (11). Our Stanford rate, where we reserve the nerve-sparing operation for young men and even then only on the side opposite to the cancer, is 18% (12).

      Radical prostatectomy is not an easy operation to perform. I do not know any experienced surgeons who would not like to do their first 100 operations again. In addition, if the surgeon is not backed by a careful and detailed pathologist who examines the excised specimen with great care, he is excluded from the opportunity to learn what he is doing wrong. As a simple example, after the specimen has been heavily inked on its outer surface, the pathologist who only cuts sections for examination at 1-cm intervals has far less chance of finding ink resting on cancer cells than the pathologist who examines the prostate at 3-mm intervals. Thus, the educational process for evolving better surgical techniques and thereby a better chance of curing the patient depends on both the surgeon and his pathologist.

    • c. Changes in quality of life after prostatectomy. As important as it is for the patient to understand his chances of a cure from radical prostatectomy, it is equally important that he fully understand the consequences of removing the prostate. The most feared is the threat of urinary incontinence. I have recently reviewed our results in all men operated at Stanford who are at least 18 months after surgery. Eighty percent of all men are dry and wear no protective pads of any type. Five percent have no urinary control and are totally incontinent. The remaining fifteen percent use some protection in their underwear, either tissue or small pads, especially when physical activity is substantial--such as gardening, golfing, tennis, etc. Realizing that urinary incontinence is the worst potential consequence of radical prostatectomy in terms of both self-image and inconvenience, I have developed in the past two years at Stanford an operation that is simple, requires no artificial sphincters, pumps or injection of foreign materials, and requires only an overnight admission to the hospital. While my longest follow-up is only two years, we believe that this development should offer great comfort to the patient who faces a 20% possibility of some degree of urinary incontinence following radical prostatectomy. A recent publication based on interviews with 824 randomly selected Medicare patients from the files of the Health Care Finance Administration found that after radical prostatectomy over 30% of patients were wearing pads or clamps and 40% lost urine upon coughing or when their bladders were full (13), indicating that patients over 65 years old, operated upon by many different surgeons, may have incontinence rates that exceed our 20% at Stanford.

    The second consequence of radical prostatectomy for patients relates to their sexuality. The critical point for every man to realize is that radical prostatectomy will not alter the quality of his orgasms even in the absence of an erection. This observation means that both nerve bundles which control erection can be removed in an effort to encompass all of the cancer without sacrificing orgasmic function. Eighty percent of our patients, including all those in whom we removed the nerve bundles, tell us that the quality of their orgasms is identical to that before surgery; 10% observe that the orgasm at climax does not last as long as before surgery, but 10% state unequivocally that the climax is far better than before surgery. Thus, regardless of whether the nerve bundles ar saved or not, orgasmic function is always preserved. Because of these observations, we prefer to perform a more complete radical prostatectomy in a major effort to cure the cancer by taking all of the fascia intimately surrounding the prostate and nerve bundles rather than run the risk of leaving behind residual cancer cells.

    Men considering radical prostatectomy should examine reports indicating a high success rate for the nerve-sparing operation very carefully. These reports in the literature are based on the answer to only one question: have you had successful intercourse with vaginal penetration at least once in the past year? While the frequency portion of this question is bad enough, what is not assessed is the quality of sexual intercourse. For reasons unknown, unless the man is very young, the quality of sexual intercourse in terms of the erection--even when both nerve bundles are spared--is rarely as satisfactory compared to the quality prior to radical prostatectomy. Our numbers at Stanford, assessed by a personal telephone call by a health care worker unknown to the patient, indicate that among men sexually active before surgery, only 30% have "successful intercourse" if both nerves are saved and 15% if one nerve is saved. Fully one-half of these patients considered the quality of their sexual encounter unsatisfactory in comparison to the quality prior to surgery. While it is true that a few young men have excellent and frequent quality erections after nerve-sparing surgery, they are not very many.

    Since orgasmic function is preserved when both nerve bundles are excised with the prostate, and since the quality of the erections are rarely satisfactory even when both nerves are saved at surgery, it simply does not make sense to risk surgical failure by cutting the nerve bundles out of the prostate. After surgery, when the patient has achieved urinary continence, he needs only to select one of several available mechanisms to produce an erection sufficient for vaginal penetration. These options range from penile implants, which are very satisfactory in 95% of patients, to more conservative solutions such as penile injections or vacuum pumps. The important observation is that a man contemplating radical prostatectomy does not need to fear any change in orgasmic function, but will need some help with his erections, if he wants the same quality of sexuality as was present before surgery. This would not appear to be a serious compromise in return for a better chance at surgical cure of the prostatic cancer. Indeed, many of our patients who were very sexually active before surgery feel that their sexuality is even better after surgery, and especially so if they choose penile implants.

  2. Radiation of the Prostate

    When I came to Stanford in 1961 and met Dr. Malcolm Bagshaw in the Department of Radiation Oncology, I decided to join his protocol and irradiate most prostate cancer patients. Because of the long history of early prostate cancer (the slow doubling time), and because PSA was not available to us until early 1985, nearly 25 years had passed before I recognized the serious limitations of radiation therapy. The prostate often became impalpable on rectal examination after irradiation. It was not until the advent of transrectal ultrasound in 1987 that we quickly learned that the prostate was indeed present and often positive for cancer when transrectal biopsies under ultrasound guidance became available. But it was really PSA that told the true story. When we recognized in early 1985--a full year before PSA became available on the market-- that the serum level of PSA was proportional to the volume of cancer within the prostate (14), Dr. Bagshaw and I began collection PSA levels on every patient whom we had irradiated or were planning to irradiate. In December 1993, we published the longest follow-up based on serial PSA levels in irradiated patients in the world's literature (15). These results showed that irradiation cured 20% of patients; they all had PSA levels less than 1.0 ng/ml (the equivalent of the Hybritech assay) at an average follow-up of nine years after irradiation. Much more worrisome, however, was the observation that the remaining 80% of patients had a steeply rising PSA with an average doubling time of 15 months for clinical stage B cancer (those tumors thought to be confined to the prostate) and 7 months for clinical state C cancer (tumors thought to be outside the prostate but within the field of radiation). Since their original doubling times for PSA before irradiation had to be substantially slower(3), we raised the question of whether irradiation converted the 80% who failed therapy into a faster-growing cancer.

    Because of these observations, we do not believe that irradiation of the prostate--by any technique--is currently justified until such time as the 20% who appear cured can be identified and clearly separated from the 80% of failures who may be made worse by the irradiation.

  3. Hormonal Therapy

    It has been over 50 years since Dr. Charles Huggins' Nobel Prize-winning discovery that removal of the testes (orchiectomy) prolonged life in men with prostate cancer that had spread to the bone (clinical stage D2 cancer). Based on 50 years of experience, we now know that if hormonal therapy is started at the time of metastases to the bones, about 10% of patients will live at least 10 years, 31% will live 5 years, and 50% live only 3 years. The smaller the number of bone metastases on the nuclear bone scan the better the prognosis. For men who prefer not to have their testes removed, monthly injections of a hormone that causes the testes to stop making the male androgen, testosterone, is equivalent to orchiectomy. However, because about 5% of testosterone comes from the adrenal glands (small hormone-secreting glands that sit on top of each kidney) anti-androgen drugs are available that prevent testosterone secreted by the adrenal glands from stimulating the cancer cells. This combination therapy is called "complete androgen blockade" or better "combined androgen deprivation". In the presence of minimal metastases to the bones, it has been shown that the combined form of therapy delays progression of the disease and can add as much as two years, on average, to survival from prostate cancer. However, this evidence of substantial prolongation life in the presence of minimal bone metastases was based on only 41 patients in each arm of the study and awaits confirmation with larger numbers of patients.

    There is evidence that the earlier hormonal therapy is started, the longer life is extended. Consequently, there is substantial merit to starting men who have cancers too large to cure by radical prostatectomy on early hormonal therapy. The side effects of hormonal therapy are not serious, but sometimes bothersome. The include "hot flashes" (similar to what women experience with menopause), some breast enlargement (usually not bothersome, but preventable by pre-hormonal irradiation to the breast,) and varying degrees of erectile impotency. Surprisingly, many men are able to continue sexual intercourse during hormonal therapy, especially with ancillary help with their erections. Long-term hormonal therapy is best achieved with orchiectomy and an oral anti-androgen. As with all therapeutic efforts in prostate cancer, serial determinations of PSA at 6 to 12 month intervals monitor success or failure with about 95% accuracy. If PSA starts to rise or symptoms develop in men on combined androgen deprivation, the anti-androgen should be stopped. For reasons unknown, stopping the anti-androgen can reverse the rise in PSA and even relieve symptoms in some men for at least a few months.

  4. Cryosurgery

    The credit belongs to Dr. Doug Johnson at the M.D. Anderson Hospital in Houston and to Dr. Jeffrey K. Cohen at the Allegheny General Hospital in Pittsburgh (16) for reviving cryosurgery (surgical freezing) of the prostate. Under anesthesia, five freezing-probes are placed into the prostate through the perineal skin just above the rectum. Using rectal ultrasound to follow the "iceball", the prostate is progressively frozen. A tube is placed into the bladder through the lower abdomen to control urination until such time in the postoperative period when the bladder can be easily emptied by normal voiding. The patient is hospitalized for one or two days at the most.

    Unless the entire prostate can be frozen right through the capsule that surrounds it (cancer is invariable very close and usually abuts the capsule), including the neck of the bladder and the most distal extent of the prostate at the urethral sphincter, cryosurgery is highly unlikely to be as curative as radical prostatectomy. Also, since the posterior capsule of the prostate abuts the anterior rectal wall, the danger of rectal injury will always be present if efforts to freeze the entire prostate are made. When we first investigated this modality three years ago, we turned it down on the basis that it was unlikely to be curative. However, since about half of all radical prostatectomies are failing because the cancer is too large, cryosurgery may be an excellent alternative for those cancers larger than 6cm3. Not only would cryosurgery appear suitable for large clinical stage B cancers, but it is also suitable for small stage C cancers (those tumors felt to be outside the prostate on rectal examination).

    In summary, it is far too early to know whether cryosurgery will cure any patients, but I believe it will be very few based on what we have learned about the spread of prostate cancer from our exacting studies on radical prostatectomy specimens at Stanford. However, it clearly represents an alternative therapy for reduction of the cancer mass with minimal morbidity to the patient. Cryosurgery appears to be a better alternative than irradiation therapy since it should not make the residual cancer cells more aggressive. Stanford University Hospital will offer cryosurgery this summer for those patients whom we believe to be incurable by radical prostatectomy.

  5. Chemotherapy--Hope for the Future

    Effective chemotherapeutic agents would change virtually every aspect of prostate cancer as we know it today. Unfortunately, there are no really effective agents known to cure the patient. However, we are making great progress and there is substantial reason for hope. Dr. Donna Peehl in the Department of Urology at Stanford, after five years of painstakingly difficult research, became the first person to solve the problem of how to grow adult human prostate cells in tissue culture, both cancerous and benign. We now maintain a large number of cancer strains from the many prostates removed at Stanford. These cancer cells are used to test 50 potential chemotherapeutic agents sent to us weekly by the National Cancer Institute. We use three different cancer cell strains, each derived from a cancer of different malignant grade, to test these potential chemotherapeutic agents. The average response of these three prostate cancer cell strains to five different concentrations of each potential chemotherapeutic agent is compared to the responses of eight other types of cancer cell lines (breast, colon, lung, etc.) performed at the National Cancer Institute. The National Cancer Institute then chooses compounds for further laboratory testing by selecting:

    1. those compounds that kill only our human prostate cancer cells and not the other cell lines tested back at the National Cancer Institute and

    2. those compounds that kill our prostate cells at extraordinarily low concentrations.
    Using these appealing criteria to select potential new chemotherapeutic agents, we have found 300 such compounds among 3,000 we have tested at Stanford in the last three years. These selected compounds are then further screened in animals at the National Cancer Institute. Ours is the only prostate cancer drug screen in existence today. It is widely recognized that this type of testing with representative human cell cultures is a necessary first step in drug development. While there is a lot of work ahead to select the best of these 300 potential chemotherapeutic agents for prostate cancer, there is at least now for the first time a solid basis for some optimism.

Concluding Remarks

Because 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

REFERENCES

1. Stamey TA, Freiha FS, McNeal JE, Redwine EA, Whittemore AS, Schmid H-P. "Localized prostate cancer: relationship of tumor volume to clinical significance for treatment of prostate cancer." Cancer Supplement) 1993;71:933-38.

2. Seidman H, Mushinski MH, Gelb SK, Silverberg E. "Probabilities of eventually developing or dying of cancer." CA Cancer J Clin 1985;35:36-5.

3. Schmid H-P, McNeal JE, Stamey TA. "Observations on the doubling time of prostate cancer. The use of serial prostate-specific antigen in patients with untreated disease as a measure of increasing cancer volume." Cancer 1993;71:2031-40.

4. Dietrick D, McNeal JE, Stamey TA. "Core cancer length in ultrasound-guided systematic, sextant biopsies: a preoperative evaluation of prostate cancer volume." Submitted to Journal of Urology (1994).

5. Oesterling JE, Martin SK, Bergstralh EJ, Lowe FC. "The use of prostate-specific antigen in staging patients with newly diagnosed prostate cancer." JAMA 1993;269:57-60.

6. Dalkin BL, Ahmann FR, Kopp, JB. "Prostate specific antigen levels in men older than 50 years without clinical evidence of prostatic carcinoma." Journal of Urology 1993;150:1837-9.

7. Stamey TA, Graves HCB, Wehner N, Ferrari M, Freiha FS. "Early detection of residual prostate cancer after radical prostatectomy by an ultrasensitive assay for prostate specific antigen." Journal of Urology 1993;149:787-92.

8. Stamey TA, McNeal JE, Freiha FS, Redwine EA. "Morphometric and clinical studies on 68 consecutive radical prostatectomies." Journal of Urology 1988;149:1235-41.

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