The prostate is a walnut-sized gland at the base of a man's urinary bladder. It surrounds the urethra and is responsible for producing seminal fluid which makes up the majority of semen. Approximately 317,000 men will be diagnosed to have prostate cancer this year and 38,000 will die. Stamey has stated that approximately 40% of men over the age of 50 will show prostate cancer in autopsy studies, although only 8% of these patients will develop prostate cancer clinically, and only 3% will die from the disease. This disparity in growth rates and death rates had lead to the controversy in prostate cancer as to who should be treated and who should have observation only. These statistics are deceiving because the great majority of men who have prostate cancer diagnosed clinically in their lifetime under the age of 70 are at risk to die from their disease. Generally individuals less than age 50 diagnosed to have prostate cancer clinically (by digital rectal exam or elevated PSA) will most likely die from the disease if untreated. At the other extreme, men over the age of 70 will often do quite well with observation or hormone treatments since the rate of growth of prostate cancer often will not progress to a point resulting in prostate cancer death before heart disease or other concurrent diseases will result in death. Because the population is generally living longer, prostate cancer is being diagnosed in a higher percentage of people. Stamey has reported that the growth rate of prostate cancer is astonishingly slow with half the cancers requiring over five years to double in size. Stamey has stated that tumors under 5.5 cm cubed are clinically insignificant, (1.0 cm cubed is about the size of a sugar cube). If a tumor starts out at less than 0.5 cm cubed and the patient is over 70 years of age, generally the paitent will not live long enough to have the cancer increase in size in order to produce a significant clinical problem. However, there are no good preoperatively or nonoperatively ways to estimate prostate cancer size based on today's technology including sonogram of the prostate, CAT scan of the prostate, and MRI scan of the prostate.

THE IMPORTANCE OF EARLY DIAGNOSIS

PSA has greatly increased our ability to diagnose prostate cancer. The number of radical prostatectomies in the United States has increased from 50,000 in 1991, to over 100,000 in 1993. PSA is a serine protease, a glycoprotein secreted by the epithelial cells of the prostate gland. Prostate cancer, as it grows, distorts the architecture of the prostate, spilling PSA into the bloodstream and raising the level of PSA systemically. Chu Wang, in 1979, purified the antigen from prostate tissue and named it prostate specific antigen. Both normal prostate epithelial cells and hyperplastic prostate tissue produce PSA, but not to the degree of malignant prostatic tissue.

Commercial Assays:

Commercial PSA assays measure the glycoprotein in the serum using immuno- assays. It is important that the assay be performed in the same laboratory for comparative purposes over time. Some assays are immunoradiometric and some are enzyme-immunoassays. PSA is age dependent with upper limits of normal for 40-49 year-olds being 2.5, 50-59 year-olds 3.5, 60-69 year-olds 4.5, and 70-79 year-olds 6.5. The importance of the PSA test in early detection is based on establishing a baseline value and doing the PSAs over time on a regular interval, usually one year. Increases in value of over 0.75 ng/ml in PSA in one year should be investigated with sonograms and prostate biopsies.

Clinical vs Latent (autopsy) diagnosis:

It has been demonstrated that patients who have prostate cancer diagnosed by PSA alone with normal rectal exams are at the same risk of death from prostate cancer as patients who are diagnosed with a hard prostate nodule by rectal exam. Other conditions can elevate the PSA including infection, prostate enlargement, or any type of manipulation of the prostate by catheter or cystoscopy. Furthermore, Proscar which is commonly used to shrink the prostate, can reduce the level of PSA by 30-50% and must be taken into consideration when interpreting PSA testing.

PSA Discovery:

In 1990 Christensson et al, discovered that PSA exists in more than one circulating form in the serum. The free PSA (PSA-F), bound PSA (PSA-ACT) and complexed PSA (PSA-MG) are all present in serum. In its complexed form, the PSA-MG is not immunoreactive and is therefore not measured in available commercial assays. Total PSA is generally measured from commercial assays. This is combination of PSA-F and PSA-ACT. PSA-II assay measures both total and free PSA. The percentage of free PSA is lowered in patients with prostate cancer. This test can be ordered as a further screening procedure to delineate prostate cancer from innocent conditions that elevate the PSA. The higher the ratio of PSA-F to total PSA, the less probability of cancer. With a cutoff at 20% of free to total PSA, the ratio for sensitivity to diagnose cancer is 80%, specificity is 49%, with a 95% confidence level. In other words, when the free PSA falls below 20%, the patient is suspect to have prostate cancer. The sensitivity of a test measures the capability of a test to identify the presence of disease. A high sensitivity means very few people with the disease are missed by the test. Specificity is the capability of a test to identify the absence of disease (low false positive) Therefore, the free PSA will pick up most patients with cancer but will also identify some false positives (only 49% specificity). The positive predictive value is the capability of a test to identify patients with disease among all patients demonstrating positive results.

Screening:

Stamey maintains that most prostate cancers can be cured if they are less than 6.0 cm cubed in size, but not greater than 12 cubic cm in size. The usual recommendation is to have a rectal exam and PSA blood test at least yearly starting at age 50, or age 40 if there is a family history of prostate cancer or in African/American males where the risk is higher. The risk of developing clinically important prostate cancer in a man with a close family relative such as father or brother is about twice that of men without a family history of prostate cancer, (16% versus 8%). Benign prostatic enlargement will increase the PSA but only about one tenth as much as the same volume of prostate cancer. In men who have greater than 50 cubic cm of benign prostatic enlargement, PSA produced can result in an elevation of serum PSA that may mask the rise of PSA caused by cancer, especially if the cancer is in the small range. This can complicate the work up and diagnosis of prostate cancer in this group of patients. Fortunately most prostates are in the 25-35 gram size.

Metastatic (Spread) Potential:

No one fully understands how prostate cancer escapes from the prostate gland. All are in agreement that surgical cures from prostate cancer require that the cancer be confined to the prostate before surgery. The volume of cancer (size) and the grade of tumor (appearance of histology) are important in evaluating a man for possible treatment modalities. Prostate cancer is graded 1-5, based on the degree of differentiation of the cancer. This is the architectural pattern of the cancer seen by pathologists. As the cancer increases in size, the grade often increases from 3 to 4 to 5. Grades 4 and 5 are poor prognostic indicators. The Gleason's score is a combination of the two most prevalent grades in a tumor. This is further used to separate patients into low and high risk categories. In general, scores of 6 or less are good because it means they have no grade 4 in their specimen, while 7 indicates a more aggressive, higher grade tumor with some grade 4 being present. While the PSA level, the grade of the tumor and the tumor size are all important prognostic indicators, there is no preoperative test which will absolutely determine whether the cancer is confined or not to the prostate. Unfortunately, there are no preoperative modalities that will absolutely define the exact extent of the cancer or the volume of the cancer in the prostate. Various computer models have been designed based on size of tumor, which is estimated from sonogram and biopsy, PSA level, and grade of tumor, to determine the likelihood of metastatic disease at the time of diagnosis. This helps the physician and patient determine a treatment modality. Generally, PSA values less than 10, prostate cancer volume less than 6 cubic cm and Gleason's score of less than 6 are all favorable prognostic indicators, suggesting that a radical prostatectomy may yield a cure. However, one third to one half of patients who have undergone radical prostatectomy will have a positive PSA 1-3 years following surgery, indicating that they have not been cured of their underlying disease.

TREATMENTS:

Radical Prostatectomy

One of the major considerations regarding treatment besides the volume of the tumor, grade of tumor and PSA level, is age of patient. Generally patients over the age of 70 are not considered good risks for radical prostatectomy. This is because, according to Stamey, over 50% of these men will die of natural causes before they reach 82 years of age. The average life expectancy in 1992 for a 70-year-old man was 82 years. Moreover, the size of prostate cancer in men over 70 years of age, at least in Stamey's experience, tends to be larger and less likely to be cured by surgery. Stamey has pointed out that somewhere between a third and half of patients who undergo radical prostatectomy have a positive PSA 1-3 years postoperatively. This is in spite of the fact that many prostate cancers clinically appear to be confined to the prostate and curable. There is a great discrepancy in volume estimation of cancer preoperatively and actual cancer identified in the prostate following radical prostatectomy. While random biopsies do give some idea of size, ( six random biopsies done appropriately can sample much of the prostate volume), both the finger and ultrasound are very subjective and poor estimates of prostate cancer size. Nomograms have been developed by Oesterling and others, demonstrating the likelihood of metastatic disease based on serum PSA level. Generally levels of greater than 10 have a higher likelihood of risk for metastatic cancer of the prostate. A high Gleason score (Gleason score 7 or higher) also correlates with a higher incidence of metastatic disease. Another concern following radical prostatectomy surgery is positive surgical margins. This means the cancer has extended to or through the surgical margin at the time of radical prostatectomy. Stamey and others have suggested, that attempts to perform nerve sparing operations described by Patrick Walsh do run the risk of incorporating a positive margin. Because of this problem most surgeons do not attempt a nerve sparing operation on the side of the palpated tumor, but try to preserve the nerves on the contralateral or opposite side. Urinary incontinence rates following radical prostatectomy have been reported as low as 5% and as high as 30%. Impotence following radical prostatectomy is age related and also varies from 50% to as high as 85%. Most patients do regain their urinary continence six weeks to six months following surgery. A small percentage of patients, ordinarily in the 5-10% range, may require an external urinary sphincter in order to regain complete urinary control. A critical point regarding sexuality following radical prostatectomy is that the quality of orgasms are not affected, even by the absence of erection. Therefore, most individuals can be rehabilitated with either penile injections or pump devices for inability to maintain erections. The quality of orgasms is generally always preserved regardless of whether nerve bundles are saved or not. Penile implants are generally very satisfactory and can be used in lieu of injections or vacuum pumps if they are unsuccessful. Generally impotence following radical prostatectomy is not as difficult to manage as the complication of urinary incontinence.

Radiation Treatment

Bagshaw's radiation treatment from Stanford, have reported that there is a 20% cure rate from radiation. This is with an average follow up of nine years. Other researchers have reported that at least half the people biopsied following radiation will show positive cancer in biopsy one year following radiation treatment. Radiation is an alternative for patients who are not surgical candidates or who wish to combine hormonal therapy with radiation as a way of slowing down the growth of prostate cancer. Radiation is generally not thought of as a curative procedure.

Hormone Treatment

Hormone therapy is extremely useful for slowing the growth rate of prostate cancer. This is generally reserved for patients older than 70 years of age in which the likelihood of death from prostate cancer is small. It also can be used in conjunction with radiation or surgical therapy. Hormone therapy can take the form of combined androgen blockade (CAB) using a drug such as Lupron or Zoladex to block the pituitary production of LH/RH and subsequent testosterone production from the testicles. This generally is combined with either Flutamide or Casodex, which will block the androgen precursors from the adrenal gland that can also stimulate prostate cancer growth. Orchiectomy can be done in lieu of Lupron and/or Zoladex. The combination of Lupron and/or Zolodex with Casodex or Flutamide is referred to as complete androgen blockade (CAB) or combined androgen deprivation. Studies are underway to see if complete androgen blockade after radical prostatectomy with positive PSA values will also extend life expectancy. Crawford has suggested that at least two years of life can be achieved with combined androgen blockade in patients with advanced prostate cancer (stage D). Studies are underway with lower stage cancer to see if combined androgen blockade delivered at an earlier time period (following radical prostatectomy with positive PSA) will prolong life expectancy. Side effects include hot flashes which are treatable (depo-provera or bellargil-S), some breast enlargement, and generally erectile impotence. It is also possible to cycle antiandrogen therapy in the face of rising PSAs to sometimes drop the PSA in prostate cancer patients.

Cryosurgery

Cryosurgery is still another alternative to treatment of prostate cancer. This type of therapy has not stood the test of time and has not been proven to be as effective as radical prostatectomy. Cryosurgery may be of value in stage C patients (tumors felt to be outside the prostate capsule on rectal exam) in primary cancer treatment.

Chemotherapy

Chemotherapy is being evaluated extensively for treatment of advanced prostate cancer. This is generally reserved for patients with positive bone lesions resistant to standard hormore treatment or rapidly accelerating PSA with positive lymphatic lesions or bone lesions. Vinblastine and etoposide have been found to lower the PSA in advanced prostate cancer in approximately 30% of patients. Ketoconazole has been used as a P450 cytochrom/oxidase inhibitor to also slow the growth of prostate cancer in hormone insensitive or resistant tumors. Suramin is a growth factor inhibitor and has been used in advanced cases of prostate cancer within experimental protocols. Research protocols can be researched through alternative web sites including the National Cancer Institute which publishes researchers names and experimental protocols for advanced prostate cancer in various institutions. Patients can contact their urologists who in turn can contact these researchers to see if they qualify for selected treatment protocols.

Conclusion

While the estimated volume of cancer, Gleason's score, PSA and age can all be used as indicators to make suggestions for treatment of prostate cancer, there is no absolute study or combination of studies which will determine when prostate cancer will metastasize. Prostate cancers that are identified clinically behave quite differently than occult prostate cancers found at autopsy. Basically, patients under the age of 70 found to have significant prostate cancer by PSA or rectal exam and subsequent sonogram/biopsy are candidates for radical prostatectomy for cure, realizing that one third to one half may have a positive PSA following surgery and necessitate further treatment such as radiation or hormone therapy. Patients greater than age 70 or patients with less than a 10 year life expectancy may be treated alternatively, either with radiation therapy alone or radiation/hormone therapy. Simple observation is generally not recommended, even in the older patients, because hormone therapy has such low morbidity and is felt to prolong life. While it will take many years to demonstrate mortality from prostate cancer death is improved by yearly screening with digital rectal exam and PSA levels, it makes exceeding common sense that early diagnosis and treatment will impact the ultimate survival of patients with this disease. The argument that we are overdiagnosing and overtreating prostate cancer has not been born out by clinical studies. A recent study from the Cleveland Clinic suggests that only 15% of patients undergoing radical prostatectomy had low enough volumes of tumor found in the specimen and low enough grade of tumor to not be at risk from ultimate death from the disease.

Disclaimer:

The above material represents a synthesis of 31 years of urology practice plus residency, including many surgeries, patients encounters, and continuing literature reviews. Each patient must educate themselves thoroughly, consult with their Urologist, and make an informed decision regarding treatment.