Prostate cancer is the second leading malignancy of men in the United States; wherein approximately 300,000 cases are diagnosed and 41,000 men die annually. It is second only to lung cancer in terms of male cancer deaths. Although this disease can be treated effectively when it is confined to the prostatic capsule at time of detection, it is beyond effective treatment in patients with advanced disease.
Knowledge for the treatment of prostate cancer began to evolve from epidemiological studies as long as five to six decades ago. In 1936, Zuckerman noted the findings of a German pathologist who reported on the low incidence of prostate disease in a Russian sect who were ritually castrated at the age of 35. In 1944, Moore reported on a study of 28 prostates obtained from patients castrated or hypopituitary before age 40 and lived to be 55 or older. He found no evidence of prostatic hyperplasia or prostate cancer in the serial sections of any of these prostates and stated “there is not a single instance in the literature of the occurrence of carcinoma of the prostate in a eunuch or true eunuchoid.” More recently Jie-ping et al reported on the prostate exams and clinical evaluation of 26 eunuchs from a dynasty in Beijing. In 21 of the patients, 18 castrated postpuberty, the prostate was nonpalpable, and in the remaining 5 it was very small, 1 to 2 cm. There was no evidence of prostate cancer in any of those prostates.
In a classical study in 1941, Huggins et al demonstrated the beneficial effect of castration on patients with advanced prostate cancer thereby establishing the concept of androgen dependence of this disease. They reported clinical remission in 80% of patients with advanced metastatic disease with surgical castration or medical castration with estrogen therapy. A 1960 study by Emmett et al. showed that these dramatic remissions were followed by a 5-year survival rate of 20% as compared to 0% in placebo or untreated patients. Later Dr. Charles Huggins won the Nobel Prize for his accomplishments in prostate cancer research.
Huggins’ experiments demonstrating androgen dependence of prostate cancer led to the concept of hormonal management of this disease. In the last five to six decades, hundreds of studies were conducted in an attempt to elucidate the exact mechanism by which androgen withdrawal induces regression of prostatic cancer and more importantly, the cellular defects which eventually lead to the loss of androgen dependence and finally the death of the patient.
Physiologic Basis for the Hormonal Management of Prostate Cancer
Androgen Metabolism In The Prostate
It has been known for several decades that prostatic neoplasms do not occur in males who are castrated prior to puberty and that androgens are involved in the etiology of prostatic neoplasms. There were several significant new developments in the 1970s which contributed to the development of new strategies for the management of metastatic prostate cancer. It was shown that testosterone, secreted by the testis, is metabolized to dihydrotestosterone (DHT) within the prostate cell. his transformation of testosterone to DHT is mediated in the prostate by the 5areductase enzyme, later shown to be the 5areductase type 2 isozyme. This factor gained further significance in the light of a later study by George et al at the molecular level which suggested that prostate growth is controlled by a feed-forward mechanism by which trace amounts of DHT induce the proliferation of 5areductase, thereby increasing DHT synthesis and triggering a positive developmental cascade. Other investigators demonstrated that DHT, produced in the prostate, forms a strong bond with the androgen receptor (AR) protein and that this high-affinity bonding with AR protein is basic to its function as the principal androgenic hormone in the prostate. These studies provided a framework for understanding the concept of androgen-mediated action at the cellular level by translocation of the androgen receptor-steroid complex into the cell nucleus where it was bound to the nuclear DNA. With this understanding of androgen metabolism in the prostate was born a new approach aimed at blocking the hormonal factors considered important in prostate cancer.
Studies which further lend to the importance of the 5areductase type 2 isozyme and characterize DHT as the principal androgenic hormone were reported by Fratianni and Imperato-McGinley. This syndrome is caused by a deficiency of this isozyme in the prostate and hence to a deficiency of DHT and is characterized by male pseudohermaphroditism at birth. Affected adult subjects have small nonpalpable prostates, decreased facial hair, and no evidence of male pattern baldness, attesting to the DHT dependency of this phenomena. They have demonstrated the male inheritance to be autosomal recessive and attributable to a defect in the 5areductase 2 gene.
Anterior Pituitary/Hypothalamic Interrelationship
The follicular stimulating hormone (FSH) and luteinizing hormone (LH), secreted by the anterior pituitary, have specific gonadotropic effects on the testis. FSH promotes spermatogenesis and has no known role in prostate cancer. Luteinizing hormone, on the other hand, stimulates testicular Leydig cell secretion of steroids stimulating testicular testosterone production. Pituitary LH release is regulated by the release of luteinizing hormone-releasing hormone (LHRH) from the hypothalamus. Hence LH stimulates testosterone production by testicular Leydig cells and in turn testosterone regulates both LH and LHRH release by negative feedback mechanisms.
Under the influence of LH, cholesterol from the plasma pool of low density lipoproteins is converted to pregnenolone. The latter is converted to testosterone through a series of steps:
The four enzymes involved in this series of transformations are:
- 3bhydroxysteroid dehydrogenase
- C17-C20 lyase
- 17bhydroxysteroid oxidoreductase in the biosynthesis of testosterone from pregnenolone.
- A later study by the same group on the analysis of human spermatic vein blood
Studies by Lombardo et al demonstrate that the 4-ene pathway predominates demonstrated that testosterone and androstenedione are the major steroid hormones elaborated by the human testis, the ratio being approximately 3 to 1.
Androstenedione and dehydroepiandrosterone (DHEA) are considered the principal androgens secreted by the adrenal. While androstenedione is quantitatively converted to testosterone by human testicular tissue, there is no evidence that DHEA is converted to androstenedione or testosterone by human testicular tissue.
Labrie et al suggest that the adrenal androgens, androstenedione and DHEA, are converted to testosterone in the prostate cell. Geller et al have contributed some supporting evidence for the importance of adrenal androgens by demonstrating that orchiectomy decreases DHT levels in prostate tissue by only 60%. However, clinical evidence suggests that adrenal androgens play a minor role in prostatic cancer.
Transition of Prostate Cancer from Androgen Dependent to Androgen Independent
Transition of Prostate Cancer from Androgen Dependent to Androgen Independent Several potential mechanisms have been suggested for the relapse of prostate cancer after conventional hormonal therapy. The clonal selection model of Isaacs suggests that androgen withdrawal would result in death of androgen dependent cells which would eventually be replaced by androgen independent cells. This model assumes that prostatic carcinoma is a heterogeneous tumor composed of clones of androgen dependent and androgen independent cells. Other possible mechanisms for the loss of hormonal dependency are loss of androgen receptor expression, androgen receptor mutations and loss of anti-oncogenes.
Hereditary and Genetic Aspects of Prostate Cancer
Multiple incidences of cancer within a patient’s family is termed familial clustering and could be caused by shared environmental factors or inherited genes within the family. Dr Patrick Walsh and his colleagues have studied and defined familial prostate cancer and have reported that the gene associated with inherited prostate cancer segregates as a Mendelian autosomal dominant gene. This gene can be inherited from either the mother or father, and being a dominant gene, the person inheriting this gene will develop prostate cancer in most cases. Early onset of the disease is often the case in familial cancers.
Management of Prostate Cancer
The devastating revelation to a man that he has prostate cancer brings fear and uncertainty to his life, threatening his very existence. This anxiety, shared by family members, starts to ease as treatment begins and as the patient gains knowledge and understanding of prostate cancer. The physician shares a major responsibility in helping the patient understand and cope with his disease. He must guide his patient through the necessary diagnostic and staging tests required to determine the exact status of his disease. Once staging of the prostate cancer for the patient is determined, the physician must outline in detail the treatment options and the advantages and disadvantages of each treatment option. To gain a better understanding of prostate cancer, patients should be encouraged to familiarize themselves with the literature relative to this disease which is readily available through the American Cancer Society (404-320-3333) and the National Cancer Institute (1-800-4-CANCER).
Detection and Staging of Prostate Cancer
Although prostate cancer is a disease of the aging, and men over 50 are at greater risk, younger men can develop the disease as well. The prostate is a walnut-sized gland which surrounds the urethra and its main function is to produce seminal fluid. This fluid is squeezed into the urethra during a man’s orgasm, mixing with sperm and other substances from the seminal vesicles and vasa deferentia. This mixture of sperm and seminal fluid is carried through the urethra and out the penis during ejaculation.
In the early stages of prostate cancer, when the cancer is confined within the organ and therefore localized, there are no symptoms. Only when the tumor becomes large enough to press on the urethra and block urinary flow, do symptoms occur. This symptom may be an indication that the cancer has spread beyond the prostatic capsule. Localized prostate cancer is one which has not spread beyond the prostate but, left untreated, will grow in time and metastasize, increasing the risk of death.
The rate of growth and spread of prostate cancer varies from one individual to the next, generally advancing more rapidly in men diagnosed at early age. Older men, for example over 80 years of age and diagnosed with prostate cancer, will most likely die of other causes before the cancer becomes clinically significant. In any event, early detection of prostate cancer is the key to successful treatment and cure of the disease. Several tests are necessary to detect prostate cancer and to determine the stage of the disease.
PAP (Prostatic Acid Phosphatase)
The first tumor marker for prostate cancer was acid phosphatase described by Gutman and Gutman in 1938. The identification of PAP in the 1950s as a unique prostatic isoenzyme increased its specificity as a tumor marker. Elevated values of PAP were accepted as confirmatory evidence of metastatic disease. The later development of more sensitive radioimmunoassays cast doubt on the specificity of PAP. With the advent of PSA, the use of PAP as a diagnostic test for prostatic cancer was virtually abandoned.
PSA (Prostate-Specific Antigen)
The PSA test has gained increasing notoriety in the 1990s as the routine test to be performed to detect prostate cancer. PSA stands for prostate-specific antigen and is a protein first shown by Wang et al in 1979 to be elaborated by the prostate gland. The primary structure of PSA was first determined in 1986 by Watt et al who showed that PSA is a single polypeptide chain containing 240 amino acid residues. PSA has become the tumor marker of this decade for prostate cancer; 2000 articles having been published in the medical literature about this polypeptide which is produced primarily by the epithelial cells of the prostate.
Although PSA is considered a good tumor marker for prostate cancer, it is not entirely specific for this disease. The physician must exercise caution in interpretation of PSA values since PSA elevations are common with diseases of the prostate other than cancer, including benign prostatic hyperplasia, acute or chronic prostatitis and prostatic infarction. Since the upper limit of normal for PSA is 4 ng/mL and since patients with a PSA value between 4 and 10 ng/mL represent the group of greatest interest for organ-confined or localized prostate cancer, other diseases of the prostate must be ruled out in making a diagnosis of prostate cancer.
DRE (Digital Rectal Examination)The DRE is a simple test by which the physician can examine the periphery of the prostate for nodular masses. Many localized cancers are detected with DRE especially when used in conjunction with PSA. Both the American Urological Association and the American Cancer Society recommend an annual digital rectal examination (DRE) and a serum prostate-specific antigen (PSA) for men who are 50 or older and for men 40 or older who are either black or have a family history of prostate cancer.
BiopsyPositive findings in either the PSA or DRE, or both, would suggest the need for a biopsy. A fine needle biopsy of the suspected area of the prostate is performed under guidance of transrectal ultrasonography (TRUS) and the aspirated tissue examined under the microscope by a pathologist. Only a positive biopsy can definitely confirm the presence of prostate cancer.
The pathologist who examines the tissue will grade the tumor by Gleason score, a system commonly employed for indicating tumor aggression. Gleason scores range from 2-10. A Gleason score of 2-4 indicates low aggressiveness, 5-6 moderate aggressiveness and 7-10 indicates an aggressive tumor.
Based on the results of the DRE, PSA and biopsy, it may behoove the physician to recommend one or more visualization procedures to determine whether the cancer has spread to other parts of the body. The recommended visualization procedures include chest x-ray, lymphangiogram, bone scan, computed tomagraphy (CT), intravenous pyelogram (IVP) and magnetic resonance imaging (MRI).
Staging Of Prostate Cancer
It is important to decide what treatment, if any, is appropriate for the patient under scrutiny. Utilizing all the analytical data gathered on a patient, the size of the tumor and degree of metastasis, if any, are estimated. One of two staging systems may be used, the TNM system or the ABCD system. A comparison of the two systems is shown in the following figure.
TNM and ABCD Staging Systems
Treatment of Prostate Cancer
Localized or Organ-Confined Prostate Cancer
There are 3 options acceptable to the American Urological Association for the treatment of localized or organ-confined prostate cancer, that is, patients with a positive diagnosis and clinically staged T1 and T2. The three options are radical prostatectomy, radiation therapy, surveillance, in order of decreasing desirability.
For newly diagnosed prostate cancer in a younger man with a life expectancy of greater than 10 to 15 years, radical prostatectomy represents one of the best available treatment options today. It is a one-time procedure that carries the highest probability of prostate cancer cure in its early stages and the best possibility for life extension. The two acceptable forms of radical prostatectomy are radical retropubic prostatectomy and radical perineal prostatectomy.
Radical Retropubic Prostatectomy
The main benefit of radical retropubic prostatectomy is that it will remove all of the tumor if it is truly localized, and offers the patient a high degree of probability that he will be free of prostate cancer for the rest of his life. The main disadvantage of this procedure is the risk of complications from the operation. The operation requires hospitalization for several days and the patient leaves the hospital with a catheter which usually must remain in place for 10 to 21 days. This procedure carries a high risk of impotency, as high as 50%, which varies with the patient’s age and health, the stage of the cancer, and the surgeon’s skill. The second major risk of this procedure is urinary incontinence, most notably “stress incontinence” and to a lesser degree “severe incontinence.” Other less common complications include excessive blood loss with a routine need for blood transfusion, pulmonary embolism, bladder neck contraction, urethral stricture, abdominal hernia, and need for postoperative narcotics for pain control.32 Death following surgery is close to the zero percent level.
Recent advances in surgical technique by Dr. Patrick C Walsh at Johns Hopkins University have significantly reduced the risks associated with radical retropubic prostatectomy. As performed by Dr. Walsh, morbidity is minimal and impotency, urinary incontinence and the need for intraoperative blood transfusions are rare. These improvements in technique have led to the wide acceptance of radical retropubic prostatectomy for the treatment of organ-confined prostate cancer.
Radical Perineal Prostatectomy
Dr. Perry B Hudson is one of the world’s outstanding experts on this procedure. With more than 40 years of experience in perfecting the radical perineal prostatectomy procedure, he has published a complete document, a book and atlas, describing the indications, surgical technique and long term results of this procedure. The numerous illustrations and color photographs, accompanied by clear and precise descriptions, make a classic which should be read by every urologist contemplating a radical prostatectomy for organ-confined prostate cancer. The operation as performed by Dr. Hudson “results in a dissection in which there is very little cutting of tissue, and no significant damage to nerves and blood vessels. The result is a safe operation with minimal blood loss, rapid healing, and the least possible deficit from the patient’s point of view.” The advantages of a radical perineal prostatectomy are no abdominal incision, minimal postoperative discomfort, reduced hospitalization and earlier return to work by the patient. On the topic of pelvic lymph node dissection, Dr. Hudson does not recommend this procedure in the course of treatment for prostate cancer and explains in detail why “there is no rationale for this useless surgical procedure.”
External beam radiation and brachytherapy are the two types of radiation procedures used in the treatment of organ-confined prostate cancer.
External Beam Radiation
The most widely used of the two procedures, treats the prostate with a carefully targeted beam of radiation from a linear accelerator. The advantage of this procedure is that no surgery is required and it can cure prostate cancer in its early stages. The patient does not have to be hospitalized to receive his daily radiation treatment, five days a week, which last only a few minutes over a course of six to eight weeks. Group studies have shown that there are risks associated with external beam radiation of the prostate. Although the risks of incontinence and impotence appear to be somewhat lower than in radical retropubic prostatectomy, the risks of proctitis and cystitis are high, which may be severe and long-lasting in some cases but mild and short-lived in most cases. The major disadvantage of external beam radiation is that it leaves the prostate in place which does not preclude the possibility some foci of cancer is left behind causing relapse in future years.
Brachytherapy is the second type of radiation therapy. It involves a surgical procedure in which radioactive “seeds” are implanted in the prostate. Although the use of brachytherapy has been increasing over the last few years, insufficient long-term results have been reported to reach general conclusions about benefits and risks of brachytherapy. As in external beam radiation, brachytherapy suffers from the same major disadvantage of leaving the prostate in place and the possibility that the cancer may erupt again in the future.
Surveillance is the management of organ-confined or localized prostate cancer of low Gleason score (2-4) with regular examinations and no active treatment. The advantages of low initial cost and no complicating side effects are obvious. Although the medical literature teaches that a patient under surveillance treatment has a reasonably strong possibility of being a prostate cancer survivor for at least 10 years, the major deadly disadvantage of surveillance in a younger man is that the cancer could progress and become incurable. Surveillance could be a costly option for the patient, for if the cancer spreads, it can metastasize to the bones and the patient’s quality of life in his final days could be a painful experience. For the older patient, e.g. an 80-year-old man diagnosed with prostate cancer and other medical problems, surveillance may be a good option for he would likely die of other causes before his prostate cancer becomes clinically significant.
Metastatic Prostate Cancer
In Stage C there is an extension of the tumor beyond the prostatic capsule invading one or both seminal vesicles and adjacent areas including the bladder neck and/or external sphincter and/or rectum. In Stage D there is an extension to a pelvic lymph node and eventually multiple lymph nodes and distant metastases, including the spine. The options available for the treatment of these patients are hormone therapy and chemotherapy.
Hormone therapy is recommended when the disease has spread beyond the prostate and into other areas of the body, e.g. Stages C and D. At this stage of the disease, complete surgical removal of the prostate is not a common procedure. The major goal of hormone therapy is to eliminate the testicular production of testosterone which is converted to dihydrotestosterone by the prostate. The second goal is to block the action of other possible dihydrotestosterone precursor steroids elaborated by the adrenal. Four approaches have been used to accomplish these goals. They are orchiectomy or surgical removal of the testis, estrogen therapy or medical castration, administration of luteinizing hormone releasing-hormone (LHRH) agonists, antiandrogens in combination with orchiectomy or LHRH agonist administration.
Orchiectomy or Surgical Removal of the Testis
First reported by Huggins et al, it demonstrated the beneficial impact of castration with a clinical remission of 80% in patients with advanced metastatic prostate disease. It was later shown that these dramatic remissions were followed by an increase of 20% in the five year survival rate. The obvious advantage of orchiectomy is that it is a relatively simple procedure performed under local anaesthetic, the patient being allowed to go home on the same day of surgery. The obvious disadvantage of this procedure is the difficulty of younger men to accept orchiectomy, a procedure which eventually leads to loss of sexual desire and impotence.
Estrogen Therapy or Medical Castration
Estrogen administration to block testosterone production by the testis was also reported by Huggins et al5 in 1941. This procedure involves the administration of an estrogen, such as diethylstilbestrol (DES), in the form of a pill to block the production of testosterone in the testis. This therapy was found as effective as orchiectomy in producing dramatic reductions in cancer mass and clinical remissions in 80% of the patients. The obvious advantage of this procedure is that it does not involve surgery and its effects can be reversed. The major disadvantage of this therapy was shown by a large scale Veterans Administration multicenter study which demonstrated that estrogen, although effective in advanced prostate cancer, had significant cardiovascular and thromboembolic morbidity rates at the usual effective dose. Other side effects of estrogen therapy include breast growth and tenderness, stomach upset and vomiting.
Luteinizing Hormone Releasing-Hormone (LHRH) Agonists
LHRH agonists are analogues of luteinizing hormone releasing hormone secreted by the hypothalamus. These analogues function by blocking luteinizing hormone release by the pituitary and hence block stimulation of testosterone production by the Leydig cells of the testis. It is a simple method which involves a monthly injection of the LHRH agonist. LHRH agonist administration is as effective as orchiectomy in reducing the circulating testosterone levels to zero. The advantages of this treatment are that it has minimal side effects and does not require surgery. It is as effective as orchiectomy and avoids the side effects of estrogen therapy. The only major disadvantage is requirement of monthly visits to the physician’s office.
Antiandrogens and Combination Therapy
An antiandrogen is a drug which blocks the interaction of dihydrotestosterone (DHT) with the androgen receptor in the prostate. Antiandrogens such as flutamide or its analogues are used in combination with surgical castration or with medical castration with LHRH agonists. This combination therapy increases the effectiveness of hormone therapy because surgical or medical castration eliminates testosterone production by the testis while antiandrogens block androgen receptor linkage of DHT, possibly synthesized from precursors of adrenal origin. Some side effects such as breast enlargement, diarrhea and nausea can be caused by antiandrogens.
Chemotherapy is the use of powerful drugs to attack and destroy the cancer cells. Unfortunately, these drugs circulating through the body destroy not only the rapidly growing cancer cells but also the normal healthy ones. This effect is somewhat minimized by strict control of dose and frequency of administration. This form of therapy is one of last resort and is largely limited to the most advanced Stage D of this disease whereby it has widely metastasized to other parts of the body. There are numerous chemotherapy drugs on the market used alone or in combination with one another. There are many side effects associated with the administration of these drugs including loss of hair, lowered white blood cell counts, increased risk of infection, increase in blood clotting time, nausea and diarrhea.