Carcinoma of the prostate

of the Prostate

Carcinoma Theodore T. Wqpr,

ELSEVIER

THE

Epidemiology Carcinoma of the prostate is the most common cancer in men, accounting for 4396 of new cancer cases, and the second most common cause of male death in the United States (1). In 1997 it is estimated that 3334,500 new cases will be detected, with 41,800 deaths. There has been a 200% rise in the incidence of prostate cancer between 1990 and 1997, which is most likely dlw to inproved detection and reporting. The estimated number of cancer deaths has increased 39% between 1990 and 1997. Demograpliically. prostate cancer incidence and death are highest among ,4frican Americans and lowest among Asians and Pacific Islanders. The true prevalence of prostate cancer is unknown but varies with age. Autopsy series indicate that 30% of males over the age of FjO harbor ~ldenocarcinom~~ of the prostate. Approximately 20% of all U.S. males can expect to develop an invasive prostate cancer in their lifetime.

Etialogy Although the exact cause of prostate cancer is unknown, both genetic and environlnental factors have been implicated. Genetic causes are supported by the disproportionately high incidence of clinical carcinoma in patients with firstand second-degree relatives with the disease (Z), as well as the significant racial differences in incidence (3). Men with an affected first-degree relative have a 2-fold risk and those with an affected second-degree relative have a 1.7-f&1 risk of developing prostate cancer. Men with two affected relatives have a *5-fold risk, and those with three affected relatives have an 1 l-fold risk. Further, if the onset is early. age 55 or below, the risk of a relative’s developing carcinoma of thcl prostate is maximized

0 1997 Elsevier

science lSSN 108%7578/87/$17.00 PII SlO82-7373~~00084-2

Inc.

01110

STATE

MD and Robert R. Bahmon, MD

UNIVERSITY.

DIVISION

(2). Hereditary prostate cancer accounts for approximately 9% of all cases of disease; however, it may account for 43% of the cases detected before the age of 55 years. \;lrlien racial differences are studied, black patients present at a younger age, with a higher stage and grade of disease (3). A black man has an 85% greater chance of being diagnosed with prostate cancer and a 114% greater chance of dying of prostate cancer than an age-matched white man. Epigenetic factors may also play a role in prostate cancer. Migration studies show an increased incidence of prostate cancer in fkunilies who move from a low- to a high-incidence area (4). Dietary fat may be a risk factor (Fi). \‘asectomy has b;en proposed as a potential risk factor; however, based on current evidence, there are insufficient data to prove a casual association (6). Sexually transmitted diseases (STDs) have been studied as an etiology of prostate carcinogenesis, but data have been inconchsive and any associations have been weak. Additionally, there are no convincing data that implicate obesity, alcohol, or tobacco as causative factors in prostate cancer.

Pathology Approximately 95% of all prostate tumors originate from epithelial cells (7). The remainder are ductal carcinomas, which include transitional and squamous cell carcinomas, sarcomas, carcinosarcomas, small cell carcinomas. and secondary tumors of the prostate. The majority of adenocarcinomas of the prostate arise in the peripheral zone of the gland (TO%), and multifocality is common (8). The grading systems for prostate cancer are based on the acinar pattern and the degree of cellular anaplasia (7). The

OF

UROLOGY,

COLUM13US.

01110

most popular grading system in use is the Gleason classification, which assesses the glandular pattern of the tw mor and the surrounding stroma. Tumor grades 1 (most differentiated) to 5 (least differentiated) are recorded, and a Gleason score is generated by adding the grade from the most and next to most prevalent patterns. Scores range from 2 to 10, and higher scores (7 and above) correlate with increased rates of progression (9).

Detection Prostate cancer is often clinically silent. In its earlier stages, an abnormal digital recta1 exam (DKE) may be the only finding on physical exam. However, it has been noted that only 39% of p”tients selected for prostate biopsy on the basis of an abnormal DRE are found to have cancer (10). In addition, while an abnormal DRE can suggest the presence of cancer, a normal DRE does not indicate its absence (11). Serum prostate-specific antigen (PSA) is the second main screening test for prostate cancer. It is the most clinicallvi useful marker for early detection and staging, as well as for following a patient’s response to therapy. The combination of PSA and DRE has resulted in increased cancer detection over either method alone. The major drawback of PSA is that it is not cancer specific. In addition to prostate cancer, elevations in PSA may occur in the presence of infection (prostatitis, cystitis, orchitis, and epididymitis), benign prostatic hyperplasia (BPH), trauma, and recent urologic instrumentation. Neither DRE nor ejaculation will lead to a significantly elelrated PSA ( 11). In order to detect prostate cancer reliably at an early stage, a serum PSA cutoff of 4.0 rig/ml has been established; however, at least 20% of men with biopsy-proven prostate cancer will have a PSA of 0.0-4.0 rig/ml (12). Given this lack of specificity, several methods have been devised to improve

MEMXL

UPDATE

Carcinoma

FOR P~YCHIATI~ISTS

the performance of PSA and thereby reduce the number of unnecessary biopsies without sacrificing sensitivity. Age-adjusted PSA reference ranges have been established to refine the parameters for the at-risk population (13). Additionally, these ranges were desigurd to decrease the biopsy rate in older men, among whom there is a higher prevalence of BPH and incidental prostate cancer. In summary, the range for a man abred 49 and below is 0.0-2.5 rig/ml; from 50 to 59, 0.0-3.5 rig/ml; from 60 to 69, 0.0-3.5 or 4.5 rig/ml; and from 70 to 79, 0.0-3.5 or 6.5. Race-specific PSA reference ranges have also been developed to account for the increased age-adjusted incidence of prostate cancer in .4frican American men (14). For an African American IIMII the ranges are: age 49 and below, O.O2.0 rig/ml, 50 to 59,0.0-4.0 rig/ml; 60 to 69, 0.0-4.5; 70 to 79, 0.0-5.5 rig/ml. PSA velocity is another method of PSA monitoring that can help differentiate between BPH and prostate cancer (15). It is based on the observation that prostate cancer may raise the PSA more quickly than a benign gland that is hyperplastic. A rate of change exceeding 0.75 rig/ml over 1 year has been identified as suspicious for cancer. PSA density, the value obtained by dividing the PSA by the volume of the ultrasound prostate at transrectal (TRUS), has also been helpful in differentiating BPH from prostate cancer (16). Larger glands can produce more PSA, but this elevation in PSA does not imply the presence of a malignancy. PSA density was designed to compensate for this ambiguity. When PSA density is greater than 0.015 in a patient with a PSA of 4.0-10 rig/ml, an occult cancer should he considered. PSA has been found to exist in both free and complexed states (17). The free to serum PSA ratio, or percent free PSA, measures the amount of PSA that exists unbound in the serum, as well as PSA that is complcxcd to alpha-l anticllymotiypsin, the inajor immunodetectable PSA complex. Additionally, prostate cancer tends to elaborate the bound form of PSA. It has been noted that in men with biopsy-proven prostate cancer with a PSA of 2.5-21 rig/ml, 4% have a percent free PSA above 25%, while only 2% of those with BPH have a percent free PSA less than 7% (IS). The actual cutoff value varies from 14%

to 23% free PSA, depending on the investigator and the assay used. Significant trends toward improved cancer detection (90%) and reduced numbers of biopsies (by 31~~) have been noted in men with a PSA of 4.1-10 rig/ml and a normal DRE (19). All of these diagnostic markers are intended to improve the sensitivity and specificity of prostate cancer detection. They guide the urologist toward or away from the performance of a core needle biopsy. This is usually accomplished with the guidance of TRUS, although some urologists prefer to use digital guidance. This procedure can be done safely on an outpatient basis with minimal complications. Multiple biopsies are performed both systematically and in a directed fashion if indicated by the DRE or the prcscnce of a hypocchoic lesion on TRUS. The false-negative rate is ‘i-27% (20). Complications occur in O-3% of patients and include urinary retention, infection, fever, and bleeding. Most patients can expect some hematuria, hematospermia, and blood per rectum for up to 6 weeks following the procedure. TRUS has vastly improved imaging of the prostate, but it is not very helpful in detecting cancer alone. Its major role is in directing the core needle biopsy of the prostate gland. A contentious issue is the appropriateness of screening for prostate cancer. This controversy is based on the observation that prostate cancer often runs an indolent course and, to date, there is no way to determine which tumors will become aggressive and which will remain clinically silent. Advocates of screening believe that early detection and treatment will result in improved survival Opponents maintain that increased detection will result in overtreatment of patients with occult, clinically insignificant disease. While it has been demonstrated that PSA screening results in detection and treatment of lower-volume tumors with lower positive margin rates (21), the ability or inability of PSA-based screening programs to improve survival has not been proven. Current American Urologic Association/American College of Surgeons guidelines for screening take into consideration the patient’s life expectancy. If a patient is between the age of 50 and 70, is in good health, and has a life 166

of. the Prostate

expectancy of IO-15 years, screening by the primary physician with an annual DRE and serum PSA should be instituted. In African Americans or patients with a family history of prostate cancer, screening should begin at age 40. Conversely, in a patient older than age 70 who has other comorbidities, PSA testing should not be performed. For the patient between age 70 and 75 who is in good health, screening should be performed only if the detection and therapy of prostate cancer are desired by the patient. Staging Staging is an attempt to quantify accu rately the extent of a patient’s cancer and allow for proper therapeutic decision making. Staging for prostate cancer is now most frequently based on the TMN staging system, although some physicians still refer to the WhitmoreJewett (ABCD) staging system (Table 1). Stage Tl is nonpalpable, detected by transurethral resection of the prostate (TURP), and clinically organ confined. Stage Tic, not represented in the Whitmore-Jewett system, is currently the fastest-growing stage of prostate cancer (11). Stage T2 is palpable and clinically organ confined. Stage T3 extends beyond the capsule or into the seminal vesicles and is considered locally advanced. Stage T4 is disease outside of the prostate or seminal vesicles. The most common site of distaut metastasis from prostate cancer is the a?iial skeleton. Evaluation of the local mass relies mainly on the rectal examination, which is known to understage extraprostatic involvement (22). Physical imaging studies such as TRUS, computed tomography (CT), and magnetic resonance imaging (MRI) have all been used to evaluate for extraorgan disease, but the results have been disappointing. As a result, none of these imaging studies can be routinely recommended for staging prostate cancer. The evaluation for disseminated disease employs biological markers, pathological grading radiographic and radionuclide imaging, and surgical lymph node sampling. Serum PSA is the major biological marker used in the diagnosis, staging, and monitoring of patients with prostate cancer. PSA levels have been observed to increase as tumor stage and

T. T. Wagner

and

Table

Whitmore-Tewett

1. The

R. R. Bahnsnn

MEDICAL

and TNM

Sta,ging

Al A2

Palpable

Bl B2 B3 Cl c2 c3

Locally

invasive

Tla T2a Tic T2a T2b T2c T3a T3b T3c T4a T4b

DO Dl D2 D3

Me&static

TxNl-3M0 TxNxM 1 TxNxMl-2

volume increase. Other biological markers, such as alkaline phosphatase and acid phosphatase, have shown less benefit in the evaluation and staging of prostate cancer. They are used in selective situations, such as after radiation therapy

or to assess

for bony

metastases.

Studies have demonstrated a correlation between increased PSA and extracapsular

extension,

seminal

vesical

in-

volvement, positive surgical margins, and lymph node positivity (23). Similar observations have been made using the Gleason score obtained at biopsy. PSA and the Gleason score have also been combined to generate nomograms for predicting which patients will have extraorgan disease (24). These modalities are helpful adjuncts in the evaluation of a patient

with

prostate

cancer

and

can

provide reliable information when considering treatment options. Current research on predictive markers for prostate cancer is ongoing and involves detection

of peripheral

cells

of treating

TMN

Whitmore-lewett Nonpalpable

Systems

containing

PSA or a prostate-specific membrane glycoprotein using reverse transcriptase polvmerase chain reaction, oncogene muiation or overexpression, cell adhesion molecules, markers for angiogenesis, and the loss of normal tumor suppresser gene p53 (25). A major site of metastatic prostate cancer is bone, and 75% of these lesions are osteoblastic (26). Bone scintigraphy is the most sensitive method for detecting skeletal metastases. A bone scan is brically obtained in patients with a PSA greater than 10 rig/ml and a Gleason score less than 7 who are candidates for definitive therapy. It is, however, nonspecific. Conditions such as benign

<5% TURP chips >5% TURP chips PSA elevation: (+) TRUS biopsy ~50% single lobe: nodule ~2 cm >50% single lobe Both lobes Unilateral extracapsular extension Bilateral extracapsular extension Seminal vesicle invasion Bladder neck/sphincter/rectum Levators/pelvic sidewall fixation Prostatic acid phosphatase elevation Positive lymph nodes Bony metastates Hormone refractory met. disease

and malignant bone lesions, osteomyelitis, Paget’s disease, metabolic bone disease, degenerative joint disease, and trauma can appear as areas of increased uptake on bone scan. Tomographic radiographs may be helpful to evaluate a suspicious area on bone scan. CT and MRI are used infrequently and selectively. Pelvic lymph node dissection, either by open or laparoscopic techniques, has been used to evaluate the extent of disease prior to offering definitive therapy. The false-negative rate is 3.5-16% (27). The invasive nature of surgical node sampling carries attendant risk and morbidity. The predictive reliabilities of PSA and the Gleason score have resulted in fewer lymph node dissections. These tests report a 7% incidence of positive lymph nodes when the PSA is less than 10 n@ll and a 2% incidence of positive node when the Gleason score is less than 7 (23). Some urologists still employ these techniques when the lymph node status is questionable, as in patients with a PSA greater than 10 rig/ml and a Gleason score greater than 7.

Therapy

166

FOR PSY~HIATHISTS

cancer.

While

the

deci-

sion to not treat may seem a reasonable option in some cases, it must be remembered that prostate cancer will kill almost 42,000 men in 1997. With this fact in mind, the issues of whether to treat prostate cancer, and how to treat it, have evolved into joint decisions between the patient and his physician. These decisions must consider the health status of the patient, his age, his quality of life at present and how this will change under therapy, the stage and grade of his tumor, and the resources of his treating physician. Patients with clinically localized tumors (stage Tl) are candidates for watchful waiting, radical surgery, or external beam radiation therapy. Invcstigational therapies for localized disease inclvde neoadjuvant hormonal therapy pri$r to surgery, cryotherapy, and radioactive seed implantation, also called “brachytherapy.” Locally advanced disease (stage T3) is treated primarily with radiation therapy. Metastatic disease is managed with hormonal therapy. Each of these therapeutic options will be discussed below. Watchful waiting is considered a reasonable option for patients with welldifferentiated tumors with a Gleason score of 4 or less and for those with a life expectancy of less than 10 years. At 10 years in patients with well-differentiated tumors, approximately 20% will develop metastatic disease and 13% will die of their disease (11). Only about 10% of prostate cancer patients fall into this grade category. Radical prostatectomy includes removal of the prostate gland and seminal vesicles. This can be achieved via a retropubic or perineal approach. A pelvic lymph node dissection is often performed simultaneously. Cancer-specific survival for organ-confined tumors is 85-90% at 15 years (11). Between 50% and 60% of tumors are pathologically organ

The prevalence of prostate cancer exceeds the incidence and mortality rates of clinically significant disease. Additionally, with the exception of hereditary prostate cancer, this disease has a slow doubling time (between 2 and 4 years) and occurs in elderly males who often have other significant comorbid conditions (28). These issues, and the morbidity associated with treatment, have led some to question the efficacy

this

UPDATE

confined,

and

the

recurrence

rate

for patients with extraorgan disease or positive surgical margins is 30-40%. The overall mortality associated with the procedure is O.l-0.2%. The serum PSA drops to undetectable levels in patients who are cured, and it serves as a reliable way to monitor a patient’s response to surgery. The major disadvantages associate-d with radical prostatectomy are the risks of impotence (3I%), despite nerve-sparing techniques, and

MEDICAL

UPDATE

Carcinoma

FOR I~YC;HI.ATRISTS

incontinence (3-30%) (29). Postsurgical erectile dysfunction is treatable via peurethral suppositories, nile injection, vacuum erection devices, and penile prostheses. The rate of impotence is influenced by age, with functional recover): seen in 91% of men aged 50 or yolmger and in 25% of men more than 70 years old. The rate of incontinence has decreased with techniques that preserve the bladder neck and urethra. It often takes 12 months for a patient to achieve his maximal degree of postsurgical continence. For the patient who remains incontinent, therapeutic options include penile clamps, periiirethral injection of collagen, and artificial urinary sphincter placement. External beam radiation therapy (XRT) is also offered as a definitive treatment for prostate cancer. While the serum PSA rarely drops to an undetectable level after therapy, the PSA nadir has been shown to correlate with treatment failure. 111 a recent study, patients with a PSA nadir CO.5 rig/ml had a biochemical disease-free rate of 94% compared to 66% in those with a PSA nadir
nary symptoms (14-16%), proctitis (O5%), and impotence (6-15%). Brachytherapy also offers the advantages of one tieatment session. This form of therapy should be considered experimental until long-term data have been compiled. Cryotherapy involves freezing the prostate gland down to -190°C while using TRUS to monitor the process. This form of cytodestruction was originally used in an open technique to treat prostate cancer 20 years ago but was largely abandoned due to the complications. The newer transurethral equipment has resulted in more controlled cooling with fewer complications. Conplications do occur, however, and include urethrorectal and urethrocutaneoils fistula (lo%), impotence (up to 84%), sloughing of urethral tissue, perineal ecchymosis, and penile edema (32). Limited data are available with respect to the durability of the response to cryotherapy, and this modality is still considered investigational. The management of metastatic prostate cancer is palliative and relies ptimarily on hormonal manipulation. This is also the therapy for patients with hiochemical failure after a radical prostatectomy. Prostate cancer has shown sensitivity to circulating androgens, which are produced by the testicles (9O-95%) and the adrenal glands (S10%). Elimination of testicular androgen production can he achieved surgically via bilateral orchiectomy or medically by the administration of lutenizing hormone-releasing hormone (LH-RH) agonists. Leuprolide acetate (Lupron) and goserlin acetate (Zolodex) are the two LH-RH agonists that have approval from the Food and Drug Administration for the treatment of prostate cancer. To block androgen production from the adrenals, antiandrogen drugs are available that bind competitively to the androgen receptor. These agents include flutamide (Eulixen), biclutamide (Casodex, Bical), and nilutamide (Nilandron). When both LH-RII agonist and antiandrogen therapy are used, the procedure is called “complete androgen deprivation” (CAD) or “total androgen blockade” (TAB). Studies have demonstrated a survival benefit of approximately 7 months for patients on CAD compared to those receiving the LH-RH agonists alone (11). When hormonal therapy is startrd at the time of 167

of the Prostate

bone metastases, survival at 3, 5, and 10 years is 50%, 30%, and lo%, respectively (11). The side effects of hormonal therapy include hot flashes, breast tenand impotence with the derness, LH-RH agonists, and diarrhea and possible hepatic dysfunction with the antiandrogens. Androgen insensitivity does develop; this dire prognostic indicator is typically heralded by a rising PSA (33). Recent attention has been given to alternative dosing re,!+mens of hormones in an attempt to lower the PSA and hopefully prolong survival. Withdrawal of antiandrogen therapy in the face of a rising PSA has resulted in a decreased PSA and relief of symptoms in some patients (34). The response is shortlived, approximatelv 5 months, and rechallenged with anGandrogens does not work. In spite of this, patients developing hormone-refractory prostate cancer should be given a trial of antiandrogen witlldrawal. PlIlsed or intermittent hormonal therapy involves discontinuing hormonal therapy when the PSA becomes undetectable and restarting it when the PSA rises to a present level. This type of regimen may also improve the quality of lift for the patient while off androgen suppression; however, the survival data on these alternative dosing regimens are still pending. Patients with metastatic hormone-refractory bone disease may have considerable discomfort seconday to the presence of meklstatir deposits in the axial skeleton. These patients may receive palliative therapy with external beam radiation. Additionally, strontium 89 (Metastron) therapy has been shown to decrease bone pain in 70-W% of men (35).

Summarg Prostate cancer is the most common cancer in men and the second most common cause of male death in the United States. While the biological aggressiveness of an individual tumor may be unpredictable, approximately 20% of all men in the United States develop an invasive prostate cancer. Current screening guidelines include an annual DRE and a serum PSA determination for men with a life expectancy of 10 years or more. In higher-risk poplll;~tions, such as Af?ican Americans or those with a family history of prostate cancer, screening should begin at age

MEDK:AL

40. Patients with an elm2ted or increasing PSA should undergo a TRUS biopsy to rule out prostate cancer. If a cancer is detected. the rmtient should be cliriially staged so &at appropriate therapv can bc instituted. For ormn-confinch

prostate cancer, radical ret&pubic prosand external beam radiotherapv are definitive therapeutic modalities. Radical retropubic prostatectomy offers better long-term survival but is associated with higher rates of incontitatectomy

nence

and

impotence.

Prostate

seed

im-

plantation and cryotherapy are considPatients with ered investigational. extraorgan or metastatic prostate cancer sl~ould receive androgen ablation for disease control. Areas of research in the field of prostate cancer include more accurate clinical staging with molecular markers, improved prediction of tumor aggressiveness and invasiveness, definitive treatment alternatives other than open surgery or external beam radiotherap): and further hormonal nianipulation to improve survival in patients with extraorgan OI- inetastatic disease. References

5. Coffv! DS. I’r-ostatca ca1Icc.r: an overview of’ ill1 incrt,asillg dilernrna. Cn VIcer (Phila.) l993:7l :X80-885. 6. Flesliner N, Fair LVH. Impact of cmironmcnt on urologic cancer. i\c:f.!ii us,-

tlofc Scric5, 1996;15:1rss011 33. 7# Kozloski JM, Grayhack of the prostate. In: Grayhack JT, Howards In Atlrdt 11ntl Pdifh-ic St. Louis: Mosb),, 1996:

JT. Carcinoma Gillenw;ltcr JY. SS, et al. (eds): L!rdog~/, :3rd cd. 1582. orgin of carci-

8. Grayhack JT. Multifocal 1~01318of the prostate. C’i-0l Dig& 1O:lY.

1974;

9. Epstein

JI, Pisov

G, Walsh

lation of pathological gression after radical

PC.

Corrc-

findings with pro-

retropubic prostatectomy. Cnrlcer (Phila.) 1993;71:3FjH293. 10. Brawer MK. The diagnosis of prostate carcinoma. Cnrlrcr (Phila.) 1993;71: 8X9-905. 11. Moul JW. Prostate cancer: Diagnosis, treatment, and experience at one tertiay-cat-c military medical center, 1989 and 1994. Milif Med 1996:161:646-653. 12 Andritrle GI, Catalona WJ. Using PSA to screen for prostate cancer. The Washington University experience. Urd Clit, Nf;ortl? Am 1993:2X(4):647-6,51. 13. Oesterling JE. Cooner WH, Jacobson

SJ, et al. Influence

of patient

strum PSA concentration. North Am 1993;20:671-680. 14. Morgan TO, Jacobson

C’ro[

age on Clin

SJ, ~M&thy WF, et al. Age specific ranges for serum PSA in black men. N Engl J MM! 1996;

335:304-10. 1.5. Carter HB, Pearson JD, Metter al. Longitudinal evaluation of

EJ, et

23.

24.

2.5.

26.

27. 28.

prostate specific arltigen level in mien with and without prostate disease. JAMA 1992;

267:2215-2220. 16. Presti JC, IIovery R, Bha~-gova V, et al. Prospective evaluation of PSA and PSAD in the detection of carcinoma pf the prostate: ethnic variations. J Ural 1996;1~5S(suppl):907-11. 17. Or~trrling JE, Jacobson SJ, Klee GG, et al. Free. complexed, and total serum PSA: the establishment of appropriate reference ranges for their concrntrations and ratios. J C’rol 1995: 154: IO901095. 18. Thicxl HE, Oesterling JE, Wojno KJ, et al. A multicenter comparison of the diagnostic perfonmance of free PSA. Urdog!y 1996:48(6A):45-50. 19. Catalona WJ, Smith DS, Wolf&t RL, et al. Evaluation of percentage of free serum PSA to improve specificity of prostate cancer screening. JAMA 1995;274: 1214-20. 20. Kozloski JM, Grayhack JT. Carcinoma of the prostate. In: Gillenwater JY, Grqhack JT, Howards SS, et al. (eds): In Adult and Perlintv-ic C’v-ology, 3rd ed. St. Louis, Mosby, 1996:1606. 21. Smith DS, Catalona WJ. Nature of prostate cancer detected through PSA based screening. J lid 1994; 1 Yj2: 1732-l 736. 22. Kozloski JM, Grayhack JT. Carcinoma of the prostate. In: Gillenwater JY, Grayhack JT, Howards SS, et al. (eds):

29.

30.

31.

32.

UPDATE

FOR Psmmmms

In Adult rind Pediatric Urology, 3rd ed. St. Louis, Moshy, 1996:1611. Stone NN. Staging prior to definitive treatment of localized prostate cancer. In: Lynch JH (ed): Prostatic Di.sea.sc: ImsighfS nnc/ In~ctllio~rs. Deerfield, IL: Discovery International, 1997:27-32. I’artin AW, Yoo J, Carter HB. Thv usr of prostate specific antigen. clinical stage. and Gleason score to predict pathological stage in men with localized prostate cancer. L’rology 1994;44(4): 5245-529. Maul JW. Molecular markers as predictors of prostate cancel prognosis. In: Lynch TH (ed): Pmsfafic Ui.seax: Intights m~nr! ~nvmxtirms. Deerfield, Discovery Intrrnational, 1997:22-26. Kozloski JM, Grayhack JT. Carcinoma of the prostate. In: Gillenwater JY, Grayhack JT. Howards SS, et al. (eds): 111 Adult nvd Pediatric Crobgy, 3rd ed. St. Louis, Mosby, 1996:1616. Ibid, p 1621. Pettaway CA. Watchful waiting for localized prostate cancer: Pros and cons. In: Lynch JH (ed): I’mstatic Di,st:n.se: Znsight~s cd Innocations. Deer-field, IL: Discovery International, 1997333-40. Lowe BA. Surgical techniques in localized disease. In: Lynch JH (ed): Prostutic Vi.sea.se: Insights and Invwtnlion~. Deerfield, Discovery International, 1997:41-43. Stone NN. Radiation therapy for prostate cancer. In: Lynch JH (ed): Prostatic Disease: lnsigllfs and Inn0c;nfion.s. Deerfield, IL: Discovery International, 1997:44-49. Bagshaw MA. Cox RS. Hancock SL. Control of prostate cancer with radiothrrapy: long-term results. J Urd 1994;152:1781-85. Kozloski JM, Grayhack JT. Carcinoma of the prostate. In: Cillcnwatcr JY, Grayhack JT, Howards SS, et al. (eds): In Adult and Pdintric Urology, 3rd ed.

St. Louis, Mosby, 1996:1690. 33.

34.

35.

Carroll PK. Cryosurgery for prostate cancer. In: Lynch JH (ed): Prmtc~tic Ihmw~ Irrsi&s and Innrmrtinm Deerfield, IL: Discovery International, 1997:56-59. Kelly WK, Scher HI. Prostate specific antigen decline after antiandrogen withdrawal: the flutamide withdrawal syndrome. J CTrrrl 1993;149(3):607-609. Robinson RG. Strontium-89: precursor targeted the]-spy fol- pain of blastic metastatic disease. Cancer (Phila.) I993;72: 3433-3435.