Prostate cancer: Detection, staging, and treatment of localized disease

Prostate Cancer: Detection, Staging, and Treatment of Localized Disease Steven R. Potter and Alan W. Partin

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ROSTATE CANCER is the most commonly diagnosed cancer and the second leading cause of cancer deaths in American men. More than 184,500 men were diagnosed with prostate cancer in 1998, and an estimated 39,200 men died of their disease. 1 Although the etiology of prostate cancer remains poorly understood, several clear risk factors exist, most notably age, race, and family history. Prostate cancer prevalence increases at a nearly exponential rate after the age of 50 years. Although the histological incidence of prostate cancer is essentially the same across different ethnic groups and in different geographic regions, the clinical incidence varies widely between ethnic groups. African Americans have a higher incidence of prostate cancer at all ages than whites living in the United States? Additionally, the average prostate cancer in African-American men is higher in stage than in white men with the same access to health care. When controlled for stage, mortality from prostate cancer is still higher in African Americans than any other group. The incidence of prostate cancer in Asian men living in the United States is lower than either white or black Americans, although much higher than in Asian men living in Asia? A small percentage of all prostate cancers appear to be inherited by autosomal-dominant transmission of one or several alleles. 4 Investigators estimate that approximately 10% of all prostate cancer, and approximately 45% of all cancer in men younger than 55 years old, is inherited. 5,6 The risk of developing prostate cancer increases markedly as the number of affected family members increases and their age at diagnosis decreases. 4 Etiologic roles may exist for vitamin D, fat intake, and cadmium exposure. 7,8 The case for increasing risk with increasing dietary fat intake appears most compelling. Prostate cancer risk parallels dietary fat intake across 32 countries. 9,1° Means of prostate cancer prevention remain speculative to date. The dominant risk factors (age, race, family history) defy modification or avoidance. However, the enormous differences in prostate cancer incidence between Asians living in the United States and Asians living in Asia suggests that other, probably dietary, influences may be critically important. 11 Finaste-

ride, which blocks the conversion of testosterone to dihydrotestosterone, is currently undergoing clinical trials as a potential preventative agent.12 DIAGNOSIS AND SCREENING

Prostate cancer rarely causes symptoms until locally advanced or metastatic. In conjunction with digital rectal examination, prostate-specific antigen (PSA) measurement provides an effective test for detection of men at increased likelihood of harboring malignancy. Most prostate cancers are asymptomatic and are diagnosed after transrectal ultrasound (TRUS)-guided biopsy is obtained for an abnormal digital rectal examination (DRE) or elevated PSA. 13 Although a minority of men still present with symptoms of locally advanced or metastatic disease, the proportion presenting with these symptoms (bone pain, urinary retention, pelvic pain, obstructive voiding) decreased dramatically between 1973 and 1991.14 Prostate cancer screening, although widely practiced, remains controversial. The American Cancer Society and American Urological Association advocate annual PSA and DRE for men over 50 years of age. 15 Men with positive family histories of prostate cancer or men of African-American descent should initiate annual testing at age 40 years. 16,~7 Proponents of screening point to the availability of effective therapy for localized, but not for advanced disease, and the availability of tests (DRE and PSA) that can detect cancer while still at a curable, localized stage. Opponents of screening point out that prospective randomized trials have not been performed to demonstrate an unequivocal benefit of early detection and definitive therapy. TM Such trials are underway in Europe and the United States, but will likely not have interpretable results for several years. 19,2° Although randomized trials to determine the use

From The Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, MD. Address reprint requests to Steven R. Potter, MD, The Johns Hopkins Hospital, Department of Urology, Marburg 1, 600 North Wolfe St, Baltimore, MD 21287. Copyright © 1999 by W.B. Saunders Company 0037-198X/99/3404-0005510.00/0

Seminars in Roentgenology, Vol XXXIV, No 4 (October), 1999: pp 269-283

269

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POTTER AND PARTIN

of screening are years from completion, strong evidence exists to support screening. 21 Following the introduction of an effective screening test into a previously unscreened population, disease incidence will increase initially before falling as preexisting cases are eliminated from the population. 22 In screening for cancer, a downward stage migration should occur. Finally, if the therapy for screening detected cancers is effective, mortality should begin to fall. In keeping with these basic epidemiological principles, the detection of prostate cancer rose dramatically with the introduction of PSA testing. 23,24Longitudinal studies from Olmsted County, MN, found a 3.4-fold increase in the age-adjusted incidence of prostate cancer between 1983 and 1992. 5 The incidence of prostate cancer has been declining precipitously since 1992 and is now approaching pre-screening incidence ratesY -27 Before the widespread use of PSA screening, only 20% to 30% of prostate cancers were found to be organ confined at surgery. 28 Since the introduction of PSA and DRE-based screening, a downward migration of cancer stage has occurred, such that currently 70% to 80% of prostate cancers are organ confined at diagnosis. 29 Multiple studies have unequivocally shown that prostate cancer detected through PSA screening efforts is more often organconfined than those detected solely by DRE. 3°,31 Finally, prostate cancer mortality in the United States fell 6.3% in 1996. 32 Together, these findings provide strong inferential evidence for the utility of prostate cancer screening. The key elements in the early detection of prostate cancer are DRE and PSA testing. These tests then trigger TRUS-guided biopsy of the prostate for provision of a histological diagnosis. TRUS is not useful as a screening or early detection test outside of its role in directing segmental biopsies. 33,34DRE has both limited specificity and sensitivity. Only about half of abnormalities of the prostate found on DRE represent cancer, whereas DRE misses from 23% to 45% of cancers subsequently found on biopsy obtained for elevations of PSA. 35,36 Despite these limitations, a DRE suspicious for cancer mandates prostate biopsy even in men with normal PSA levels.t3 PSA AND PSA DERIVATIVES PSA is a 33-kDa serine protease that exists in the bloodstream largely bound to endogenous protease inhibitors. Christensson et aP 7 first reported the

presence of different molecular forms of PSA in 1990. Serum PSA is predominantly bound to cxl-antichymotrypsin (PSA-ACT), with a smaller percentage of serum PSA bound to o~2-macroglobulin (A2M). 38 These protease inhibitors exist in the bloodstream at 10- to 100,000-fold the concentration of circulating PSA, ensuring that most circulating PSA exists in bound form (50% to 95% of the immunoreactive serum PSA exists as PSA-ACT). 39 In these complexes, PSA is covalently and irreversibly bound to its respective protease inhibitor and is primarily eliminated from the body by the liver (Table 1). A smaller fraction of circulating PSA exists in an enzymatically inactive, but unbound state (free PSA). PSA-ACT maintains immunoreactivity but is enzymatically inactive, whereas PSA-A2M maintains weak protease activity despite having no exposed immunoreactive epitopes (Fig 1). PSAA2M is thus unmeasured by all current assays. Conventional (total PSA) assays measure both PSA-ACT and a variable, assay-dependent, percentage of free PSA. 4° PSA is produced by both the healthy and diseased prostate, and therefore is organ- but not cancer-specific. Trace amounts of PSA are found in extraprostatic sites, including endometrium and female serum. 4~-43 However, for clinical purposes the prostate can be considered the only source of PSA. 44 PSA elevations produced by benign prostatic hyperplasia (BPH) and prostatitis are potential confounders in the use of PSA for cancer detection. 45 Although production by benign prostate tissue in general, and BPH in particular, lowers the specificity of PSA significantly, prostate cancer is associated with PSA levels approximately 10-fold higher per gram of tissue than levels caused by

BPH.46,47 A major concern associated with the development of PSA testing was the possible detection of large numbers of biologically insignificant cancers. Epstein et a148,49 studied a large series of prostate Table 1. Major PSA Subtypes Detectable in Serum FreePSA Molecular weight (kDa) Enzyme activity Covalently bound to % of Total PSA (healthy men)

Complexed PSA

33 Active Free

100 Inactive cq-antichymotrypsin

5% to 50%

50% to 95%

Major forms of PSA measured by totaJ PSA assays and used in the calculation of percent-free PSA.

LOCALIZED PROSTATE CANCER

271

Form

Free PSA

PSA-ACT

~

Molecular weight

Immunoreactive

~:

30 kDa

Yes

])

100 kDa

Yes

~780 kDa

No

PSA-AMG

Fig 1. Schematic representation of PSA subtypes illustrating PSA-associated proteins and their effect on immunoreactivity. PSA bound to ~2maeroglobulin is not detected by current assays. (Reprinted with permission. TM)

cancers detected solely on the basis of elevated PSA values (stage Tlc), finding that they more closely resemble palpable but organ-confined cancers than the latent cancers found incidentally at autopsy or transurethral resection of the prostate. More than 90% of PSA-detected cancers are biologically significant by tumor volume and tumor grade criteria. 28 As a single test, PSA has the highest positive predictive value for prostate cancer. 13 However, PSA is limited by a lack of specificity within a "diagnostic gray zone" of 4 to 10 ng/mL. Approximately 25% of men with PSA values within this range harbor malignancy, mandating a recommendation of biopsy at enormous economic and human expense. Some 15 million men in the United States underwent PSA testing in 1998, with roughly 15% of those men having an elevated PSA and thus facing the prospect of prostate biopsy. 5° A clear need exists for increased specificity (elimination of some unnecessary biopsies) in the use of PSA for early detection of prostate cancer. The desire for an increase in accuracy of PSA testing has led to investigation of molecular forms of PSA, PSA velocity, and PSA density. Free PSA

A flurry of exciting work over the past decade has characterized a family of molecular forms of PSA and their possible clinical roles. Percent free PSA has emerged as perhaps the most clinically

useful of the molecular forms of PSA, with the potential to provide improvements in the early detection, staging, and monitoring of prostate cancer. In 1993, Christensson et a151 found that the percentage of free PSA was significantly lower in a group of men with histologically proven prostate cancer than in a group of men with BPH. 5~ In using a percent free PSA cutoff of 18%, the investigators found that 95% of the men with BPH and 71% of the men with prostate cancer had percent free PSA values below the cutoff point. Numerous investigators have confirmed the statistically significant decrease in the percent free PSA in men with prostate cancer relative to those with benign disorders of the prostate. 52-55The physiological basis for the consistently decreased percentage of circulating PSA found in the unbound form in the circulation of men with prostate cancer remains unknown. A large study by Catalona et a152 limited to men with PSA values between 4 and 10 ng/mL confirmed the increased specificity possible with use of percent free PSA. Catalona et aP 6 recently reported on the results of a prospective, blinded, multiinstitutional study involving 773 men with normal rectal examinations and total PSA levels between 4 and 10 ng/mL. 56 This is the most definitive study to date documenting the role of percent free PSA in early detection of prostate cancer. The authors found that a 25% free PSA cutoff detected 95% of cancers while sparing 20% of the negative biopsies.

272

Multivariate analysis found percent free PSA to be an independent predictor of prostate cancer risk. They concluded that, in patients with normal rectal examinations and PSA values of 4 to 10 ng/mL, a percent free PSA cutoff of 25% would increase the specificity of PSA testing while missing few cancers. This assay was recently approved by the Food and Drug Administration for use in the early detection of prostate cancer. As data mount that percent free PSA offers improved specificity over the use of total PSA alone in the range of 4 to 10 ng/mL, it also becomes evident that percent free PSA might provide improved sensitivity at total PSA values less than 4 ng/mL. Catalona et al57 studied a population of men with PSA values restricted to 2.6 to 4.0 ng/mL and benign prostates on examination. They found that percent free PSA predicted cancer in this group of patients and that over 80% of the cancers so detected were organ confined. Detection of cancers in men with PSA levels under 4.0 ng/mL is a possible means of increasing the percentage of organ-confined disease, and further work is needed to clarify the role of percent free PSA in early detection of cancer in these men. Other critical factors, including a history of recent prostate manipulation or finasteride therapy, are important for understanding the clinical role of both total and percent free PSA. 58 Prostate biopsy causes elevation of total PSA levels that can take 4 weeks to resolve. 59 Free PSA is more rapidly cleared from the circulation than total PSA, potentially allowing for falsely low percent free PSA levels to be obtained in the post-biopsy period. 6° Total PSA levels are not significantly affected by rigid or flexible cystoscopy, TRUS without biopsy, o r D R E . 61 Although controversial, minor and transitory changes in free PSA have been reported after ejaculation, DRE, and cystoscopy. Finasteride therapy for BPH has a profound effect on total PSA, reducing levels in most men by 50%. 62,63 Total and free PSA levels fall to the same degree, thus preserving the utility of percent free PSA in men taking finasteride. 64

PSA Velocity The change in PSA values over time is the PSA velocity. Carter et a165 determined that an increase of more than 0.75 ng/mL/year was predictive of the presence of prostate cancer. In addition, less than 5% of men without prostate cancer have a PSA

POTTER AND PARTIN

velocity more than 0.75 ng/mL/year, potentially allowing an increase in specificity (reduction in unnecessary biopsies) over total PSA alone. A large prospective study by Smith and Catalona 66 found a sensitivity of 79% and specificity of 66% in serially screened men with PSA values less than 4.0 ng/mL. However, when these investigators applied a cutoff of 0.40 ng/mL/year to men with PSA values greater than 4.0 ng/mL, sensitivity and specificity fell to 63% and 62%, respectively. Finally, PSA values can vary significantly between measurements in the absence of cancer. 67 The use of PSA velocity is limited by the requirement for three serial PSA measurements over at least a 2-year period. Data to suggest usefulness primarily in men with PSA values less than 4.0 ng/ml. 44

PSA Density PSA density (PSAD) requires measurement of prostate volume by TRUS and is expressed as PSA value in ng/mL divided by the prostate volume in mL. PSAD was proposed by Benson et a168 as a means to discriminate prostate cancer and the most frequent cause of PSA elevation, BPH. Seaman et 0.169 suggested 0.15 as a PSAD cutoff in men with PSA values between 4 and 10 ng/mL and a negative DRE. 69 Although some studies support the usefulness of PSAD, Catalona et al70 found that the recommended cutoff of 0.15 would have missed 50% of the cancers in a group of men with PSA values of 4 to 10 ng/mL and a normal DRE. Brawer et a171 studied a similar group of men, finding that PSAD failed to provide predictive power for the detection of cancer over the use of PSA alone. Two of the central shortcomings of PSAD may stem from limitafions in the accuracy of prostate volume measurements and differences in transition zone volume in prostates of the same overall volume. 72 PSA has not proven to be a reliable adjunct to PSA alone in men with palpably normal prostates and intermediate PSA levels. STAGING PROSTATE CANCER Staging is the systematic classification of disease extent. The goals of staging are to provide prognostic information and determine the proper course of therapy. Prognosis is directly related to the extent and aggressiveness of disease. Accurate staging is critical because therapy for disease that has escaped the confines of the prostate is limited. Thus understaging can deny patients the chance for curative

LOCALIZED PROSTATE CANCER

therapy, whereas overstaging of prostate cancer can commit men to potentially morbid intervention that will not provide cure. The primary modalities available for staging are DRE, serum PSA and its derivatives, histological grade, imaging studies, and lymphadenectomy. The most widely used staging system for prostate cancer is the TNM classification (Table 2). 73 Partin et a174 prospectively evaluated the role of DRE in staging. Of men with organ-confined disease by DRE, 52% actually had organ-confined disease at surgery, whereas in the men with DRE consistent with extraprostatic (T3) spread of cancer, 19% actually had organ-confined cancer on pathological staging. In isolation, DRE had a sensitivity of 52% and specificity of 81% in predicting organ-confined disease. 74 Both prostatic acid phosphatase (PAP) and PSA have been used in efforts to stage prostate cancer. PAP was widely used before the discovery of PSA. It is neither prostate-specific nor cancer-specific.75 Although elevated PAP levels portend a high likelihood of extraprostatic disease, normal PAP levels do not reliably predict low-stage disease. 76 Burnett et al7v found that PAP offered virtually no additional information to that obtained with routine history, DRE, PSA, and biopsy. The routine use of PAP in staging is of extremely limited value. Many studies have confirmed a correlation between PSA levels and likelihood of extraprostatic disease on clinical and pathological examination. 74'78 However, in the individual patient, PSA alone does not provide sufficiently accurate staging information for decision making. Although the use Table 2. The TNM Prostate Cancer Staging System Stage

Description

TO T1

No evidence of primary tumor Clinically unapparent tumor--not palpable or visible by imaging Palpable tumor confined within the prostate Palpab{e tumor extending through prostate capsule and/or involving seminal vesicles Tumor is fixed or invades adjacent structures other than seminal vesicles No regional lymph-node metastases Metastasis in a single node, -<2 cm Metastasis in a single node, >2 cm, <5 cm or multiple nodes, -<5 cm Metastasis in a single node, >5 cm No distant metastases Distant metastases

T2 T3 T4 NO N1 N2 N3 M0 M1

Data from International Union Against Cancer. 73

273

of PSA alone is limited, combining PSA with other predictors of disease extent has proved a powerful means of predicting stage. The use of nomograms, or probability tables, using data from DRE, biopsy Gleason score, and serum PSA can provide validated estimates of the likelihood of organ-confined disease and thus potential benefit from surgical intervention. Partin et a179 recently performed a multi-institutional analysis of more than 4,000 men in the construction of a nomogram that allows preoperative estimation, with a high level of confidence, of pathological stage. For example, given a patient with T2a disease clinically, a PSA of 8 ng/mL, and Gleason score 6 on biopsy, the likelihood of organ-confined disease is 51%. The same patient has a 3% likelihood of seminal vesicle invasion and 2% likelihood of lymph-node involvement. Conversely, a man with a stage T2c, Gleason score 8 cancer and a PSA of 21 has a 3% likelihood of organ confinement and a 35% probability of positive lymph nodes. Imaging studies used for staging prostate cancer have included intravenous urography (IVP), computed tomography (CT), magnetic resonance imaging (MRI), TRUS, radionuclide bone scan, and plain radiography. 13 The key requirement for a staging imaging test is the ability to accurately evaluate for extraprostatic extension of disease. IVP is not recommended as part of the routine evaluation of men with newly diagnosed prostate cancer. TRUS has not proven useful for evaluating the local extent of prostate cancer because of limited sensitivity.8°,81 TRUS as used for detection of seminal vesicle involvement by tumor has been associated with poor specificity.82 CT has likewise not proven useful for evaluation of the local extent of tumor, which is not surprising given the microscopic or low-volume nature of extraprostatic disease in most patients. The prostatic apex and seminal vesicles are poorly visualized by CT. 83 Recent advances in endorectal (erMRI) and phased array pelvic MRI has renewed interest in the role of MR in the staging of prostate cancer. 84 Kindrick et a185 recently examined the role of erMRI in select patients before radical prostatectomy. They found erMRI to have a sensitivity and specificity of 65% and 100%, respectively, in the identification of established capsular penetration and seminal vesicle invasion. Importantly, in this small series, no men would have been inappropriately excluded from surgery on the basis of a false-positive study.

274

POTTER AND PARTIN

Both CT and MR are widely used by urologists for detection of pelvic lymph-node metastasis but are often unhelpful because of their low sensitivity for small metastases. 86 A recent survey of practice patterns suggests that these studies are overused in men at low risk for detectable lymph-node involvement. 85 Pelvic imaging with MRI or CT may be warranted in the minority of men at high risk of locally advanced or metastatic disease (PSA > 20 ng/mL, high-grade, clinical T3 disease). 87 Plain skeletal radiography is too insensitive to be useful as a method of screening for bone metastasis and is not used. Radionuclide bone scintigraphy is the most sensitive method for detecting bony metastases. In the PSA era, the probability of a positive staging bone scan has decreased markedly. Men without bone pain and with PSA values less than 10 ng/mL are extremely unlikely to have bony metastasis, and it may not be cost-effective to routinely imaging these men. s8,89

MANAGEMENT OF LOCALIZED PROSTATE CANCER

Patients with a life expectancy of more than 15 years, in whom staging indicates an acceptable likelihood of organ-confined but clinically significant disease, may benefit from curative therapy. The major modalities available are radical prostatectomy (RP) and radiotherapy (RT). Recently, brachytherapy has reemerged as a possible curative therapy for organ-confined prostate cancer.

Natural History of Untreated Prostate Cancer Despite prostate cancer's epidemic proportions, it has a protracted clinical course and characteristically afflicts older men. Because of this, great controversy has surrounded the natural history of prostate cancer and the role of surgery in its management. Randomized and appropriately powered studies comparing active therapy with watchful waiting are underway, but will not produce useful data for many years. Men newly diagnosed with prostate cancer, and their physicians, require useful information to aid in making rational decisions regarding treatment. Insight into this decision process can be obtained by careful study of the natural history of deferred and ineffective therapies.

Results of Deferred Therapy Several major series have attempted to evaluate the natural history of prostate cancer based on patient cohorts receiving no therapy until progression. These studies have been widely viewed as providing evidence of the benignity of prostate cancer and support for a program of deferred therapy but have often been limited by selection bias. Johansson et al,90 in a widely quoted study, found 5- and 10-year progression-free survival rates of 68% and 53%, respectively. Johansson et al reported on only 223 of 306 eligible patients. For the initial 24 months of patient accrual in this series, only men with welldifferentiated (grade 1) tumors were enrolled. Although subsequent years saw the enrollment of men with moderately (grade 2) and poorly differentiated (grade 3) tumors, these men represented an unrealistically small fraction of the study population to allow valid comparison with men who are actually candidates for radical prostatectomy. These men had a mean age of 72 years. The patients in the Johansson series had predominantly low-grade disease, were significantly older than contemporary radical prostatectomy series, and had a mean follow-up of only 10 years. This study population cannot be considered typical of patients considered for curative therapy in the United States. Despite this,47% of the patients in this series progressed at 10 years of follow-up. This compares unfavorably with contemporary surgical series despite the much higher percentage of high-grade cancers in those series. The problems inherent in studying a handpicked cohort of men were dealt with effectively by A u s 9t in a retrospective analysis of all 536 patients diagnosed with prostate cancer who died over a 2-year period in a single Swedish town. The interval between diagnosis and death was as long as 25 years. In contrast to the findings of Johansson, approximately 63% of men who were metastasis free at diagnosis and survived more than 10 years ultimately succumbed to prostate cancer. When managed with noncurative intent, 75% of men less than 65 years of age at diagnosis died of prostate cancer. Albertsen et a192 used the Connecticut Tumor Registry to examine outcomes in 451 men with T1 and T2 cancers treated with immediate or delayed hormonal therapy. Tumor grade had a defining influence on long-term outcomes, with 15-year

LOCALIZED PROSTATE CANCER

275

cancer-specific mortalities of 9% in men with Gleason sum 2 to 4 tumors, 28% in Gleason sum 5 to 7 tumors, and 51% in men with Gleason sum 8 to 10 tumors. Although the long-term survival of men with well-differentiated tumors was not significantly different from the general population, these low-grade tumors comprised only 10% of the study population. These low-grade tumors are rarely diagnosed on needle biopsy today and are not representative of tumors in men considered for radical prostatectomy. Albertsen et al have continued to follow the natural history of localized prostate cancer through the Connecticut Tumor Registry. In a recent analysis of men followed for 15 years, men with Gleason score 7 and Gleason score 8 to 10 tumors had 45% and 63% cancerspecific death rates, respectively. 93 Patient age at diagnosis minimally impacted annual prostate cancer mortality. Chodak et al94 summarized the results of six nonrandomized studies totaling more than 800 men treated with observation and delayed hormonal therapy for clinically localized prostate cancer. All of the included studies in this analysis were highly selected series. Although 60% of the men in this study had grade 1 disease, overall metastatic rates of 10 and 15 years were substantial. At 15 years, 40% of grade 1 tumors had metastasized, as had 70% of grade 2 and 85% of grade 3 tumors (Fig 2). It must be noted that many men in this study received hormonal therapy at progression, thus delaying the appearance of metastatic disease. As detailed earlier, it is difficult to draw conclusions about surgical therapy from deferred therapy series containing patients who would be unlikely to be surgical candidates. Brachytherapy, as widely practiced 15 to 20 years ago, has proven ineffective in providing local control or stable biochemical 1.00 -

"~ 0.75-

O3 o

Grade 1

0.50~ 1 1

0.25-

] Grade 2

i - [

0.00

1'0

o

-

-

Grade 3

i 15

Years

Fig 2. Metastasis-free survival among untreated patients with localized prostate cancer, by tumor grade. (Reprinted with permissionP 4)

freedom from cancer progression. These men are better matched with current surgical series in terms of clinical stage and tumor grade. Indeed, most of these patients underwent staging lymphadenectomy before seed implantation, affording additional staging information. Fuks et a195 reviewed a 15-year experience during which time 679 men underwent seed implantation for presumably localized prostate cancer. These men had a mean follow-up of 8 years, mean age of 61 years, and negative lymph nodes at staging lymphadenectomy. Clinical stage at presentation was divided between T2 (87%) and T3 (13%) cancers, whereas histological grade was low, moderate, and high in 37%, 53%, and 6% of these men, respectively. This distribution more closely resembles contemporary surgical series. At 10 years, metastatic disease had developed in 30% of the men with low, 50% with moderate, and 70% with high-grade disease. Fuks found 5- and 10-year progression rates of 32% and 66%, respectively, in this group as a whole, concluding that "early and complete eradication of the primary tumor is required if long-term cure is to be achieved." The devastating effect of cancer in these men, and the favorable outcomes of surgery in relation to deferred or ineffective therapies, lend support to the advocacy of radical prostatectomy in properly selected patients.

Selection of Patients for Surgical Therapy The ideal candidate for radical prostatectomy has an organ-confined tumor of clinical significance. Additionally, patients should be young enough to have a reasonable likelihood of living 10 to 20 years after surgery and be free of serious comorbidities. Conservative therapy of men with localized prostate cancer yields 50% to 75% 10year progression rates. 94 Without treatment, some 13% to 20% of these men will die during the decade following diagnosis. In men with a life expectancy long enough to benefit from surgery, the key becomes selecting those with curable disease. Men presenting with clinically significant stage T l c or T2 disease are ideal candidates for radical prostatectomy. Patients presenting with clinical T3 disease are not ideal candidates for surgical cure. However, many men with low-grade disease and extracapsular extension have durable biochemical freedom from recurrence. The surgeon must consider the likely patho-

276

POTTER AND PARTIN

logical stage and the age and health of the patient. In men with poor odds of favorable pathology, where surgery is unlikely to be curative, but without evidence of systemic disease, external beam radiotherapy is an excellent alternative and should be encouraged.

Surgical Technique A series of critical anatomic discoveries have transformed the surgeon's ability to extirpate prostate cancer while reducing attendant morbidity. Definition of the anatomy of the dorsal vein complex by Reiner and Walsh 96 allowed radical prostatectomy to be performed in a controlled fashion in a relatively bloodless field. Further anatomic studies led to delineation of the autonomic nerves essential for potency running outside the prostatic capsule and Denonvillier's fascia (Fig 3). 97 The identification of these nerves and their relationship to the capsular vessels and prostatic fascia made attainment of wider margins of resection possible. 98 Preservation of these nerves allows the maintenance of potency. 99 The techniques involved in delineation and preservation of these nerves have led to the somewhat inapt moniker of nerve-sparing prostatectomy. In fact, radical prosta-

~ ]

O(J

'

..Smoo~h

OO

S~r'i~{ed ure~h~-~l ", s p h i n c t e r complex

rnus.

/~--.,~"~!:,

"

~#Z~f "~

I B

Den~nvitI~ers' f~sci~ Fig 3. Schematic illustration of the striated urethral sphincter and its relation to the dorsal vein complex, smooth musculature of the urethra, and neurovascular bundles (NVB). Arrow indicates site of division of the striated sphincter. (Reprinted with permission. 1°9)

tectomy as formerly practiced through either perineal or retropubic approaches did not include excision of these nerves and associated vasculature. Instead, these neurovascular bundles were cut and left in place. ~°° Most recently, modifications to the apical dissection and improved understanding of the striated urethral sphincter have allowed improved continence rates secondary to modifications in the preparation of the vesicourethral anastomosis.101.102

Treatment Outcomes A number of institutions have reported on large radical prostatectomy series followed with respect to biochemical disease progression. Table 3 provides a summary of patient characteristics and outcomes in several of these series. The Johns Hopkins Hospital series of Walsh has recently been summarized by Pound et al.m3 In a series of 1,623 men with a mean follow-up of 5 years undergoing radical prostatectomy for clinically localized prostate cancer, recurrence occurred in 276 (13%). Overall actuarial biochemical (PSA) progressionfree rates at 5 and 10 years were 80% and 68%, respectively (Fig 4). No patient developed a local or distant recurrence without concomitant PSA elevation. Overall actuarial cancer-specific survival rates were 99% and 93% at 5 and 10 years, respectively. Patients with clinical stage Tlc disease are presenting in increasing numbers, representing 21% of all men in this series and more than 60% of men presenting since 1997. The actuarial progression-free rate for all T l c patients was 86% at 5 years. Preoperative PSA values were obtained in 1,354 (83%) of 1,623 men. When analyzed based on division of preoperative PSA values into groups of less than 4 ng/mL, 4 to 10 ng/mL, 10.1 to 20 ng/mL, and greater than 20 ng/mL, there was a statistically significant correlation between preoperative PSA and biochemical progression-free likelihood in all groups. Recurrence-free rates also fell with increasing Gleason scores. The best predictor of likelihood of recurrence was a combination of pathological stage, Gleason score, and surgical margin status. 1°4,m5 Several large radical prostatectomy series have confirmed results from the Johns Hopkins series. Actuarial biochemical progression-free probabilities in the Washington University series of 78% and 65% were obtained at 5 and 10 years, respectively5 °6 The Baylor group demonstrated PSA

277

LOCALIZED PROSTATE CANCER

Table 3. A Summary of Several Contemporary Radical Retropubic Prostatectomy Series

n

Mean Age (years)

Follow-up, Mean (months)

Partin et a1135

894

59

Pound et al 1°3

1623

59

Catalona et al 1°6

925

Ohori et a1107

Series

Zincke et a) 136

T1 Lesions (%)

T2 Lesions (%)

5-year PSA Progression-free Likelihood

10-year PSA Progression-free Likelihood

53

17

59

31

83

87

77

66

80

63

63

68

21

79

78

500

63

65

36

22

78

76

3170

65

73

60

7

93

70

52

Adapted and reprinted with permission? °3

progression-free rates of 76% at 5 years and 73% at 10 years.l°7 These data indicate that radical prostatectomy is curative for most men presenting with organconfined disease. Most men with well-differentiated to moderately differentiated tumors with focal capsular penetration but otherwise negative margins can expect cure as well. In men with poorly differentiated tumors and capsular penetration, cure is less likely regardless of surgical margin status, whereas patients with lymph-node involvement at the time of surgery are never free of progression with adequate follow-up.

Postoperative Management and Surgical Complications Most men undergoing radical retropubic prostatectomy have an uneventful postoperative course. Patients ambulate and start a clear liquid diet the morning after surgery and are typically discharged to home on the morning of the third postoperative day. The urethral catheter is removed from 2 to 3 weeks after surgery. Operative mortality, defined as death within 30 days of surgery, occurred in 11 1.00 -

f " Local Distant "L~ PSA Only

~075

All Recurrence rr

"6 0.50-

L~ 0 . 2 5 -

0-

0

. . . 4.

2

6

8

'o

1

'2

1

' 14

Years Postoperative

Fig 4. Kaplan-Meier actuarial progression-free likelihood for overall progression, isolated PSA elevation only, local recurrence, and distant progression -+ local progression. There were 1,623 men included in the analysis. (Reprinted with permission. 10z)

(0.3%) of 3,834 men in a recent multi-institutional review. 1°8 The experience at the Johns Hopkins Hospital mirrors these results, with an operative mortality of 0.2%.1°9 Hemorrhage has historically been the most frequent and troublesome intraoperative complication of radical prostatectomy. Refinements in technique have reduced blood loss substantially and average blood loss is less than 1,000 mL in most recent series. 11° With careful technique and the use of preoperatively donated autologous blood, transfusion of banked blood is necessary in only 2% of men. 1°9Rectal injury is a rare intraoperative complication, occurring in 10 (0.5%) of 1,800 consecutive cases at our institution, m All patients recovered without need for colostomy and without developing a wound infection. Even rarer are obturator nerve and ureteral injuries. Obturator nerve injuries are repaired by direct reanastomosis, whereas ureteral injuries occur at or near the trigone and are repaired by reimplantation. Postoperative complications include thromboembolic events, anastomotic stricture, and delayed bleeding. Deep venous thrombosis and pulmonary embolus occur in approximately 1% to 1.5% of patients. In our experience, thromboembolic events as a whole occurred in 1.5% of 1,300 consecutive patients, with associated deaths in 2 (0.15%) patients. 112 Because most clinical events will occur after discharge from the hospital, thorough patient education and close follow-up are required. Anastomotic stricture has been reported in 0.5% to 9% of men after radical retropubic prostatectomy. Precise construction of the vesicourethral anastomosis is critical in providing mucosal apposition and limiting the rate of bladder neck contracture. 113 Most strictures require cold knife incision under direct vision. Postoperative bleeding requiring acute transfusion to maintain hemodynamic stability occurred in 7 (0.5%) of 1,300 consecutive men after radical

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prostatectomy at our institution. ~14 The undrained pelvic hematoma will eventually liquefy and drain through the vesicourethral anastomosis. Patients stabilized with transfusion and not returned to the operative theater for exploration and drainage of their pelvic hematoma risk bladder neck contracture and are more likely to suffer imperfect urinary continence. In summary, most men have an uneventful course during surgery and in the perioperative period. Improvements in surgical technique have decreased complication rates dramatically. Extensive experience has improved management of the few complications that occur.

Continence and Potency Urinary incontinence is a potentially devastating sequela of radical prostatectomy. The rate and severity of incontinence is minimized through careful apical dissection, excellent visualization through control of hemorrhage, preservation of sphincteric innervation, and avoidance of injury to the smooth muscle of the urethral sphincter during anastomosis construction. Evaluation of 593 consecutive cases treated by Walsh et al ~15 at our institution revealed complete continence in 92%, with some degree of stress incontinence in 8%. Of those with stress incontinence, 6% required 0 to 1 pad per day and no patients were totally incontinent. Ultimately, 2 men (0.3%) underwent artificial urinary sphincter placement. Similar results have been found at other centers. 1t6 Although centers of excellence consistently report incontinence rates under 10%, with most incontinent patients having mild stress incontinence easily managed with pads, survey studies of results from community hospitals throughout the United States show wide variation in results following radical prostatectomy. Murphy et a1117surveyed 1,796 preoperatively continent men undergoing surgery at 484 hospitals. Postoperatively, 19% of these men required pads on a daily basis, whereas 3.6% were totally incontinent. H7 Despite higher rates of incontinence in this and other broad-based population surveys, most men adapt well to pad use and report satisfaction with surgical outcomes. Quality of life studies surprisingly find that most men are minimally bothered by postoperative stress incontinence. Hs Improvement in continence may occur up to 2 years after surgery. ~19 During this time, patients need constant encouragement and

POTTER AND PARTIN

reinforcement. 12° Because improvement may continue long after prostatectomy, definitive surgery should be deferred for at least a year after surgery. 11° Before identification of the location of the autonomic branches of the pelvic plexus innervating the corpora cavernosa and modification of the technique to spare these nerves, virtually all men were impotent after radical prostatectomy. The identification of these nerves by Walsh and Donker resulted in modification of the technique of radical prostatectomy, which allowed preservation of these nerves and maintenance of potency. Six hundred consecutive men aged 34 to 72 years underwent anatomic radical prostatectomy at our institution between 1982 and 1988, forming the initial experience with this procedure. In the 503 of these men who were potent preoperatively and followed for a minimum of 18 months after surgery, 68% were remained potent postoperatively. 121 Preservation of potency correlates to patient age, stage, and preservation or excision of the neurovascular bundles. Potency was preserved in 91% of men younger than 50 years of age, in 75% of men 50 to 60 years of age, in 58% of men aged 60 to 70 years old, and in 25 % of men 70 years of age or older. Preservation of both rather than one neurovascular bundle assumed increasing importance with age, whereas young patients had similar potency rates with preservation of one or both neurovascular bundles. After controlling for age, the relative risk of postoperative impotence was twice as great in the presence of capsular penetration or seminal vesicle invasion. Similar experiences with preservation of potency have been reported from a number ofinstitutions.ll6,12%~23 Zippe et al124have recently examined the role of sildenafil (Viagra) in post-prostatectomy impotence. They found that 12 of 15 men who had undergone bilateral nerve-sparing procedures obtained erections sufficient for intercourse with sildenafil at standard dosages, whereas no men who had undergone excision or ligation of both neurovascular bundles had a positive response to this agent. This confirms the physiological role of the autonomic innervation of the corpora first defined by Walsh and further strengthens the case for surgical intervention in appropriate patients.

Radiation Therapy Radiation acts by causing irreparable levels of DNA damage. The damaged cancer cells lose the

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ability to divide, and eventually die. 125 Therapeutic radiation for the treatment of prostate cancer is most commonly applied as external b e a m therapy. The development of three-dimensional conformal radiotherapy (3DCRT) allows dose escalation to the prostate while reducing morbidity. 126,127Countless nonrandomized studies have compared RT to radical prostatectomy for the treatment of clinically organ confined prostate cancer, but none are able to circumvent the fact that RT and surgical series are incomparable because of an inability to match prognostic factors, t28 Historically, RT series have contained more high-stage patients than surgical series. RT patient series are not often surgically staged before treatment, and the likely understaging of at least a portion of the men undergoing RT would worsen apparent outcomes in relation to surgical series. Outcome comparison after RT and RP for localized disease is further complicated by the ambiguity of interpretation of post-RT P S A measurements. The most widely used definitions of biochemical treatment failure after RT require two or three consecutive P S A rises after a nadir P S A is reached, a process that may take longer than 3 years. In contrast, biochemical failure after RP is defined by a single detectable PSA. Thus, 5- and 10-year outcome data after RT may provide inflated estimates of freedom from recurrence. Despite these limitations, RT offers acceptable morbidity and disease control for clinically localized prostate cancer. 129-131 Brachytherapy involves the permanent or temporary implantation of radioactive seeds

into the prostate. The availability of improved imaging modalities and mechanisms of seed placement has fostered a resurgence in interest in this technique; however, long-term data suggest that brachytherapy provides rates of biochemical freedom from progression that are inferior to external beam RT o r s u r g e r y . 132,133

CONCLUSIONS

Prostate cancer continues to take an enormous human toll, but promising developments, on many fronts, give hope for the future. Largely due to the widespread use of P S A testing, men are more often presenting with organ-confined disease. After years of steady increases, the prostate cancer mortality rate fell for the first time in 1996. This provides inferential evidence of benefit from aggressive efforts at early detection of and definitive therapy for localized prostate cancer. The past two decades have seen enormous advances in the treatment of localized prostate cancer through improvements in the technique of radical prostatectomy and the application of radiation therapy. The morbidity of surgery has been reduced dramatically, hospital stays have been shortened, and potency is preserved in many men. These improvements have made it possible to cure most men with clinically organ-confined cancer. For those men with occult metastases at the time of surgery or RT, further improvements in cancer control will depend on earlier diagnosis and the advent of effective systemic therapies.

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