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WHO IS BEST BENEFITED BY RADICAL PROSTATECTOMY?
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PROSTATE CANCER
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WHO IS BEST BENEFITED BY RADICAL PROSTATECTOMY? Robert B. Nadler, MD, and Gerald L. Andriole, MD
Adenocarcinoma of the prostate is the most commonly diagnosed cancer in American men. This year 317,100 men will be diagnosed with prostate cancer in the United States, and approximately 41,400 men will die of it.37It has been estimated that up to one third of men with newly diagnosed prostate cancer undergo radical prostatectomy, translating to an estimated 70,000 radical prostatectomies in 1995.15The increase in the number of radical prostatectomies to treat men with prostate cancer has occurred for several reasons. First is the dramatic increase in the detection of prostate cancer that has occurred over the past several years owing primarily to the use of serum prostate-specific antigen (PSA) testing in conjunction with digital rectal examination (Fig. By comparison, 10 years ago in 1986, prior to widespread use of PSA testing, 90,000 new cases of prostate cancer were diagnosed.26Thus, in 1996 there are more than 3 times more new cases of prostate cancer diagnosed than 10 years ago in the United States, and this trend may continue as a higher proportion of the population undergoes early detection. Second, the last few years have witnessed a profound “stage and age migration” for newly detected prostate cancer: Whereas only about 60% of cancers of the prostate detected in 1984 and 1990 were clinically organ-confined,15 more than 95% of tumors detected in aggressive early-detection programs are clinically organ-confined” Therefore, a higher proportion of newly detected tumors are potentially amenable to radical prostatectomy. Moreover, the application of early-detection strategies to younger men in their forties and fifties (as recommended by the American Cancer Society and American UroIogical Association) has also tended to increase the proportion of men with newly diagnosed organ-confined cancer who are suitable operative candidates. This increased and earlier (in terms of both patient age and tumor stage) detection of prostate cancer has coincided with a substantial increase in our 1 ) ? g 6
From the Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri
HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 10 NUMBER 3 JUNE 1996
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NADLER & ANDRIOLE
21.4
10.0
PSA>4
DRE(+)
PSA>4
PSA<=4
PSA>4
DRE(-)
DRE (+)
DRE (+)
Method of Detection
PSA>4 DRE (+) TRUS (+)
Figure 1. Positive predictive value of various detection methods. DRE = digital rectal examination; TRUS = transrectal ultrasound. (From Catalona WJ, Richie JP, Ahmann FR, et al: Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: Results of a multicenter clinical trial of 6,630 men. J Urol 151:1283-1290, 1994; with permission.)
understanding of male pelvic anatomy, the third factor contributing to the increasing use of radical prostatectomy. Specifically, delineation of the precise anatomic pathways of the cavernosal nerves32and a greater understanding of the functional anatomy of the striated urinary ~phincter’~,” allowed for development of surgical techniques that allow removal of the prostate with low risk of side effects, especially impotence and urinary incontinence. The ability to perform anatomic radical prostatectomy without compromising potency or urinary continence has made radical prostatectomy substantially more acceptable to both the patient and the urologist. The fourth development that has tended to increase the utilization of radical prostatectomy as the treatment for patients with early-stage prostate cancer has been the impression among urologists that radiation therapy is associated with a substantial risk of biochemical failure, especially if patients are followed for a
WHO IS BEST BENEFITED BY RADICAL PROSTATECTOMY?
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prolonged period (more than 5 years). Some of the more compelling data have been reported from Stanford, an institution historically associated with a large experience with external beam radiation therapy for prostate cancer. In 1993, Stameyzs updated 124 unselected consecutive stage Tla to T4a prostate cancer patients treated with external beam radiation. At a mean follow-up of 2.6 years, 51% of patients demonstrated biochemical failure (rising serum PSA levels), and actuarial projections at 6 years were that 78% of patients would have precipitously increasing serum PSA levels. Subsequently, other investigators have generally confirmed the relatively high biochemical failure rates after radiation therapy: Z a g a r ~found ~ ~ a PSA failure rate approaching 50% at 5 years; Goad et all1 reported a 4-year actuarial biochemical progression rate of 56% even among patients proven histologically to be node negative; and Kaplan et all7reported a 41% failure rate defined by rising PSA or clinical relapse among men followed for a mean of 2.7 years. These relatively high biochemical failure rates, coupled with the high probability of histologically proven local failure (that is, positive prostatic biopsy) in up to 90% of such coupled with the known adverse implications of biopsy-proven local failure for the subsequent development of metastatic disease, have conspired to cause urologists to recommend radiation therapy less frequently for their patients with organ-confined prostate cancer. Although these trends have dramatically changed the way in which earlystage prostate cancer has been managed over the last several years, three new developments on the horizon may yet again significantly alter our approach to this disease. These developments, when completely exploited, may result in a more selective application of radical prostatectomy to men with early stage disease. These potential new developments are (1)an enhanced appreciation of the natural history of this disease, ( 2 ) a realistic assessment of the limitations of radical prostatectomy in controlling prostate cancer, and (3) a better understanding of various prognostic markers that will theoretically allow stratification of prostate cancers into one of three groups: those that are too small to warrant treatment, those that are both clinically significant and amenable to surgery, and those that are untreatable by surgery alone. Although our knowledge in each of these areas is currently relatively limited, further investigation holds the promise to accurately define who is best benefitted by radical prostatectomy. NATURAL HISTORY OF PROSTATE CANCER The natural history of prostate cancer generally has not been well defined for several reasons. Compared with many other cancers, adenocarcinoma of the prostate may be relatively slow growing and occur in elderly men who have a limited life expectancy. Moreover, prostate cancer is histologically recognizable in the prostates of more than one third of men over 50 years of age.1a,24 For these reasons, many clinicians have believed that prostate cancer is a relatively benign disease for most men, and that many patients will succumb to other causes. Epidemiologic studies have been interpreted to support this position, because men over age 50 traditionally have had a 9% chance of clinically evident prostate cancer and a 3% chance of death from prostate cancer, suggesting that only one man in three with clinically evident prostate cancer will die of it. Several recent studies, however, have caused many urologists to refine this view of the natural history of prostate cancer. 36 reported 75 men (selected from more than Whitmore and 4000 patients) with clinical stage B (T2) prostate cancer at Memorial Sloan-
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NADLER & ANDRIOLE
Kettering Cancer Center who were managed expectantly if they failed to progress after 1 year of follow-up. Forty-five percent (34 of 75) of the patients were stage T2a or T2b and grade I. The overall disease-specific survival at 5 and 10 years was 100% and 91%, respectively, but it fell significantly at 15 and 20 years (67% and 37%, respectively). Most men needed palliative treatment for prostate cancer, and this was administered at a median of 9 years after diagnosis. These data suggest that, even among men with prostate cancer selected to do well (that is, low grade tumor and failure to progress during initial evaluation), prolonged follow-up (beyond 10 years) discloses that a majority will succumb to prostate cancer. Johansson et all3,l4 reported on the expectant management of a select group of 223 men (from a total of 654 newly diagnosed prostate cancer patients) who were followed a mean of 12.5 years. Only 10% of patients died of prostate cancer, whereas 84% died of other causes. The 10-year disease-specific survival rate was 85%. There are important limitations of this study; one is that 66% (148 of 223) of the patients had grade I cancer often diagnosed by transurethral resection of prostate (TURP) and staged as clinical A1 (maximum of 5% chips positive). The impact of overweighting this study group with low-grade tumors is evident when one notes that only 7 of 48 patients (14%) with grade I disease died of prostate cancer, whereas 7 of 66 (11%)of grade I1 and five of nine patients (56%) with grade 111 prostate cancer died of prostate cancer. Second, during the first 2 years of patient accrual, only patients with grade I disease were treated expectantly, whereas patients with higher-grade tumors were randomized to active, early treatment or delayed therapy. This policy introduces a significant bias in this study group because patients with the most favorable tumors have been followed the longest, thus having a proportionally greater impact on the actuarial outcomes of this cohort. Furthermore, the study patients were elderly; their mean age at diagnosis was 71.4 years. By comparison, most series of radical prostatectomy consist of men with mean ages of 59 to 64.2l Overall, the results of the Johansson study cannot be considered definitive because of the substantial number of favorable selection factors among the study population. If anything, one may argue that this study merely validates urologists' historical approach to septuagenarians with low-grade disease, that is, watchful waiting. It is important to consider that one third of men with newly diagnosed prostate cancer in 1992 were treated with watchful waitingm Chodak et a17 performed a pooled analysis (meta-analysis) using data on individual patients from six nonrandomized studies of men with clinically localized prostate cancer treated expectantly. Disease-specific survival at 10 years was 87% for grade I or I1 tumors and 34%for grade 111tumors. Metastasisfree survival was 81% for grade I, 58% for grade 11, and 26% for grade I11 disease at 10 years. Of the 828 patients in the analysis, the median age was 69 years and the mean follow-up was only 6.5 years. As is common among studies evaluating the natural history of prostate cancer, more than half (59%) of the patients had grade I tumors. Interpreted another way, the data from this evaluation demonstrate that even in a relatively favorable select group of patients, the metastatic rate at 15 years is 40% for grade I, 70% for grade 11, and 85% for grade 111, again suggesting that longer-term follow-up (more than 10 years) is necessary to truly define the natural history of prostate cancer. Recently, a new long-term analysis of 514 prostate cancer patients treated with noncurative intent (watchful waiting with or without hormonal manipulation) was reported from Sweden by Aus et al.'rz All patients with prostate cancer who died consecutively from 1988 to 1990 were analyzed. Prostate cancer was diagnosed between 1961 and 1990; thus, untreated patients were followed for
WHO IS BEST BENEFITED BY RADICAL PROSTATECTOMY?
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Table 1. CAUSE OF DEATH IN STAGE MO PROSTATE CANCER PATIENTS IN 5-YEAR PERIODS Years
0 to 5 5tO 10 10 to 15 15 to 20 20 + Total No. (%)
No. Cancer Deaths
No. Deaths of Other Causes
Percent at Risk of Cancer Death
51 57 21 15 5
80 48 16 6 2
39 54 57 71 71
149 (50)
152 (50)
from Aus G, Hugosson J, Norlen L: Long-term sutvival and mortality in prostate cancer treated with non-curative intent. J Urol 154:460-465, 1995; with permission.
up to 30 years. Aus et a1 found that prostate cancer was the direct cause of death or contributed to death in 62% (319 of 514) of patients. Metastases were known to be present in at least 58% (296 of 514) of patients at death (the metastatic status at death was unknown in 21%). The mean survival time for the entire group of men was 6.8 years. Of 301 patients with stage MO (no bony or soft-tissue metastases) prostate cancer at diagnosis, 149 (50%) died as a consequence of prostate cancer (Table 1).Among the 71 (24%) who were considered radical prostatectomy candidates (that is, Tlb-T3MO, grade I or I1 and age 70 or less), 59% died of prostate cancer. This study is important because it highlights the substantial increased risk of prostate cancer-related death and morbidity that occurs when patients are followed for more than 10 years. Long follow-up is necessary to record the cause of death for each patient with prostate cancer. This study supports the conclusion that 10 years of follow-up is inadequate, and that it is not safe to assume that a patient who has not died of prostate cancer (or developed metastatic disease) at 10 years will not do so at 15 to 20 years. This study also shows that age at diagnosis is directly linked to the probability of developing metastatic disease or of dying of prostate cancer. Seventy percent of men with stage MO prostate cancer at age 65 or less and 100% of men age 55 or less died of prostate cancer. Thus, natural history studies evaluating men who are in their seventies do not adequately portray the relentless, progressive nature of prostate cancer, especially among younger men. Finally Aus et al’s study quantified the significant morbidity associated with expectant management of prostate cancer. Invasive procedures to achieve local control and palliative radiation are often necessary. Sixty-one percent (193 of 319) of patients who later died of prostate cancer needed one or more palliative treatments (TURP, radiation treatment, or upper tract urinary diversion). The probability of needing palliative therapy was directly correlated with young age and survival beyond 10 years. These procedures are associated with lengthy hospitalization times, which average 5 weeks for patients dying of prostate cancer in Aus et al’s study.* These additional procedures and long hospitalizations add obvious associated expense (Table 2). In the aggregate, our knowledge of the natural history of prostate cancer is increasing. It appears that many patients with early-stage disease will do well for the first 10 years; however, over the long term, for men with at least 15 years’ expected survival, prostate cancer often progresses, metastasizes, and causes death. The “benign” picture painted by some studies of expectant man-
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NADLER & ANDRIOLE
Table 2. PATIENTS WHO LATER DIED OF PROSTATE CANCER DIVIDED BY M STAGE AT DIAGNOSIS* Stage MO (149 patients)
Mean Values ____~
~
Stage M1 (152 patients)
P Value
~
Days hospital care Occasions/patient Mean months’ survival No. patients undergoing transurethral prostatic resection (“10) No. transurethral prostatic resections No. patients receiving palliative radiation (%) No. patients undergoing upper urinary tract procedure (%)
35 3.2 26
87 (58)
38 (25) 49
<0.0001
47 (31)
NS
18 (12)
0.0315
155
52 (35) 33 (22)
~~
NS
41 4.3 94
~
<0.0004 <0.0001 <0.0001
~
‘301 patients with stage Mx disease excluded. NS = not significant. From Aus G. Hugosson J, Norlen L: Need for hospital care and palliative treatment for prostate cancer treated with non-curative intent. J Urol 154:466469, 1995; with permission.
(El
Local Progression
1.00 -
0.75
-
(68)
n
Overall (23)
0 L
(6)
a
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L
LL I
0.50 -
c 0 -A Lo Lo
0.25 -
m 0 L
11.
0.00 -
d
1
4
i
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lb
First year of progression
Figure 2. Kaplan-Meier actuarial progression-free likelihood for overall progression, PSA detectability only, local progression, and distant progression. Numbers in parentheses represent number of men in analysis at time interval. (From Partin AW, Pound CR, Clemens JQ, et al: Serum PSA following anatomical radical prostatectomy: The Johns Hopkins experience after 10 years. Urol Clin North Am 20:71%725, 1993.)
WHO IS BEST BENEFITED BY RADICAL PROSTATECTOMY?
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agement are misleading, because their follow-up is relatively brief and they considered predominantly elderly men with low-grade tumors. AN APPRAISAL OF THE DISEASE-CONTROL CAPABILITIES OF RADICAL PROSTATECTOMY IN CONTEMPORARY
SERIES Several studies have now been reported that delineate the ability of radical prostatectomy to eradicate prostate cancer. One such study reported on 955 men with clinically localized prostate cancer (clinical stage T1 and T2) who underwent anatomic radical retropubic prostatectomy. The average age of these patients was 59.4 years (that is, 10 to 15 years younger than that of most observation series), 49% were T2a, and 45% had Gleason score 6 or greater. Patients were followed by annual examinations and serum PSA levels.21,33 At 10 years the likelihood of an undetectable PSA level was 70% for the entire group; 23% had an isolated PSA elevation, 7% developed distant metastases, and 4% developed local recurrence (Fig. 2). The likelihood of a detectable postoperative PSA elevation was directly related to pathologic stage, grade, and preoperative serum PSA level. At 10 years’ actuarial analysis, 85% of men with pathologically organ-confined disease and 82% with focal capsular penetration had undetectable serum PSA levels. In comparison, 54% with established capsular penetration and low- or moderate-grade disease, 42% with established capsular penetration and high-grade disease, 43% with seminal vesical involvement, and none with positive lymph nodes have an undetectable PSA (Table 3). It is clear from these data that radical prostatectomy cures most men with pathologically organ-confined disease and tumors that manifest only minimal capsular penetration. Patients with high-grade disease, locally advanced disease (capsular penetration or seminal vesicle invasion), or distant disease (nodal metastases) are infrequently cured. The fact that almost one third of men in the entire series had evidence of disease recurrence should be put in perspective; many patients entered in the series had relatively large tumors diagnosed in the pre-PSA era. Unlike the Johansson study, which entered the most favorable patients earliest, in this study (and all other reports of radical prostatectomy) the ”worst” patients were entered first and are followed the longest, thus imparting inappropriately high overall failure rates when actuarial analysis is performed. Catalona and Smith3reported similar results in 925 men with clinical T1 or
Table 3.10-YEAR ACTUARIAL LIKELIHOOD OF UNDETECTABLE PSA AFTER RADICAL PROSTATECTOMY Undetectable PSA (“YO) Pathologic Stage
Walsh et a133
T1 orT2 T3a (focal) T3a (established) Gleason 2-6 Gleason 7-10 T3b N1
85 82
54 42 43 0
Ohori et alZo
Catalona and Smith3
90
71
59
58
-
-
-
-
21 0
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NADLER & ANDRIOLE
T2 prostate cancer. Recurrence was defined as a detectable PSA level postoperatively. The probability of nonprogression correlated with tumor stage and grade: 91% of patients with organ-confined disease had no progression at 5 years as compared with 74% of patients with positive margins or microcapsular penetration. Only 32% of patients with positive seminal vesicles and virtually no one with positive lymph nodes had no progression at 5 years, and at 10 years the success rates were slightly worse (see Table 3). These data support the conclusion that radical prostatectomy effectively eradicates prostate cancer in patients with pathologically organ-confined disease or early (focal) capsular penetration. Pathologic stage is a powerful predictor of outcome from radical prostatectomy, even in men with poorly differentiated disease. Ohori et a120 evaluated 500 patients with clinical T1 to T3 prostate cancer. Gleason score 7-10 cancers comprised 40% of the population and were pathologically more advanced than tumors with Gleason score less than or equal to 6: 58% penetrated the capsule and 21% invaded the seminal vesicle. These pathologic findings predicted a higher probability of failure: At 5 years 36% of Gleason score 7 or greater cancers versus only 10% of Gleason score 6 or less cancers. In this study, poorly differentiated prostate cancer was found to be pathologically advanced more than 70% of the time, but among the minority with poorly differentiated tumors that were pathologically organ-confined, 85% had no evidence of progression at 5 years (Fig. 3). In summary, the data from these series demonstrate that radical prostatectomy nearly always eradicates pathologically organ-confined tumors of any grade, as well as a large majority that penetrate the capsule if they are low to moderate grade (Gleason score 6 or less). Radical prostatectomy is much less
-
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1 1
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2
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1 5
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Logrank test p=N.S. I I I 8 9 10
Figure 3. Among 226 cancers confined to prostate, there were no significant differences
in rates of progression, regardless of Gleason score of cancer in radical prostatectorny specimen. Ticks above line represent censored patients. N.S. = not significant. (From Ohori M, Goad JR, Wheeler TM, et al: Can radical prostatectomy alter the progression of poorly differentiated prostate cancer? J Urol 152:1843-1849, 1994; with permission.)
WHO IS BEST BENEFITED BY RADICAL PROSTATECTOMY?
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effective at curing patients with high-grade (Gleason score 7 or greater) prostate cancer if there is capsular penetration or seminal vesicle invasion. Patients with pelvic lymph node involvement have little chance of being cured by surgery (see Table 3). The implications of these observations should be juxtaposed to the current stage/grade distribution of tumors discovered in early detection tumors: Up to 85% are pathologically organ-confined (especially if repetitive screening strategies are employed) and approximately 90% are well or moderately differentiated. Thus, early-detection strategies find precisely the type of tumors that radical prostatectomy can effectively eradicate. One can anticipate that future reports of radical prostatectomy will show overall improved results as more of the patients in these series will have more favorable pathologic stages. USE OF PROGNOSTIC MARKERS
Because only pathologically organ-confined prostate cancer and those with very early microscopic evidence of capsular penetration are effectively eradicated by radical prostatectomy, it is necessary to develop better tools than those currently available to predict preoperatively which patients harbor surgically amenable disease. Moreover, it is also important to exclude men with clinically "insignificant" prostate cancer. At the present time, the best predictor of pathologic stage is the combination of serum PSA, Gleason score, and clinical T stage. Partin et alz2from Johns Hopkins published a series of nomograms to help the clinician predict the pathologic stage of patients with clinically localized prostate cancer. Although the nomograms are helpful in managing patients, they provide relatively crude probabilities that often cluster around 50%. Moreover, they often fall short of identifying which patients with high Gleason score tumors are good surgical candidates and which patients have small-volume disease. Some authors have attempted to use additional information beyond T stage, serum PSA, and tumor grade to improve ability to predict pathologic stage. Most studies have attempted to exploit the information contained in sextant prostatic biopsies. Most have focused on the number of positive cores and the total length of cancer in all cores as predictors of tumor volume, clinical significance and pathologic stage. Stamey and colleaguesz7have attempted to use tumor volume as a surrogate for pathologic stage. They have assumed that cancers that are less than 0.5 cc among patients aged 65 years or less, and less than 1.0 cc among men 72 years or less are too small to deserve treatment. They derive this assumption from Surveillance, Epidemiology, and End Results (SEER) data from the National Cancer Institute. Because an estimated 8% of all men present with clinically significant prostate cancer (stage Tlb and Stamey applied this 8% cut-off to 139 men undergoing cystoprostatectomy for bladder cancer in which 55 (40%) were incidentally found to have prostate cancer.I6The 11 men (8% of 139) with the largest cancers were inferred to be the men with the highest probability of developing clinically evidence cancer. All 11of these men had tumors larger than 0.5 cc. These authors have also estimated that tumors larger than 6.0 cc are incurable, based on detailed prostate cancer maps on 850 consecutive radical prostatectomy patient^.^' These authors support these estimates by noting that 80% of prostate cancers are less than 0.5 cc and 50% are less than 0.05 cc, and with the 4 to 5 years needed for prostate cancer to double, most men will not live long enough to be affected by such a small volume of prostate cancer.=, 27 To predict tumor volume, they consider the presence of core cancer lengths greater than or equal to 3 mm or more to define tumors larger than 0.5 cc. For men with a total core cancer length less than or
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NADLER & ANDRIOLE
equal to 3 mm on sextant biopsy, repeat biopsies are recommended to ensure the tumor size has not been underestimated. Beyond length of cancer on sextant core biopsy, any high grade (Gleason score 4 or 5) tumor (irrespective of prostate cancer length) is considered significant? The validity of these assumptions must be tested before they are universally accepted. This is evident from the fact that other centers cannot duplicate these this findings. Cupp and colleaguess at the Mayo Clinic showed that transrectal needle biopsy is not accurate at predicting "significant" versus "insignificant" tumors. They found that less than 10% of "clinically insignificant" cancers (volume less than 0.5 cc, Gleason score less than 7) could be predicted preoperatively based on the percentage of cores involved, the length in millimeters of cancer per core, percent cancer in each core, or Gleason score. Humphrey and ColleagueP at Washington University looked at serum PSA, PSA density, number of positive biopsies, millimeters of carcinoma, percentage of carcinoma in biopsy tissue, and histologic grade with respect to tumor grade, volume, .and stage in 50 completely embedded radical prostatectomy specimens. They found no correlation between millimeters of carcinoma or percentage of carcinoma in biopsy cores and tumor size, stage, or grade. They did find PSA density (PSAD) and histologic grade on needle biopsy to be predictors of final histologic grade. More importantly, they found PSA, PSAD, and the number of needle biopsies with cancer could predict tumor size, but not stage, raising a question about the validity of using tumor volume as a surrogate for stage. Similar findings have also been reported by Peller and colleague^.^^ They found the number of positive sextant cores, preoperative PSA and Gleason score to be significant predictors of stage and volume. Specifically, they found a PSA value greater than 4.0 ng/dL and one or more positive sextant biopsies to be predictive of clinically significant tumor volume, and four or more positive cores and Gleason score 7-9 disease to be indicative of extraprostatic disease (Table 4). Epstein et allo used biopsy findings to distinguish "latent" from "significant" cancers in patients with stage Tlc prostate cancer. They did not find low length (less than 3 mm) cancer on needle biopsy to be predictive of small-volume tumors on radical retropubic prostatectomy. They did find any Gleason score 4 or 5 tumor, three or more positive biopsy cores, and any core with more than 50% tumor involvement to predict adverse pathologic Table 4. PROBABILITY OF PATHOLOGIC STAGE 3 DISEASE BY PREOPERATIVE GLEASON SCORE AND THE NUMBER OF POSITIVE SEXTANT BIOPSY SPECIMENS BASED ON LOGISTIC REGRESSION No. Positive Sextant Biopsy Specimens
Preoperative Gleason Score 4
5
6
7
8
9
0.06 0.12 0.23 0.39 0.57 0.74 0.86
0.31 0.49 0.67 0.81 0.90 0.95
-
-
~
0 1 2 3 4 5 6
0.01
-
-
-
0.02 0.04 0.09 0.17 0.30
-
0.59 0.75 0.87 0.93 0.97 0.98
0.99
'No data points for extrapolation. From Peller PA, Young DC, Marmaduke DP, et al: Sextant prostate biopsies, a histopathologic correlation with radical prostatectomy specimens. Cancer 75530-538, 1995; Copyright 0 1995, with permission of Wiley-Liss, a division of John Wiley and Sons, Inc.
WHO IS BEST BENEFITED BY RADICAL PROSTATECTOMY?
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characteristics. They also found PSA level and PSAD to be accurate predictors of tumor stage. These results collectively suggest that currently clinical and biopsy parameters are not predictive of pathologic stage and cannot discriminate "insignificant" from "significant" tumors.
SUMMARY
The last few years have taught us much about prostate cancer. We now recognize that prostate cancer, even if it is of low stage and low grade, is a relentlessly progressive disease, especially if found in men with prolonged (greater than 15 years) life expectancy. We now know that serum PSA is a valid endpoint after radical prostatectomy to definitively assess its ability to eradicate prostate cancer. We are learning better how to use a variety of clinical parameters to predict pathologic stage, and we are in the process of developing other markers that may be exploited to predict which patients with early-stage prostate cancer have surgically curable lesions. From these observations it is reasonable to conclude that the best candidates for radical prostatectomy are young men (those with 10 to 20 years of life expectancy) with impalpable, clinically organ-confined low- or moderate-grade prostate cancers.
References 1. Aus G, Hugosson J, Norlen L Long-term survival and mortality in prostate cancer treated with non-curative intent. J Urol 1W460-465, 1995 2. Aus G, Hugosson J, Norlen L: Need for hospital care and palliative treatment for prostate cancer treated with non-curative intent. J Urol 154:466-469, 1995 3. Catalona WJ, Smith D S 5 Year tumor recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J Urol 152:1851-1842, 1994 4. Catalona WJ, Richie JP, Ahmann FR, et al: Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: Results of a multicenter clinical trial of 6630 men. J Urol 151:1283-1290, 1994 Detection of organ-confined prostate 5. Catalona WJ, Smith DS, Ratliff TL, Basler JW: cancer is increased through prostate specific antigen-based screening. JAMA 27948954, 1993 6. Catalona WJ, Smith DS, Ratliff TL, et al: Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med 324:1156-1161, 1991 7. Chodak GW, Thisted RA, Gerber GS, et a 1 Results of conservative management of clinically localized prostate cancer. N Engl J Med 330:242-248, 1994 8. Cupp, MR, Bostwick DG, Myers RF, Oesterling J E The volume of prostate cancer in the biopsy specimen cannot reliably predict the quantity of cancer in the radical prostatectomy specimen on an individual basis. J Urol 153:1543-1548, 1995 9. Dietrick DD, McNeal JE, Stamey T A Core cancer length in ultrasound-guided systematic sextant biopsies: A preoperative evaluation of prostate cancer volume. Urology 45:987-992, 1995 10. Epstein JI, Walsh PC, Carmichael M, Brendler C B Pathologic and clinical findings to predict tumor extent of nonpalpable (Stage Tlc) prostate cancer. JAMA 271:368-374, 1994 11. Goad JR, Chang, SJ, Ohori M, Scardino PT: PSA after definitive radiotherapy for clinically localized prostate cancer. Urol Clin North Am 20727-736, 1993
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12. Humphrey PA, Baty J, Keetch D: Relationship between serum prostate specific antigen, needle biopsy findings, and histopathological features of prostatic carcinoma in radical prostatectomy tissues. Cancer 75:1842-1849, 1995 13. Johansson JE: Expectant management of early stage prostatic cancer: Swedish experience. J Urol 152:1753-1756, 1994 14. Johansson JE, Adami HO, Anderson S, et al: High 10 year survival rate in patients with early, untreated prostate cancer. JAMA 2672191-2196, 1992 15. Jones GW, Mettlin C, Murphy GP, et al: Patterns of care for carcinoma of the prostate gland: Results of a national survey of 1984 and 1990. J Am Coll Surg 180545-554,1995 16. Kabalin JN, McNeal JE, Price HM, et a1 Unsuspected adenocarcinoma of the prostate in patients undergoing cystoprostatectomy for other causes: Incidence, histology and morphometric observations. J Urol 141:1091-1094, 1989 17. Kaplan ID, Cox RS, Bagshaw M A Prostate specific antigen after external beam radiotherapy for prostatic cancer: Follow-up. J Urol 149:519-522, 1993 18. Montie JE, Wood DP, Pontes JE, et a1 Adenocarcinoma of the prostate in cystoprostatectomy specimens removed for bladder cancer. Cancer 63:381-385, 1989 19. Myers RP, Goellner JR, Cahill DR Prostate slope, external strictured ureteral sphincter and radical prostatectomy: The apical dissection. J Urol 138:543, 1987 20. Ohori M, Goad JR, Wheeler TM, et a1 Can radical prostatectomy alter the progression of poorly differentiated prostate cancer? J Urol 1521843-1849, 1994 21. Partin AW, Pound CR, Clemens JQ, et al: Serum PSA following anatomical radical prostatectomy: The Johns Hopkins experience after 10 years. Urol Clin North Am 20:713, 1993 22. Partin AW, Yo0 J, Carter HB, et al: The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol 15O:llO-114, 1993 23. Peller, PA, Young DC,Marmaduke DP, et al: Sextant prostate biopsies, a histopathologic correlation with radical prostatectomy specimens. Cancer 75:530-538, 1995 24. Rich AR On the frequency of occult carcinoma of the prostate. J Urol33215-223, 1935 25. Schmid HP, McNeal TE, Stamev T A Observations on the doubling time of prostate cancer: The use of several prostate-specific antigen in patients with untreated disease as a measure of increasing cancer volume. Cancer 71:7031-7040, 1993 26 Silverberg E, Lubera J: Cancer Statistics, 1986. Cancer 36:9-18, 1986 27 Stamey TA: Making the most out of six systematic sextant biopsies. Urology 452-12, 1995 28 Stamey TA, Ferrari MK, Sermid HP: The value of serial prostate specific antigen determinations 5 years after radiotherapy: Steeply increasing values characterize 80% of patients. J Urol 150:1856-1859,1993 29 Stamey TA, Freiha FS, McNeal JE, et a1 Localized prostate cancer. Relationship of tumor volume to clinical significance for treatment of prostate cancer. Cancer 71:933938, 1993 30 Steele GD, Jessup JM, Winchester DP, et al: National Cancer Data Base: Annual Review of Patient Care. Atlanta, American Cancer Society, 1995 31. Terris MK, Henry DJ, Johnstone IM,et al: Prediction of prostate cancer volume using prostate-specific antigen levels, transrectal ultrasound and systematic sextant biopsies. Urology 45:75-80, 1995 32. Walsh PC, Donker PJ: Impotence following radical prostatectomy: Insight into etiology and precaution. J Urol 128492, 1982 33. Walsh PC, Partin AW, Epstein J I Cancer control and quality of life following anatomical radical retropubic prostatectomy: Results of 10 years. J Urol 1521831-1836, 1994 34. Walsh PC, Quinlan DM, Morton RA, Steiner M S Radical retropubic prostatectomy: Improved anastomosis and urinary continence. Urol Clin North Am 17679, 1990 35. Warner J, Whitmore WF: Expectant management of clinically localized prostate cancer. J Urol 1521761-1765, 1994 36. Whitmore WF Jr, Warner JA, Thompson IM Jr: Expectant management of localized prostate cancer. Cancer 671091-1096, 1991 37. Parker SL, Tong T, Bolden S, et a 1 Cancer statistics 1996. Cancer 465-27, 1996
-
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38. Zagars G K Serum PSA as a tumor marker for patients undergoing definitive radiation therapy. Urol Clin North Am 20737-747, 1993 39. Zagars GK, vonEschenbach AC: Prostate specific antigen: An important marker for prostate cancer treated by external beam radiotherapy. Cancer 72.58, 1993
Address reprint requests to Gerald L. Andriole, MD Division of Urologic Surgery Washington University School of Medicine 4960 Children’s Place St. Louis, MO 63110
PROSTATE CANCER
+ 20
WHO IS BEST BENEFITED BY RADICAL PROSTATECTOMY? Robert B. Nadler, MD, and Gerald L. Andriole, MD
Adenocarcinoma of the prostate is the most commonly diagnosed cancer in American men. This year 317,100 men will be diagnosed with prostate cancer in the United States, and approximately 41,400 men will die of it.37It has been estimated that up to one third of men with newly diagnosed prostate cancer undergo radical prostatectomy, translating to an estimated 70,000 radical prostatectomies in 1995.15The increase in the number of radical prostatectomies to treat men with prostate cancer has occurred for several reasons. First is the dramatic increase in the detection of prostate cancer that has occurred over the past several years owing primarily to the use of serum prostate-specific antigen (PSA) testing in conjunction with digital rectal examination (Fig. By comparison, 10 years ago in 1986, prior to widespread use of PSA testing, 90,000 new cases of prostate cancer were diagnosed.26Thus, in 1996 there are more than 3 times more new cases of prostate cancer diagnosed than 10 years ago in the United States, and this trend may continue as a higher proportion of the population undergoes early detection. Second, the last few years have witnessed a profound “stage and age migration” for newly detected prostate cancer: Whereas only about 60% of cancers of the prostate detected in 1984 and 1990 were clinically organ-confined,15 more than 95% of tumors detected in aggressive early-detection programs are clinically organ-confined” Therefore, a higher proportion of newly detected tumors are potentially amenable to radical prostatectomy. Moreover, the application of early-detection strategies to younger men in their forties and fifties (as recommended by the American Cancer Society and American UroIogical Association) has also tended to increase the proportion of men with newly diagnosed organ-confined cancer who are suitable operative candidates. This increased and earlier (in terms of both patient age and tumor stage) detection of prostate cancer has coincided with a substantial increase in our 1 ) ? g 6
From the Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri
HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 10 NUMBER 3 JUNE 1996
581
582
NADLER & ANDRIOLE
21.4
10.0
PSA>4
DRE(+)
PSA>4
PSA<=4
PSA>4
DRE(-)
DRE (+)
DRE (+)
Method of Detection
PSA>4 DRE (+) TRUS (+)
Figure 1. Positive predictive value of various detection methods. DRE = digital rectal examination; TRUS = transrectal ultrasound. (From Catalona WJ, Richie JP, Ahmann FR, et al: Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: Results of a multicenter clinical trial of 6,630 men. J Urol 151:1283-1290, 1994; with permission.)
understanding of male pelvic anatomy, the third factor contributing to the increasing use of radical prostatectomy. Specifically, delineation of the precise anatomic pathways of the cavernosal nerves32and a greater understanding of the functional anatomy of the striated urinary ~phincter’~,” allowed for development of surgical techniques that allow removal of the prostate with low risk of side effects, especially impotence and urinary incontinence. The ability to perform anatomic radical prostatectomy without compromising potency or urinary continence has made radical prostatectomy substantially more acceptable to both the patient and the urologist. The fourth development that has tended to increase the utilization of radical prostatectomy as the treatment for patients with early-stage prostate cancer has been the impression among urologists that radiation therapy is associated with a substantial risk of biochemical failure, especially if patients are followed for a
WHO IS BEST BENEFITED BY RADICAL PROSTATECTOMY?
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prolonged period (more than 5 years). Some of the more compelling data have been reported from Stanford, an institution historically associated with a large experience with external beam radiation therapy for prostate cancer. In 1993, Stameyzs updated 124 unselected consecutive stage Tla to T4a prostate cancer patients treated with external beam radiation. At a mean follow-up of 2.6 years, 51% of patients demonstrated biochemical failure (rising serum PSA levels), and actuarial projections at 6 years were that 78% of patients would have precipitously increasing serum PSA levels. Subsequently, other investigators have generally confirmed the relatively high biochemical failure rates after radiation therapy: Z a g a r ~found ~ ~ a PSA failure rate approaching 50% at 5 years; Goad et all1 reported a 4-year actuarial biochemical progression rate of 56% even among patients proven histologically to be node negative; and Kaplan et all7reported a 41% failure rate defined by rising PSA or clinical relapse among men followed for a mean of 2.7 years. These relatively high biochemical failure rates, coupled with the high probability of histologically proven local failure (that is, positive prostatic biopsy) in up to 90% of such coupled with the known adverse implications of biopsy-proven local failure for the subsequent development of metastatic disease, have conspired to cause urologists to recommend radiation therapy less frequently for their patients with organ-confined prostate cancer. Although these trends have dramatically changed the way in which earlystage prostate cancer has been managed over the last several years, three new developments on the horizon may yet again significantly alter our approach to this disease. These developments, when completely exploited, may result in a more selective application of radical prostatectomy to men with early stage disease. These potential new developments are (1)an enhanced appreciation of the natural history of this disease, ( 2 ) a realistic assessment of the limitations of radical prostatectomy in controlling prostate cancer, and (3) a better understanding of various prognostic markers that will theoretically allow stratification of prostate cancers into one of three groups: those that are too small to warrant treatment, those that are both clinically significant and amenable to surgery, and those that are untreatable by surgery alone. Although our knowledge in each of these areas is currently relatively limited, further investigation holds the promise to accurately define who is best benefitted by radical prostatectomy. NATURAL HISTORY OF PROSTATE CANCER The natural history of prostate cancer generally has not been well defined for several reasons. Compared with many other cancers, adenocarcinoma of the prostate may be relatively slow growing and occur in elderly men who have a limited life expectancy. Moreover, prostate cancer is histologically recognizable in the prostates of more than one third of men over 50 years of age.1a,24 For these reasons, many clinicians have believed that prostate cancer is a relatively benign disease for most men, and that many patients will succumb to other causes. Epidemiologic studies have been interpreted to support this position, because men over age 50 traditionally have had a 9% chance of clinically evident prostate cancer and a 3% chance of death from prostate cancer, suggesting that only one man in three with clinically evident prostate cancer will die of it. Several recent studies, however, have caused many urologists to refine this view of the natural history of prostate cancer. 36 reported 75 men (selected from more than Whitmore and 4000 patients) with clinical stage B (T2) prostate cancer at Memorial Sloan-
584
NADLER & ANDRIOLE
Kettering Cancer Center who were managed expectantly if they failed to progress after 1 year of follow-up. Forty-five percent (34 of 75) of the patients were stage T2a or T2b and grade I. The overall disease-specific survival at 5 and 10 years was 100% and 91%, respectively, but it fell significantly at 15 and 20 years (67% and 37%, respectively). Most men needed palliative treatment for prostate cancer, and this was administered at a median of 9 years after diagnosis. These data suggest that, even among men with prostate cancer selected to do well (that is, low grade tumor and failure to progress during initial evaluation), prolonged follow-up (beyond 10 years) discloses that a majority will succumb to prostate cancer. Johansson et all3,l4 reported on the expectant management of a select group of 223 men (from a total of 654 newly diagnosed prostate cancer patients) who were followed a mean of 12.5 years. Only 10% of patients died of prostate cancer, whereas 84% died of other causes. The 10-year disease-specific survival rate was 85%. There are important limitations of this study; one is that 66% (148 of 223) of the patients had grade I cancer often diagnosed by transurethral resection of prostate (TURP) and staged as clinical A1 (maximum of 5% chips positive). The impact of overweighting this study group with low-grade tumors is evident when one notes that only 7 of 48 patients (14%) with grade I disease died of prostate cancer, whereas 7 of 66 (11%)of grade I1 and five of nine patients (56%) with grade 111 prostate cancer died of prostate cancer. Second, during the first 2 years of patient accrual, only patients with grade I disease were treated expectantly, whereas patients with higher-grade tumors were randomized to active, early treatment or delayed therapy. This policy introduces a significant bias in this study group because patients with the most favorable tumors have been followed the longest, thus having a proportionally greater impact on the actuarial outcomes of this cohort. Furthermore, the study patients were elderly; their mean age at diagnosis was 71.4 years. By comparison, most series of radical prostatectomy consist of men with mean ages of 59 to 64.2l Overall, the results of the Johansson study cannot be considered definitive because of the substantial number of favorable selection factors among the study population. If anything, one may argue that this study merely validates urologists' historical approach to septuagenarians with low-grade disease, that is, watchful waiting. It is important to consider that one third of men with newly diagnosed prostate cancer in 1992 were treated with watchful waitingm Chodak et a17 performed a pooled analysis (meta-analysis) using data on individual patients from six nonrandomized studies of men with clinically localized prostate cancer treated expectantly. Disease-specific survival at 10 years was 87% for grade I or I1 tumors and 34%for grade 111tumors. Metastasisfree survival was 81% for grade I, 58% for grade 11, and 26% for grade I11 disease at 10 years. Of the 828 patients in the analysis, the median age was 69 years and the mean follow-up was only 6.5 years. As is common among studies evaluating the natural history of prostate cancer, more than half (59%) of the patients had grade I tumors. Interpreted another way, the data from this evaluation demonstrate that even in a relatively favorable select group of patients, the metastatic rate at 15 years is 40% for grade I, 70% for grade 11, and 85% for grade 111, again suggesting that longer-term follow-up (more than 10 years) is necessary to truly define the natural history of prostate cancer. Recently, a new long-term analysis of 514 prostate cancer patients treated with noncurative intent (watchful waiting with or without hormonal manipulation) was reported from Sweden by Aus et al.'rz All patients with prostate cancer who died consecutively from 1988 to 1990 were analyzed. Prostate cancer was diagnosed between 1961 and 1990; thus, untreated patients were followed for
WHO IS BEST BENEFITED BY RADICAL PROSTATECTOMY?
585
Table 1. CAUSE OF DEATH IN STAGE MO PROSTATE CANCER PATIENTS IN 5-YEAR PERIODS Years
0 to 5 5tO 10 10 to 15 15 to 20 20 + Total No. (%)
No. Cancer Deaths
No. Deaths of Other Causes
Percent at Risk of Cancer Death
51 57 21 15 5
80 48 16 6 2
39 54 57 71 71
149 (50)
152 (50)
from Aus G, Hugosson J, Norlen L: Long-term sutvival and mortality in prostate cancer treated with non-curative intent. J Urol 154:460-465, 1995; with permission.
up to 30 years. Aus et a1 found that prostate cancer was the direct cause of death or contributed to death in 62% (319 of 514) of patients. Metastases were known to be present in at least 58% (296 of 514) of patients at death (the metastatic status at death was unknown in 21%). The mean survival time for the entire group of men was 6.8 years. Of 301 patients with stage MO (no bony or soft-tissue metastases) prostate cancer at diagnosis, 149 (50%) died as a consequence of prostate cancer (Table 1).Among the 71 (24%) who were considered radical prostatectomy candidates (that is, Tlb-T3MO, grade I or I1 and age 70 or less), 59% died of prostate cancer. This study is important because it highlights the substantial increased risk of prostate cancer-related death and morbidity that occurs when patients are followed for more than 10 years. Long follow-up is necessary to record the cause of death for each patient with prostate cancer. This study supports the conclusion that 10 years of follow-up is inadequate, and that it is not safe to assume that a patient who has not died of prostate cancer (or developed metastatic disease) at 10 years will not do so at 15 to 20 years. This study also shows that age at diagnosis is directly linked to the probability of developing metastatic disease or of dying of prostate cancer. Seventy percent of men with stage MO prostate cancer at age 65 or less and 100% of men age 55 or less died of prostate cancer. Thus, natural history studies evaluating men who are in their seventies do not adequately portray the relentless, progressive nature of prostate cancer, especially among younger men. Finally Aus et al’s study quantified the significant morbidity associated with expectant management of prostate cancer. Invasive procedures to achieve local control and palliative radiation are often necessary. Sixty-one percent (193 of 319) of patients who later died of prostate cancer needed one or more palliative treatments (TURP, radiation treatment, or upper tract urinary diversion). The probability of needing palliative therapy was directly correlated with young age and survival beyond 10 years. These procedures are associated with lengthy hospitalization times, which average 5 weeks for patients dying of prostate cancer in Aus et al’s study.* These additional procedures and long hospitalizations add obvious associated expense (Table 2). In the aggregate, our knowledge of the natural history of prostate cancer is increasing. It appears that many patients with early-stage disease will do well for the first 10 years; however, over the long term, for men with at least 15 years’ expected survival, prostate cancer often progresses, metastasizes, and causes death. The “benign” picture painted by some studies of expectant man-
586
NADLER & ANDRIOLE
Table 2. PATIENTS WHO LATER DIED OF PROSTATE CANCER DIVIDED BY M STAGE AT DIAGNOSIS* Stage MO (149 patients)
Mean Values ____~
~
Stage M1 (152 patients)
P Value
~
Days hospital care Occasions/patient Mean months’ survival No. patients undergoing transurethral prostatic resection (“10) No. transurethral prostatic resections No. patients receiving palliative radiation (%) No. patients undergoing upper urinary tract procedure (%)
35 3.2 26
87 (58)
38 (25) 49
<0.0001
47 (31)
NS
18 (12)
0.0315
155
52 (35) 33 (22)
~~
NS
41 4.3 94
~
<0.0004 <0.0001 <0.0001
~
‘301 patients with stage Mx disease excluded. NS = not significant. From Aus G. Hugosson J, Norlen L: Need for hospital care and palliative treatment for prostate cancer treated with non-curative intent. J Urol 154:466469, 1995; with permission.
(El
Local Progression
1.00 -
0.75
-
(68)
n
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0 L
(6)
a
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c 0 -A Lo Lo
0.25 -
m 0 L
11.
0.00 -
d
1
4
i
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lb
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Figure 2. Kaplan-Meier actuarial progression-free likelihood for overall progression, PSA detectability only, local progression, and distant progression. Numbers in parentheses represent number of men in analysis at time interval. (From Partin AW, Pound CR, Clemens JQ, et al: Serum PSA following anatomical radical prostatectomy: The Johns Hopkins experience after 10 years. Urol Clin North Am 20:71%725, 1993.)
WHO IS BEST BENEFITED BY RADICAL PROSTATECTOMY?
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agement are misleading, because their follow-up is relatively brief and they considered predominantly elderly men with low-grade tumors. AN APPRAISAL OF THE DISEASE-CONTROL CAPABILITIES OF RADICAL PROSTATECTOMY IN CONTEMPORARY
SERIES Several studies have now been reported that delineate the ability of radical prostatectomy to eradicate prostate cancer. One such study reported on 955 men with clinically localized prostate cancer (clinical stage T1 and T2) who underwent anatomic radical retropubic prostatectomy. The average age of these patients was 59.4 years (that is, 10 to 15 years younger than that of most observation series), 49% were T2a, and 45% had Gleason score 6 or greater. Patients were followed by annual examinations and serum PSA levels.21,33 At 10 years the likelihood of an undetectable PSA level was 70% for the entire group; 23% had an isolated PSA elevation, 7% developed distant metastases, and 4% developed local recurrence (Fig. 2). The likelihood of a detectable postoperative PSA elevation was directly related to pathologic stage, grade, and preoperative serum PSA level. At 10 years’ actuarial analysis, 85% of men with pathologically organ-confined disease and 82% with focal capsular penetration had undetectable serum PSA levels. In comparison, 54% with established capsular penetration and low- or moderate-grade disease, 42% with established capsular penetration and high-grade disease, 43% with seminal vesical involvement, and none with positive lymph nodes have an undetectable PSA (Table 3). It is clear from these data that radical prostatectomy cures most men with pathologically organ-confined disease and tumors that manifest only minimal capsular penetration. Patients with high-grade disease, locally advanced disease (capsular penetration or seminal vesicle invasion), or distant disease (nodal metastases) are infrequently cured. The fact that almost one third of men in the entire series had evidence of disease recurrence should be put in perspective; many patients entered in the series had relatively large tumors diagnosed in the pre-PSA era. Unlike the Johansson study, which entered the most favorable patients earliest, in this study (and all other reports of radical prostatectomy) the ”worst” patients were entered first and are followed the longest, thus imparting inappropriately high overall failure rates when actuarial analysis is performed. Catalona and Smith3reported similar results in 925 men with clinical T1 or
Table 3.10-YEAR ACTUARIAL LIKELIHOOD OF UNDETECTABLE PSA AFTER RADICAL PROSTATECTOMY Undetectable PSA (“YO) Pathologic Stage
Walsh et a133
T1 orT2 T3a (focal) T3a (established) Gleason 2-6 Gleason 7-10 T3b N1
85 82
54 42 43 0
Ohori et alZo
Catalona and Smith3
90
71
59
58
-
-
-
-
21 0
588
NADLER & ANDRIOLE
T2 prostate cancer. Recurrence was defined as a detectable PSA level postoperatively. The probability of nonprogression correlated with tumor stage and grade: 91% of patients with organ-confined disease had no progression at 5 years as compared with 74% of patients with positive margins or microcapsular penetration. Only 32% of patients with positive seminal vesicles and virtually no one with positive lymph nodes had no progression at 5 years, and at 10 years the success rates were slightly worse (see Table 3). These data support the conclusion that radical prostatectomy effectively eradicates prostate cancer in patients with pathologically organ-confined disease or early (focal) capsular penetration. Pathologic stage is a powerful predictor of outcome from radical prostatectomy, even in men with poorly differentiated disease. Ohori et a120 evaluated 500 patients with clinical T1 to T3 prostate cancer. Gleason score 7-10 cancers comprised 40% of the population and were pathologically more advanced than tumors with Gleason score less than or equal to 6: 58% penetrated the capsule and 21% invaded the seminal vesicle. These pathologic findings predicted a higher probability of failure: At 5 years 36% of Gleason score 7 or greater cancers versus only 10% of Gleason score 6 or less cancers. In this study, poorly differentiated prostate cancer was found to be pathologically advanced more than 70% of the time, but among the minority with poorly differentiated tumors that were pathologically organ-confined, 85% had no evidence of progression at 5 years (Fig. 3). In summary, the data from these series demonstrate that radical prostatectomy nearly always eradicates pathologically organ-confined tumors of any grade, as well as a large majority that penetrate the capsule if they are low to moderate grade (Gleason score 6 or less). Radical prostatectomy is much less
-
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Figure 3. Among 226 cancers confined to prostate, there were no significant differences
in rates of progression, regardless of Gleason score of cancer in radical prostatectorny specimen. Ticks above line represent censored patients. N.S. = not significant. (From Ohori M, Goad JR, Wheeler TM, et al: Can radical prostatectomy alter the progression of poorly differentiated prostate cancer? J Urol 152:1843-1849, 1994; with permission.)
WHO IS BEST BENEFITED BY RADICAL PROSTATECTOMY?
589
effective at curing patients with high-grade (Gleason score 7 or greater) prostate cancer if there is capsular penetration or seminal vesicle invasion. Patients with pelvic lymph node involvement have little chance of being cured by surgery (see Table 3). The implications of these observations should be juxtaposed to the current stage/grade distribution of tumors discovered in early detection tumors: Up to 85% are pathologically organ-confined (especially if repetitive screening strategies are employed) and approximately 90% are well or moderately differentiated. Thus, early-detection strategies find precisely the type of tumors that radical prostatectomy can effectively eradicate. One can anticipate that future reports of radical prostatectomy will show overall improved results as more of the patients in these series will have more favorable pathologic stages. USE OF PROGNOSTIC MARKERS
Because only pathologically organ-confined prostate cancer and those with very early microscopic evidence of capsular penetration are effectively eradicated by radical prostatectomy, it is necessary to develop better tools than those currently available to predict preoperatively which patients harbor surgically amenable disease. Moreover, it is also important to exclude men with clinically "insignificant" prostate cancer. At the present time, the best predictor of pathologic stage is the combination of serum PSA, Gleason score, and clinical T stage. Partin et alz2from Johns Hopkins published a series of nomograms to help the clinician predict the pathologic stage of patients with clinically localized prostate cancer. Although the nomograms are helpful in managing patients, they provide relatively crude probabilities that often cluster around 50%. Moreover, they often fall short of identifying which patients with high Gleason score tumors are good surgical candidates and which patients have small-volume disease. Some authors have attempted to use additional information beyond T stage, serum PSA, and tumor grade to improve ability to predict pathologic stage. Most studies have attempted to exploit the information contained in sextant prostatic biopsies. Most have focused on the number of positive cores and the total length of cancer in all cores as predictors of tumor volume, clinical significance and pathologic stage. Stamey and colleaguesz7have attempted to use tumor volume as a surrogate for pathologic stage. They have assumed that cancers that are less than 0.5 cc among patients aged 65 years or less, and less than 1.0 cc among men 72 years or less are too small to deserve treatment. They derive this assumption from Surveillance, Epidemiology, and End Results (SEER) data from the National Cancer Institute. Because an estimated 8% of all men present with clinically significant prostate cancer (stage Tlb and Stamey applied this 8% cut-off to 139 men undergoing cystoprostatectomy for bladder cancer in which 55 (40%) were incidentally found to have prostate cancer.I6The 11 men (8% of 139) with the largest cancers were inferred to be the men with the highest probability of developing clinically evidence cancer. All 11of these men had tumors larger than 0.5 cc. These authors have also estimated that tumors larger than 6.0 cc are incurable, based on detailed prostate cancer maps on 850 consecutive radical prostatectomy patient^.^' These authors support these estimates by noting that 80% of prostate cancers are less than 0.5 cc and 50% are less than 0.05 cc, and with the 4 to 5 years needed for prostate cancer to double, most men will not live long enough to be affected by such a small volume of prostate cancer.=, 27 To predict tumor volume, they consider the presence of core cancer lengths greater than or equal to 3 mm or more to define tumors larger than 0.5 cc. For men with a total core cancer length less than or
590
NADLER & ANDRIOLE
equal to 3 mm on sextant biopsy, repeat biopsies are recommended to ensure the tumor size has not been underestimated. Beyond length of cancer on sextant core biopsy, any high grade (Gleason score 4 or 5) tumor (irrespective of prostate cancer length) is considered significant? The validity of these assumptions must be tested before they are universally accepted. This is evident from the fact that other centers cannot duplicate these this findings. Cupp and colleaguess at the Mayo Clinic showed that transrectal needle biopsy is not accurate at predicting "significant" versus "insignificant" tumors. They found that less than 10% of "clinically insignificant" cancers (volume less than 0.5 cc, Gleason score less than 7) could be predicted preoperatively based on the percentage of cores involved, the length in millimeters of cancer per core, percent cancer in each core, or Gleason score. Humphrey and ColleagueP at Washington University looked at serum PSA, PSA density, number of positive biopsies, millimeters of carcinoma, percentage of carcinoma in biopsy tissue, and histologic grade with respect to tumor grade, volume, .and stage in 50 completely embedded radical prostatectomy specimens. They found no correlation between millimeters of carcinoma or percentage of carcinoma in biopsy cores and tumor size, stage, or grade. They did find PSA density (PSAD) and histologic grade on needle biopsy to be predictors of final histologic grade. More importantly, they found PSA, PSAD, and the number of needle biopsies with cancer could predict tumor size, but not stage, raising a question about the validity of using tumor volume as a surrogate for stage. Similar findings have also been reported by Peller and colleague^.^^ They found the number of positive sextant cores, preoperative PSA and Gleason score to be significant predictors of stage and volume. Specifically, they found a PSA value greater than 4.0 ng/dL and one or more positive sextant biopsies to be predictive of clinically significant tumor volume, and four or more positive cores and Gleason score 7-9 disease to be indicative of extraprostatic disease (Table 4). Epstein et allo used biopsy findings to distinguish "latent" from "significant" cancers in patients with stage Tlc prostate cancer. They did not find low length (less than 3 mm) cancer on needle biopsy to be predictive of small-volume tumors on radical retropubic prostatectomy. They did find any Gleason score 4 or 5 tumor, three or more positive biopsy cores, and any core with more than 50% tumor involvement to predict adverse pathologic Table 4. PROBABILITY OF PATHOLOGIC STAGE 3 DISEASE BY PREOPERATIVE GLEASON SCORE AND THE NUMBER OF POSITIVE SEXTANT BIOPSY SPECIMENS BASED ON LOGISTIC REGRESSION No. Positive Sextant Biopsy Specimens
Preoperative Gleason Score 4
5
6
7
8
9
0.06 0.12 0.23 0.39 0.57 0.74 0.86
0.31 0.49 0.67 0.81 0.90 0.95
-
-
~
0 1 2 3 4 5 6
0.01
-
-
-
0.02 0.04 0.09 0.17 0.30
-
0.59 0.75 0.87 0.93 0.97 0.98
0.99
'No data points for extrapolation. From Peller PA, Young DC, Marmaduke DP, et al: Sextant prostate biopsies, a histopathologic correlation with radical prostatectomy specimens. Cancer 75530-538, 1995; Copyright 0 1995, with permission of Wiley-Liss, a division of John Wiley and Sons, Inc.
WHO IS BEST BENEFITED BY RADICAL PROSTATECTOMY?
591
characteristics. They also found PSA level and PSAD to be accurate predictors of tumor stage. These results collectively suggest that currently clinical and biopsy parameters are not predictive of pathologic stage and cannot discriminate "insignificant" from "significant" tumors.
SUMMARY
The last few years have taught us much about prostate cancer. We now recognize that prostate cancer, even if it is of low stage and low grade, is a relentlessly progressive disease, especially if found in men with prolonged (greater than 15 years) life expectancy. We now know that serum PSA is a valid endpoint after radical prostatectomy to definitively assess its ability to eradicate prostate cancer. We are learning better how to use a variety of clinical parameters to predict pathologic stage, and we are in the process of developing other markers that may be exploited to predict which patients with early-stage prostate cancer have surgically curable lesions. From these observations it is reasonable to conclude that the best candidates for radical prostatectomy are young men (those with 10 to 20 years of life expectancy) with impalpable, clinically organ-confined low- or moderate-grade prostate cancers.
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Address reprint requests to Gerald L. Andriole, MD Division of Urologic Surgery Washington University School of Medicine 4960 Children’s Place St. Louis, MO 63110