PROSTATE-SPECIFIC ANTIGEN AFTER ANATOMIC RADICAL RETROPUBIC PROSTATECTOMY

PROSTATE-SPECIFIC ANTIGEN: THE BEST PROSTATIC TUMOR MARKER

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PROSTATE-SPECIFIC ANTIGEN AFTER ANATOMIC RADICAL RETROPUBIC PROSTATECTOMY Patterns of Recurrence and Cancer Control Charles R. Pound, MD, Alan W. Partin, MD, PhD, Jonathan I. Epstein, MD, and Patrick C. Walsh, MD

Prostate-specific antigen (PSA) is a valuable tumor marker in the follow-up evaluation of men who have been treated for prostate cancer. An undetectable level of PSA serves as the gold standard for tumor-free status in men after radical prostatectomy.'O,l2 In 1993, we reported our initial 10-year experience with PSA values after anatomic radical retropubic prostatectomy (RRP) for 955 men with localized disease.12 We now have expanded this series to include 1623 men. In this article we describe the actuarial likelihood of an undetectable PSA level for this group of men who have undergone surgery at The Johns Hopkins Hospital since 1982. We examine the influence of clinical and pathologic parameters, which alone and in combination are shown to have a significant effect on the actuarial rate of PSA recurrence after surgery. In addition, we show that anatomic RRP with preservation of the neurovascular bundles had no adverse effect on cancer control. A Gleason score of at least 8 or involvement of the seminal vesicles or lymph nodes is indicative of eventual failure from distant metastases. We show that in addition to these variables, the timing of the development of a detectable serum PSA also is important in predicting eventual local versus distant failure. MATERIALS AND METHODS Patients

Between May 1982 and March 1995, 1699 men underwent anatomic RRP with pelvic lymph-node

dissection for clinically localized adenocarcinoma of the prostate (Tl, T2, T3a) at our institution. All procedures were performed by a single surgeon. The average age was 59 & 6 years (range 34-76). Of these men, 1623 (95%) were included in this analysis. Table 1 illustrates the distribution of the clinical stages of these men.15 To evaluate the ability of radical prostatectomy as single therapy to cure localized prostate cancer, 76 men (4.5%) were excluded from the study group: 20 men (1.2%) were excluded based on inadequate postoperative PSA data; 23 men (1.4%) underwent immediate adjuvant radiation therapy; 11 men (0.6%) were treated with immediate adjuvant hormonal therapy; nine men (0.5%) were clinical stage DO/D2 and were excluded for this reason; nine men (0.50/,) received preoperative hormonal therapy; three men (0.2%) received preoperative radiation therapy; and one patient (0.1%) died in the immediate postoperative interval. Twenty of the 23 men excluded from the group because of immediate adjuvant radiation therapy received this therapy because of a positive surgical margin. Pathologically, three of these men had organ-confined disease, 12 men had capsular penetration only, five men had positive seminal vesicles without involvement of the pelvic lymph nodes, and three men had metastases to pelvic lymph nodes. Eight of 23 men who received immediate adjuvant radiation therapy have undetectable PSA levels 2 or more years after surgery without additional therapy. More than half (63%) of these men

From the Departments of Pathology (JIE) and Urology (CRP, AWP, JIE, PCW), James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland

UROLOGIC CLINICS OF NORTH AMERICA VOLUME 24 NUMBER 2 * MAY 1997

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Table 1. CLINICAL STAGE, PREOPERATIVE PSA LEVEL, GLEASON SCORE, AND PATHOLOGIC STAGE IN MEN UNDERGOING ANATOMIC RADICAL RETROPUBIC PROSTATECTOMY Variable

No. of Patients

Percent of Total

TNM T1a Tlb T1c T2a T2b T2c T3a Total

55 109 343 638 337 97 44 1623

3 7 21 39 21 6 3 100

399 619 253 83 1354

29 46 19 6 100

61 308 563 538 153 1623

4 19 35 33 9 100

658 380

41 23

373

23

95

6

115

7

1621

100

Serum PSA (ng/mL)

0-4 4.1-10 10.1-20 >20 Total Gleason score 2-4 5 6 7 8-1 0 Total Pathologic stage Organ confined Capsular penetration with Gleason score less than 7 Capsular penetration with Gleason score greater than or equal to 7 Involvement of the seminal vesicles, negative lymph nodes Micrometastases to pelvic lymph nodes Total

have been followed for at least 5 years postoperatively: seven of 23 men have detectable PSA levels as the only indication of disease recurrence, but three received additional hormonal therapy, five men have developed metastatic disease, and one man is dead from cancer. None of the 11 patients excluded from our analysis because of immediate adjuvant hormonal therapy showed organ-confined disease. Seven men had microscopic metastatic spread to the pelvic lymph nodes discovered in the final pathologic specimen, and the four men with negative lymph nodes had involvement of the seminal vesicles. There were four men with positive surgical margins. Only two of 11 men have an undetectable PSA after at least 2 years of follow-up, and two other men have a detectable PSA as their only evidence of disease recurrence. Seven men developed distant metastases, and six of these seven are dead of cancer.

Preoperative Evaluation and Pathologic Characteristics

Preoperative evaluation involved a digital rectal examination, a serum PSA assay measured in ng/ mL (Hybritech-Tandem, Hybritech, San Diego, CA), a serum enzymatic prostatic acid phosphatase measurement (thymolphthalein monophosphate assay; normal less than 0.8 IU/L), and a nuclear bone scan. The PSA assay was performed on serum that was collected before or at least 4 weeks after prostate biopsy or transurethral resection of the prostate. Pathologic diagnosis of prostate cancer preoperatively was based on examination of prostatic tissue obtained through transrectally or digitally guided prostate biopsy, transurethral resection of the prostate, or fine-needle aspiration. Histologic scoring was performed using the Gleason scoring system. Pathologic evaluation of the operative specimen was performed as previously described.'* Based on this evaluation, tumors were determined to be organ-confined disease, penetrating the prostatic capsule without extension to the seminal vesicles, involving the seminal vesicles without nodal disease, or spread to pelvic lymph nodes. A complete description and justification of this pathologic staging system has been p ~ b l i s h e d . ~ In , ~ *our ' ~ previous report, we subdivided the category of capsular penetration into focal capsular penetration (<2-3 glands beyond the prostatic capsule) and established capsular penetration (>2-3 glands beyond the prostatic capsule). Although Epstein et a15 have shown that there is a significant difference in recurrence between tumors with focal capsular penetration or established capsular penetration, they also have determined that the best pathologic predictor of disease progression was obtained using a multivariate model combining postoperative Gleason score, surgical margin status, and the presence or absence of and extent of capsular penetration. In this work, we chose to group patients with capsular penetration into a single category that greatly simplifies interpretation of the graphic analyses. Table 1 describes the distribution of patients according to the TNM clinical staging system, preoperative PSA, postoperative Gleason score, and final pathologic stage.

Patient Follow-up and Definitions of Progression and Potency

Postoperative follow-up data were obtained through routine serum PSA assays and digital rectal examinations performed every 3 months for the first year, semiannually the second year, and annually thereafter. Average length of follow-up was 5 f 3 years (range 1-13 years). One-hundred ninety-three men (12%)were followed for at least 10 years postoperatively. More than half of these men (829/1623, 51%) have been followed for 5

PROSTATE-SPECIFIC ANTIGEN AFTER ANATOMIC RADICAL RETROPUBIC PROSTATECTOMY

397

years or longer. Table 2 illustrates the length in years of follow-up available for all 1623 patients. Disease recurrence is defined in three ways. A biochemical recurrence is a serum PSA level which is detectable postoperatively (>0.2 ng/mL). A local recurrence is defined as palpable induration at the operative site in the presence of an elevated serum PSA with or without a positive biopsy. A positive biopsy without palpable induration also is evidence of local recurrence. Distal recurrence is shown by a positive bone scan or radiographic evidence of retroperitoneal adenopathy. By our exclusion criteria, no patient included in this analysis received radiation or hormonal therapy postoperatively before demonstration of disease recurrence as evidenced by a detectable.PSA level or clinical evidence of local or distant failure. Therefore, adjuvant therapy had no impact on time to progression. To determine if the anatomic approach with preservation of sexual function had an effect on cancer control, we reviewed the postoperative potency status of our patient group in relationship to likelihood of disease progression. only men known to be potent before radical prostatectomy were included in this analysis. Information regarding a patient’s preoperative as well as postoperative potency status was available on 1534 of 1623 patients (95%). Potency following surgery is an indication of surgical preservation of at least one neurovascular bundle. Men were considered potent after radical prostatectomy if they had erections that were sufficient for intercourse. Men without erections, as well as those with partial erections not sufficient for penetration were considered impotent.

detectable PSA (>0.2 ng/mL) was the only evidence of recurrence in 129 men (7.9%). Forty-one men (2.5%) have recurred locally without evidence of distant spread, and 88 men (5.4%) have distant metastases with or without evidence of local recurrence. Nine men (0.6%) who received radiation for an isolated elevation of PSA had a subsequent return of PSA to an undetectable level. Although their PSA continues to be undetectable, they are included in calculations of overall PSA progression as failures but are not included in determinations of type-specific recurrence in that their site of recurrence (local versus distant) has not been determined. Kaplan-Meier statistical analysis (Fig. 1) showed an overall actuarial 5- and 10-year recurrence-free likelihood for any type of recurrence of 80% and 68% (confidence intervals 78%-83% and 63%-72%, respectively). The actuarial likelihoods of having an isolated elevation of serum PSA only at 5 and 10 years after anatomic RRP were 10% and l8%, respectively. Overall, the actuarial 5- and 10-year PSA recurrence-free rates for men who developed local recurrence without distant metastases were 96% and 92%. For men who developed distant metastases with or without local recurrence, the overall actuarial 5- and 10-year PSA recurrence-free rates were 93% and 91%. The 5and 10-year actuarial likelihood of remaining free of a PSA, local without distant, or distant with or without local recurrence is included in Figure 1. Although it has been reported by other authors; no patient in our analysis was determined to have developed a local recurrence or distant metastases with an undetectable PSA at the time of progression.

RESULTS AND DISCUSSION

Clinical Stage and Progression

Overall Progression

Figure 2 illustrates the Kaplan-Meier analysis of the likelihood of having an undetectable PSA based on the TNM clinical stage, preoperative serum PSA, and postoperative Gleason score. No patient with Tla disease had a detectable PSA postoperatively. Patients with Tlc disease had an 86% progression-free probability at 5 years. This differs from our previous report, in which no Tlc patient had evidence of progression at 7 years of follow-up. This is undoubtedly because of the recent increase in the number of men treated with Tlc disease. Five- and 10-year actuarial progression-free probabilities for the remainder of the clinical stages are provided in Table 3 (upper panel). We had previously shown a significant difference in the 10-year recurrence-free probability between stages T2a and T2b; the present analysis suggests that stage T2a and T2b tumors behave similarly with extended follow-up.

Of one thousand six hundred twenty-three men, 267 (17%) have shown a recurrence after RRP. A Table 2. YEARS OF FOLLOW-UP AVAILABLE ON 1623 MEN AFTER ANATOMIC RADICAL RETROPUBIC PROSTATECTOMY

Years of Follow-up 1 2 3 4 5 6 7 8 9 10 11 12 13

Totals

Percent

.

No. of Patients

of Total

1623 1328 1141 973 829 687 535 41 1 293 193 103 42 11 1623

100 82 70 60 51 42 33 25 18 12 6 3 1 100

Preoperative PSA and Progression

Of the 1623 men, 1354 (83%) had preoperative PSA values available. These patients were divided

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Years Postoperative Figure 1. Kaplan-Meier actuarial progression-free likelihood for overall progression, isolated PSA elevation only, local recurrence, and distant progression f local progression. One thousand six hundred twenty three men were included in the analysis.

into four groups based upon this measurement: PSA less than 4 ng/mL, PSA 4.1 to 10 ng/mL, PSA 10.1 to 20 ng/mL, and PSA greater than 20 ng/mL. Table 1 and Figure 2 show actuarial progression-freeprobability based on the preoperative PSA value. There was a statistically significant difference between recurrence-free likelihoods of men in all PSA groups. Unlike our previous analysis, the probability of remaining free of recurrence at 10 years was statistically significant ( P = 0.0003) between men with preoperative PSA level of 10.1 to 20 ng/mL and those with a level greater than 20 ng/mL.

Gleason Score and Progression

In the analysis of Gleason score and its relationship to disease recurrence, Gleason scores 2 to 4 were considered as a single group, as were scores 8 to 10. Kaplan-Meier analysis of Gleason score with regard to progression-free probability is shown in Figure 2 as well as in Table 3. The recurrence-free probability of men with Gleason score 7 was previously shown not to be significantly different from that of men with higher grade disease (Gleason score Although not shown in our previous report, other reports have shown a significant difference in progression between tumors with Gleason score 7 and those of In the present higher grade (Gleason score 8-10).3,5 analysis, the likelihood of an having an undetectable PSA at 10 years was statistically different between men with Gleason score 7 and those with

Gleason score 8 to 10 (46% versus 23%, P < 0.00001). At 10 years, the likelihood of men with Gleason 8 to 10 disease having a PSA recurrence is greater than 80%.

Pathologic Stage, Gleason Score, and Surgical Margins in Relation to Progression

The best stratification of actuarial progressionfree probabilities at 5 and 10 years is obtained by grouping patients based on a combination of pathologic stage, Gleason score, and surgical margin status, as was previously demonstrated by Epstein et a1.5 Kaplan-Meier progression-free analyses for men grouped in accordance with these variables are illustrated in Figure 3. In men with capsular penetration with Gleason scores 2 to 6, the status of the surgical margin had a significant ( P < 0.01) effect on outcome at 10 years, but the outcome in both groups was good (likelihood of an undetectable PSA at 10 years was 89% with a negative margin and 72% for men with a positive margin). In men with capsular penetration but higher-grade tumors (CP+, Gleason score 2 7), the presence of a positive surgical margin had a significant effect ( P < 0.00001) on actuarial progression-free likelihood (see Fig. 3). Also notable is the fact that men with capsular penetration, high-grade disease, and a positive surgical margin had recurrence at a rate similar ( P = 0.6) to tumors in men with involvement of the seminal vesicles (see Fig. 3).

PROSTATE-SPECIFIC ANTIGEN AFTER ANATOMIC RADICAL RETROPUBIC PROSTATECTOMY

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Figure 2. Kaplan-Meier actuarial likelihood of PSA recurrence by clinical stage (A), preoperative serum PSA levels (ng/mL) (B), and Gleason score (C).

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Table 3. CLINICAL STAGE, PREOPERATIVE PSA, AND GLEASON SCORE IN RELATION TO ACTUARIAL RECURRENCE-FREE RATE AT 5 AND 10 YEARS AFTER ANATOMIC RADICAL RETROPUBIC PROSTATECTOMY Actuarial Percentage (95% CI) Variable

5Y

10 Y

TNM T1a Tlb T1c T2a T2b T2c T3a Serum PSA (ng/mL)

100 89 (81-94) 86 (7593) 85 (81-88) 69 (63-75) 63 (51-73) 61 (42-75)

100 89 (81-94) 86 (75-93) 68 (61-75) 57 (48-65) 53 (38-66) 52* (28-71)

94 (91-96) 82 (76-86) 72 (63-79) 54 (39-66)

87 (74-94) 75 (67-81) 30 (5-62) 28 (9-51)

100 97 (94-99) 92 (88-95) 66 (61-71) 41 (32-50)

94 91 78 46 23

0-4 4.1-10 10.1-20 >20

Gleason score 2-4 5 6 7 8-1 0

(62-99) (84-95) (66-86) (34-56)

(13-35)

'&year data.

Progression: Comparison with Other Reported Series

Several radical prostatectomy series have reported on the follow-up of men after surgery with

respect to PSA recurrence.', 11, 16, l9 Table 4 summarizes the demographics and clinical and pathologic stages in these series. The Washington University series showed actuarial PSA progression rates of 78% and 65% at 5 and 10 years respectively after radical prostatectomy in a cohort of nearly 1000 men.' The Baylor group showed a 76% and 73% 5- and 10-year PSA progression-free rate after radical prostatectomy in more than 500 men." These data are similar to our previously reported 5- and 10-year PSA recurrence rates and to those of the present series. Two other radical prostatectomy series do not confirm our PSA progression results. The UCLA group showed PSA progression-free rates of 69% and 47% at 5 and 10 years in a group of more than 600 men.16The Mayo Clinic series of more than 3000 men treated with radical prostatectomy showed only a 52% PSA progression-free rate at 10 years after s~rgery.'~ The distribution of clinical stage T1 versus T2 patients in the present series differs from that of our earlier report. Whereas our 1993 report consisted of 17% T1 and 83% T2 patients, the present study is more heavily weighted to T1 patients (31%; Tlc-21%), with only 66% T2 patients (see Table 1). This observation can be explained by the recent increase in patients presenting with Tlc disease because of the increased use of PSA for early detection of localized prostate cancer. The present study also includes 3% T3 patients, which were not included previously. These factors, in conjunction with the fact that additional follow-up has shown that prostate cancer does recur after 5 years, explains the slight decrease in the 5- and 10year progression-free likelihoods in the present series.

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Years Postoperative Figure 3. Kaplan-Meier actuarial likelihood of PSA recurrence by a combination of pathologic stage, Gleason score, and surgical margin status (N = 1623). See section of text on methods for complete definitions of pathologic stages. OC = organ-confined; CP+ < 7, SM- = capsular penetration, Gleason score less than 7, and negative surgical margins; CP + , 2 7, SM + = capsular penetration, Gleason score greater than or equal to 7, and positive surgical margins; SV+ = positive seminal vesicles with negative lymph nodes; LN+ = positive lymph nodes.

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PROSTATE-SPECIFIC ANTIGEN AFTER ANATOMIC RADICAL RETROPUBIC PROSTATECTOMY Table 4. COMPARISON OF SEVERAL RETROPUBIC PROSTATECTOMY SERIES

Institution Johns Hopkins Washington University Baylor University UCLA The Mayo Clinic Present study

Primary Author Pattin12 Catalona’ Ohori” Trapassoq6 Zin~ke’~ Pound

No. 894 925

500 601 3170 1623

Mean Age (Y)

Months Follow-up, Mean (Range)

Percent T1

59?6 63c7 63 65 65c4 59?6

53 (12-120) 28 (0-123) 36 (1-110) 34’ (12-237) 60 60.4(12-156)

17 21 22 27 7 31

Percent T2

5-year PSA Progressionfree Likelihood

10-year PSA Progressionfree Likelihood

83 79 78t 73 93 66$

87 78 76 69 70 80

77 65 73 47 52 68

‘Median. t 4 % stage T3. $3% stage T3a. Modified from Partin AW, Walsh PC: Surgical management of localized prostate cancer. In Ragharan D, Scher H. Leibel S, et al (eds): Principles and Practice of Genitourinary Oncology. Philadelphia, Lippincott-Raven, 1997; with permission.

Progression and Postoperative Potency

In an effort to determine if the technique of anatomic RRP with preservation of neurovascular bundles influences cancer control, we compared actuarial recurrence-free probabilities according to pathologic stage and margin status between men who were potent and impotent postoperatively. These two groups are similar with regard to age distribution, Gleason score, and pathologic stage. Within all pathologic stages, there was no difference in actuarial recurrence-free probability between potent and impotent men after anatomic RRP (Fig. 4). In addition, there was no difference in actuarial PSA recurrence rates between potent and impotent men postoperatively if grouped according to low-grade (Gleason score 2-6) or highgrade (Gleason score 7-10) disease. One would expect differences in cancer control secondary to preservation of a neurovascular bundle to be most evident among men with capsular penetration and positive surgical margins. Yet, the actuarial PSA recurrence rates for these two groups are identical (see Fig. 4).

Timing of PSA Recurrence, Gleason Score, and Pathologic Stage to Distinguish Local Recurrence from Distant Metastases With or Without Local Recurrence

We previously showed that the timing of PSA recurrence, pathologic stage, and the Gleason score provided useful information for distinguishing local recurrence from distant metastases with or without local rec~rrence.’~ This information can be used to aid in the decision of the timing and type of adjuvant therapy following radical prostatectomy for men with an isolated elevation of PSA. In our previous study, 51 men were followed for an isolated elevation in PSA until clinical evidence of either local recurrence (N = 16 as defined in the methods section of this article) or distant me-

tastases with or without local recurrence (N = 35). Variables that best distinguished local recurrence from distant metastases were the timing of PSA recurrence, Gleason score, and pathologic stage. In general, those men who showed PSA recurrence less than 2 years following surgery had tumors with a Gleason score greater than 7 or had positive seminal vesicles or positive lymph nodes at the time of surgery and were more likely to demonstrate distant metastases. Nine of the men included in that report were excluded from the present series based on our previously mentioned exclusion criteria. Since that initial report, 87 additional patients have failed clinically with local recurrence (N = 29) or distant metastases (N = 58). We now have a combined total of 129 men (local, N = 41, and distant, N = 58) who have had recurrence. We tested the ability of the previously determined predictive variables to distinguish local recurrence from distant metastases in this combined group of patients. Table 5 shows the percentage of men with local recurrence versus distant metastases for the various clinical and pathologic variables. In summary, the variables that best distinguished between local recurrence and distant metastases were the timing of PSA recurrence, a Gleason score greater than 7, and positive seminal vesicles or pelvic lymph nodes. We recommend that all three variables be evaluated in attempting to distinguish between eventual local recurrence or distant metastases associated with a detectable postoperative PSA. The most important predictive variable, however, is the timing of PSA recurrence, and this should be weighted accordingly.

Survival

Overall actuarial cause-specific survival rates at 5 and 10 years in this group of 1623 men after anatomic RRP were 99% and 93%, respectively. There was no difference in cause-specific survival among men when grouped by TNM stage or pre-

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Figure 4. Kaplan-Meier actuarial likelihood of PSA recurrence by various pathologic stages for men who were preoperatively potent (N = 1573). See section of text on methods for complete definitions of pathologic stages. PSA recurrence data are presented based on postoperative potency status. Table 1 details the likelihood of PSA recurrence for all men in the study (N = 1623) by the various pathologic stages. Illustration continued on opposite page

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Figure 4 (Continued). Organ-confined (A), capsular penetration (B), capsular penetrationwith negative surgical margins (C), capsular penetration with positive surgical margins (D), seminal vesicle involvement (€), and lyrnpn noae invoivement (f).

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Table 5. COMPARISON OF GLEASON SCORE, PATHOLOGIC STAGE, AND TIMING OF PSA RECURRENCE BY

SITE OF RECURRENCE AFTER ANATOMIC RADICAL PROSTATECTOMY Variable

Number Gleason score 2-4 5-6 7 8-1 0

Pathologic stage Organ-confined Capsular penetration with negative surgical margins Capsular penetration with positive surgical margins Involvement of seminal vesicles Micrometastases to pelvic lymph nodes Timing of PSA recurrence In year 1 Within years 1-2 After year 2 After year 3

operative PSA level. With advancing histologic grade and pathologic stage, however, there was a significant difference in the cause-specific survival. Table 6 shows 5- and 10-year actuarial metastasesfree rates based on Gleason score and pathologic stage. Note that in this table, we have grouped Gleason scores into three categories-I (24), I1 (5-7), and I11 (8-l0)-for the purpose of comparison with previously reported data.z Chodak et alz summarized the results of six nonrandomized studies totaling more than 800 men who were treated conservatively with observation and delayed hormonal therapy for clinically localized prostate cancer. Actuarial survival statistics showed that grade was the most significant variable in predicting survival, with 81% of men with grade I (Gleason score 2 4 ) , 58% of men with grade I1 (Gleason score 5-7), and only 26% of men with grade I11 (Gleason score 8-10) tumors showing metastases-free survival at 10 years. The series analyzed and the summary presented by Chodak et al2 have been criticized severely for selection bias.17 The study Chodak et a12 included by Whitmore et all8 consisted of 65 hand-picked men who were selected for conservative management during a 40-year period. Johansson et a16 excluded 83 of 306 patients for their hand-picked series. Moskowitz et als excluded 38% of men and Jones7reported on only 233 of 312 men who underwent observation for clinically localized prostate cancer. As further evidence of selection bias in this meta-analysis, nearly 60% of the men in the Chodak analysis had grade I tumors, compared with only 4% in the present series. Chodak and associatesZshowed that 42% and 70% of the men with grade I1 disease, followed conservatively, developed metastatic disease at 10

Local Recurrence

Distant Metastases With or Without Local Recurrence

41 (34%)

88 (66Yo)

0% 55% 39% 11%

0% 45% 61Yo 89%

40% 54%

60% 46%

48%

52%

16% 7%

84% 93%

7% 10% 61 % 74%

93% 90% 39% 26%

and 15 years respectively. These progression statistics, although skewed by favorable selection bias within the individual studies, show the best data to date documenting the natural history of untreated clinical stage Tlc and T2 prostate cancer. Eighty-six percent of men with clinically localized prostate cancer in our present series presented with grade I1 disease (Gleason score 5-7), and of this group, 87% were at clinical stage Tlc or T2. This group of men (grade 11) showed only a 16% actuarial rate of development of metastatic disease (positive bone scan) 10 years after anatomic RRP. We believe that the higher failure rate for men

Table 6. ACTUARIAL 5- A N D 10-YEAR METASTASISFREE SURVIVAL IN RELATION TO GLEASON SCORE

AND PATHOLOGIC STAGE Actuarial Metastasisfree Survival f%) Variable

5Y

10 Y

100 95 76

100 84 38

99 99

99 99

98

91

92

77

96

68

Grade (Gleason score) I(2-4) II (5-7) 111 (8-10)

Pathologic stage Organ-confined Capsular penetration with Gleason score less than 7 Capsular penetration with Gleason score greater than or equal to 7 Involvement of seminal vesicles Micrometastases to pelvic lymph nodes

PROSTATE-SPECIFIC ANTIGEN AFTER ANATOMIC RADICAL RETROPUBIC PROSTATECTOMY

treated with conservative therapy in comparison to those with surgical treatment justifies radical prostatectomy as the treatment of choice for men with clinically localized (Gleason grades 2-7, TNM T1-T2) prostate cancer who are otherwise healthy and have a greater than 10-year life expectancy.

SUMMARY

In a series of 1623 men with a follow-up of 5 -t 3 years (range 1-13) after anatomic RRP for clinically localized prostate cancer, 17% (276/1623) have shown recurrence. A detectable PSA was the only evidence of recurrence in 7.9%, whereas 2.5% have recurred locally and 5.4% have developed distant metastases. The overall actuarial progression-free rate for these men at 10 years was 68%. Actuarial rates at 10 years were 18% for development of an isolated PSA recurrence, 8% for local recurrence, and 9% for distant recurrence. The actuarial likelihood of a postoperative recurrence increased with increasing clinical stage, Gleason score, preoperative PSA level, and pathologic stage. Although not shown in our previous report, the actuarial rate of recurrence of tumors with a Gleason score of 7 was statistically different from that of tumors of higher Gleason score (8-10). As well, men with preoperative PSA levels of 10.1 to 20 ng/mL experienced recurrence at a significantly lower rate than did men with preoperative PSA levels greater than 20 ng/mL. By using a combination of Gleason score, pathologic stage, and surgical margin status, we demonstrated that the presence of a positive surgical margin did not dramatically affect recurrence in tumors of Gleason scores 2 to 6 with capsular penetration. Surgical margin status was important in high-grade tumors with capsular penetration. In fact, tumors with capsular penetration, Gleason score of at least 7, and a positive surgical margin behaved similarly to tumors with invasion of the seminal vesicles. Preservation of potency did not adversely influence cancer control. The Gleason score, presence or absence of seminal vesicle or lymph node involvement, and the timing of PSA recurrence are all important variables in predicting eventual local versus distant failure associated with an isolated rise in serum PSA. Overall actuarial cause-specific survival at 5 and 10 years was 99% and 93%. Although there was no difference in survival among men grouped by TNM stage or preoperative PSA, advancing histologic grade and pathologic stage did have an effect on actuarial cause-specific survival. Men undergoing RRP for clinically localized prostate cancer showed a 16% actuarial rate of development of metastatic disease at 10 years. This is considerably better than conservative therapy and justifies RRP as the treatment of choice for men with clinically localized disease who are oth-

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erwise healthy and have a greater than 10-year life expectancy.

ACKNOWLEDGMENT We would like to express our sincere appreciation to Bonnie Baxley for her assistance in the preparation of the tables and references in this manuscript.

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Address reprint requests to Charles R. Pound, MD James Buchanan Brady Urological Institute Department of Urology The Johns Hopkins Hospital 600 North Wolfe Street Baltimore, MD 21287-2101