Do Margins Matter? The Prognostic Significance of Positive Surgical Margins in Radical Prostatectomy Specimens

0022-5347/05/1743-0903/0 THE JOURNAL OF UROLOGY® Copyright © 2005 by AMERICAN UROLOGICAL ASSOCIATION

Reprinted from Vol. 174, 903–907, September 2005 Printed in U.S.A.

DOI: 10.1097/01.ju.0000169475.00949.78

DO MARGINS MATTER? THE PROGNOSTIC SIGNIFICANCE OF POSITIVE SURGICAL MARGINS IN RADICAL PROSTATECTOMY SPECIMENS PETER SWINDLE,* JAMES A. EASTHAM,†, ‡ MAKOTO OHORI,* MICHAEL W. KATTAN,* THOMAS WHEELER,* NORIO MARU,* KEVIN SLAWIN§ AND PETER T. SCARDINO储 From the Department of Urology, Memorial Sloan-Kettering Cancer Center, Sidney Kimmel Center for Prostate and Urologic Cancer, New York, New York (PS, JAE, MO, MWK, PTS), and the Departments of Urology and Pathology, Baylor College of Medicine, Houston, Texas (TW, NM, KS)

ABSTRACT

Purpose: The prognostic significance of positive surgical margins (PSM) in radical prostatectomy (RP) specimens remains unclear. While most studies have concluded that a PSM is an independent adverse prognostic factor, others report that surgical margin status has no effect on prognosis. One reason for these discordant conclusions is the variable number of patients with a PSM who receive adjuvant therapy and the differing statistical methods used to account for the effects of the time course of adjuvant treatment on recurrence. We evaluated the prognostic significance of PSMs using multiple methods of analysis accounting for patients who received adjuvant therapy. Materials and Methods: We analyzed 1,389 consecutive patients with clinical stage T1–3 prostate cancer treated with RP by 2 surgeons from 1983 to 2000. Of 179 patients with a PSM, 37 received adjuvant therapy (AT), 29 radiation therapy and 8 received hormonal therapy. Because the method used to account for men receiving AT can affect the outcome of the analysis, data were analyzed by the Cox proportional hazards technique accounting for patients receiving AT using 5 methods: 1) exclusion, 2) inclusion (AT ignored), 3) censoring at time of AT, 4) failing at time of AT and 5) considering AT as a time dependent covariate. Results: Overall 179 patients (12.9%) had a PSM, including 6.8% of 847 patients with pT2 and 23% of 522 patients with pT3 disease. A PSM was a significant predictor of cancer recurrence when analyzed using methods 1, 3, 4 and 5 (p⫽0.005, p⫽0.014, p⫽0.0005, p⫽0.002, respectively). However, it was not a predictor of recurrence using method 2 in which AT was ignored (p⫽0.283). Using method 5 multivariate analysis demonstrated that a PSM (p⫽0.002) was an independent predictor of 10-year progression-free probability (PFP) along with Gleason score (p⫽0.0005), extracapsular extension (p⫽0.0005), seminal vesicle invasion (p ⬍0.0005), positive lymph nodes (p ⬍0.0005) and preoperative serum prostate specific antigen (p ⬍0.0001). Using method 5 the 10-year PFP was 58% ⫾ 12% and 81% ⫾ 3% for patients with and without a PSM, respectively (p ⬍0.00005). The relative risk of recurrence in men with a PSM using method 5 was 1.52 (95% confidence interval 1.06 –2.16). Conclusions: We confirm that a PSM has a significant adverse impact on PFP after RP in multivariate analysis using multiple statistical methods to account for patients who received AT. While prostate cancer screening strategies have resulted in a majority of men having organ confined disease at RP, surgeons should continue to strive to reduce the rate of positive surgical margins to improve cancer control outcomes. KEY WORDS: prostatectomy, prognosis, recurrence, treatment outcome

Recurrence of prostate cancer after radical prostatectomy (RP) has been associated with multiple factors including pretreatment serum prostate specific antigen (PSA), clinical stage, biopsy Gleason grade, pathological stage (level of exSubmitted for publication August 9, 2004. Supported by the Leon Lowenstein Foundation, the Bendhein Prostate Diagnostic Center and a SPORE (CA92629) Grant from the National Cancer Institute. * Nothing to disclose. † Correspondence: Department of Urology, Sidney Kimmel Center for Prostate and Urologic Cancer, Memorial Sloan-Kettering Cancer Center, 353 East 68th St., Suite 527, New York, New York 10021 (telephone: 646-422-4390; FAX: 212-988-0759; e-mail: [email protected]). ‡ Financial interest and/or other relationship with Novartis. § Financial interest and/or other relationship with GlaxoSmithKline, National Institutes of Health, Merck, Urology, MedReviews and Oncovance. 储 Financial interest and/or other relationship with Steba Pharmaceuticals, Oncovance Inc, Merck, Sanofi Aventis, National Cancer Institute, National Institutes of Health, Prostate Cancer Foundation, Astra Zeneca, Pfizer, Nature Urology and Penguin Putnam Inc.

tracapsular extension, seminal vesicle invasion [SVI] and pelvic lymph node status), and surgical margin status.1, 2 Of these prognostic factors only surgical margin status can be influenced by surgical technique. A positive surgical margin (PSM) is defined as tumor at the inked margin of the resected specimen.3, 4 A PSM can result from incising into extraprostatic tumor in patients with extracapsular extension (ECE) or by inadvertent incision into an otherwise organ confined cancer (pT2⫹).5 The reported incidence of PSMs ranges from 6% to 41% and in general the PSM rate in academic institutions has decreased during the last 15 years.6⫺8 This decrease in PSM rate has likely resulted from a combination of stage migration with a larger proportion of patients having clinical stage T1c disease and Editor’s Note: This article is the first of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 1160 and 1161.

S47 Please cite this article as J Urol 2008;179: S47–S51. DOI: 10.1016/j.juro.2008.03.137. Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION.

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POSITIVE SURGICAL MARGINS IN RADICAL PROSTATECTOMY SPECIMENS

pathologically organ confined cancer, and from improved surgical techniques. Numerous studies report that a PSM adversely affects prognosis after RP.3, 4, 9, 10 The 5-year biochemical failure rate in patients with a PSM ranges from 42% to 64%.6 Despite these findings there is still controversy regarding the clinical significance of PSMs on outcome.2, 11, 12 Using the Cox proportional hazards model Stamey et al concluded that a PSM was not independently predictive of biochemical failure following radical prostatectomy, although this study excluded men with transition zone cancers and the role/use of adjuvant therapy in this study was not discussed.11 Furthermore, several studies that have assessed the significance of positive margins excluded from the analysis patients who received adjuvant therapy (AT), while other studies counted those receiving AT as immediate treatment failures.2, 3, 13–15 Either of these methods of analysis creates the potential for bias because the outcome for men receiving AT is unknown. To address the impact of a PSM on biochemical recurrence after RP more appropriately, we used multiple methods of statistical analyses to account for the use of AT in a large series of patients. To compare with previous reports assessing the impact of a positive surgical margin on patient outcome, we analyzed the data by the Cox proportional hazards technique dealing with patients who received AT in 5 ways, namely 1) exclusion, 2) inclusion (AT ignored), 3) censoring at the time of AT, 4) failing at the time of AT and 5) considering AT as a time dependent covariate. Moreover we examined the significance of a PSM when other adverse factors were considered by means of a multivariate analysis. MATERIALS AND METHODS

Patient population. From August 1983 to September 2000, 1,389 consecutive patients with clinical stage T1-T3 prostate cancer underwent radical prostatectomy by 2 surgeons (PTS and KS) at Baylor College of Medicine. Mean patient age was 62 years (range 38 to 81). Overall 179 of the 1,389 patients had a PSM (12.9%). Ten patients had no pathology slides available for review and were excluded from analysis. Pathology. Radical prostatectomy specimens were fixed intact in 10% neutral buffered formalin and then sectioned transversely at 4 to 5 mm intervals. All specimens were whole mounted and reviewed by 1 pathologist (TW). The location and extent of cancer were identified and mapped in each section. The presence of tumor cells at the inked margin of resection was considered to represent a PSM.5 A positive surgical margin in an area where no capsule was identified was referred to as pT2⫹ and was thought to indicate where the plane of dissection entered the prostatic capsule or alternatively where no capsule was present, ie apex and anteriorly.5 The presence and level of extracapsular extension, Gleason grade, and PSM presence and sites were recorded. Total tumor volume was measured from a tumor map using image analysis software.16 Followup. The 1,389 patients were followed from 1 to 202 months with a median of 50 months (mean 52.3). Clinical examination and serum PSA were performed every 3 months during year 1, every 6 months during years 2 to 5 and yearly thereafter. Biochemical recurrence was defined as a PSA greater than 0.4 ng/ml confirmed on 1 subsequent PSA evaluation. The Hybritech® PSA assay was used for PSA followup. A total of 37 patients received adjuvant therapy before evidence of biochemical or clinical recurrence, 29 adjuvant radiation therapy (26 had a PSM) and 8 adjuvant hormonal therapy (6 had a PSM). Statistical analysis. We first analyzed AT as a time dependent covariate in a Cox model, adjusting for commonly available postoperative factors. For comparison we ran other models, variously excluding or including patients who received AT. The probability of recurrence was analyzed by the Cox

proportional hazards technique first by excluding all patients who received AT from analysis, then by including those who received AT and ignoring the AT, then by censoring those patients at the time of AT, and finally by considering AT as treatment failure or recurrence. Categorical variables were compared by the chi-square test. The ordinal and continuous outcomes were compared with the Kruskal-Wallis or Wilcoxon rank sum test. Progression-free probability was calculated using the Kaplan-Meier method, and the differences between progression-free rates were assessed by the log rank test. Cox proportional hazards regression analysis was used to test association of various pathological and clinical features with recurrence. Logistic regression analysis was used to evaluate the association between year of surgery and PSM. Statistical analyses were performed with Stata® version 7.0 or S-PLUS® version 6.1. RESULTS

Clinicopathological parameters and margin status. Overall 179 of 1,389 patients had a PSM (12.9%). A PSM was identified in 6.8% (58 of 847) of patients with organ confined disease (pT2⫹) and in 23% (121 of 522) of patients with ECE (pT3). Table 1 demonstrates the relationship between PSM and the clinicopathological features. The incidence of PSM increases with increasing preoperative serum PSA, Gleason score in the RP specimen and pathological stage. PSA progression-free probability. Figure 1 shows the PSA progression-free probability (PFP) for all patients based on the status of the surgical margins. Overall patients with a PSM had a 10-year PFP of 58% ⫾ 12% compared with patients with negative surgical margins who had a 10-year PFP of 81% ⫾ 3% (p ⬍0.00005). PSA progression-free probability varied depending on how patients who received AT were considered in the statistical analysis. Of the 37 patients receiving AT, 10 subsequently had PSA recurrence and the remaining 27 patients remained free of cancer recurrence (median followup 93 months, range 12 to 160). Data were analyzed using 5 methods and the results are displayed in table 2. A PSM was a significant predictor of cancer recurrence when analyzed using methods 1, 3, 4 and 5 (p⫽0.005, p⫽0.014, p⫽0.0005 and p⫽0.0021, respectively) but not method 2 in which AT was ignored (p⫽0.283). Multivariate analysis. Pretreatment serum PSA, Gleason

TABLE 1. Association of clinical and pathological features with surgical margin status No. Pts PSA (ng/ml):* 0.1–4.0 4.1–10.0 10.1–20.0 Greater than 20.0

261 729 214 112

Total ⫹ SM % (No.) 5.4 9.2 20.6 34.8

(14) (67) (44) (39)

Total RP Gleason score:† 2–6 7 (3⫹4) 7 (4⫹3) 8–10

1,316

12.5 (164)

981 247 70 77

10.9 (110) 12.1 (31) 18.6 (13) 33.3 (24)

Total Clinical stage: T1a T1b T1c T2a T2b T2c T3

1,375

12.9 (178)

35 53 491 262 322 150 76

Total 1,389 * No available PSA results for 73 patients. † No available RP Gleason score results for 14 patients.

0 26.4 11.2 9.2 14.3 15.3 22.4

(14) (55) (24) (46) (23) (17)

12.9 (179)

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POSITIVE SURGICAL MARGINS IN RADICAL PROSTATECTOMY SPECIMENS

organ confined cancer from 40% before 1990 to 78% after 2000. There has been a similar decrease in the PSM rate especially in patients with pT3a or greater cancers, with the margin rate decreasing from 31.7% before 1990 to 11.1% after 2000. Using logistic regression analysis, year of surgery (p⫽0.02) and presence of organ confined cancer (p⫽0.001) contributed to the decrease in PSM incidence (fig. 4). DISCUSSION

FIG. 1. PSA progression-free probability curves demonstrating difference in outcomes for all patients with (⫹) and without (-) positive surgical margin (SM) (p ⬍0.00005).

score in the radical prostatectomy specimen, presence of extracapsular extension, SVI and lymph node invasion (LNI) were all found to be independent predictors of progression in all 5 methods of analysis (table 3). A PSM was found to be a significant predictor of progression for all methods of analysis except for method 2 (p⫽0.283), in which patients who received AT were included in analysis and the effect of AT was ignored. The relative risk of biochemical failure in men with a PSM ranged from 1.2 to 2.7 depending on statistical method. For patients with ECE (pT3a) a PSM was significant using all statistical methods of examining patients who received AT (fig. 2, table 2). The significance of a PSM for patients with organ confined tumors (pT2⫹) is less clear (fig. 3, table 2). Of the 5 methods only method 4, failing at AT, indicated that a PSM was a statistically significant factor in this group. Variation in PSM rate over time. Figure 4 shows the variation in PSM rate over time in conjunction with the proportion of patients with or without organ confined cancer. There has been a steady increase in the proportion of patients with

Our results suggest that cancer present at the margin of resection (a positive surgical margin) in a radical prostatectomy specimen is associated with an increased risk of recurrence after adjusting for other known risk factors including pretreatment serum PSA, clinical stage, Gleason score and pathological stage (level of extracapsular extension, SVI and pelvic lymph node status). A similar analysis has been previously performed on a larger cohort of patients (2,518) which produced similar results.17 Of these prognostic factors only the surgical margin status can be influenced by surgical technique. Indeed in a recent analysis of risk factors for positive margins, the volume of cases performed by the surgeon and the individual surgeon were each associated with the risk of a positive margin after controlling for all other clinical and pathological variables.18 In the present study we found a decrease in PSM rate by year independent of the favorable stage migration to more organ confined cancers (fig. 4). Surgical experience and careful attention to surgical details, adjusted for the characteristics of the cancer being treated, can decrease PSM rates and improve cancer control with radical prostatectomy. Our overall PSM rate for the 18 years of study was 12.9%, within the range of but substantially lower than the average PSM rate reported in other series,3, 7, 8 with a reported mean PSM rate of 25% to 28% and ranging from 6% to 41%.5 A PSM may occur as a result of incising into prostate cancer that extends beyond the prostatic capsule (ECE and PSM) and may also result from incising into intraprostatic tumor in otherwise organ confined cancer (pT2⫹).5 Our PSM rate was 12.9% overall, 23% for patients with ECE and 6.8% for patients with organ confined disease compared to a mean in the literature of 28% overall, 46.5% for patients with ECE and

TABLE 2. Impact of margin status on outcomes depending on the method of analysis Mean ⫾ SD

No. pts All pts: 5 Yrs 10 Yrs ⫹SM 5 yrs ⫹SM 10 yrs ⫺SM 5 yrs ⫺SM 10 yrs p Value pT2 (organ confined): ⫺SM 5 yrs ⫺SM 10 yrs ⫹SM 5 yrs ⫹SM 10 yrs p Value pT3a (ECE): ⫺SM 5 yrs ⫺SM 10 yrs ⫹SM 5 yrs ⫹SM 10 yrs p Value pT3b/⫹LN (SVI or LNI): ⫺SM 5 yrs ⫺SM 10 yrs ⫹SM 5 yrs ⫹SM 10 yrs p Value

Method 1

Method 2

Method 3

Method 4

Method 5

1,352

1,389

1,389

1,389

1,389

82.6 ⫾ 2 78.9 ⫾ 3 62.4 ⫾ 10 58.3 ⫾ 10 85.0 ⫾ 2 81.4 ⫾ 3 ⬍0.00005

82.3 ⫾ 2 78.0 ⫾ 3 65.6 ⫾ 8 58.0 ⫾ 12 84.9 ⫾ 2 81.4 ⫾ 3 ⬍0.00005

82.6 ⫾ 2 79.0 ⫾ 3 63.5 ⫾ 10 59.4 ⫾ 10 85.0 ⫾ 2 81.4 ⫾ 3 ⬍0.00005

80.2 ⫾ 2 76.7 ⫾ 3 50.5 ⫾ 8 47.2 ⫾ 10 84.6 ⫾ 2 81.1 ⫾ 3 ⬍0.00005

82.3 ⫾ 2 78.0 ⫾ 3 65.6 ⫾ 8 58.0 ⫾ 12 84.9 ⫾ 2 81.4 ⫾ 3 ⬍0.00005

93.9 ⫾ 2 92.1 ⫾ 2 91.6 ⫾ 10 80.5 ⫾ 16 0.1560

93.9 ⫾ 2 92.1 ⫾ 2 92.7 ⫾ 8 84.1 ⫾ 14 0.2761

93.9 ⫾ 2 92.1 ⫾ 2 91.8 ⫾ 10 80.6 ⫾ 16 0.1667

93.6 ⫾ 2 91.8 ⫾ 2 82.9 ⫾ 16 72.8 ⫾ 16 0.0001

93.9 ⫾ 2 92.1 ⫾ 2 92.7 ⫾ 8 84.1 ⫾ 14 0.2761

83.9 ⫾ 6 78.9 ⫾ 6 62.2 ⫾ 16 62.2 ⫾ 16 0.0046

83.9 ⫾ 6 78.9 ⫾ 6 64.3 ⫾ 14 60.7 ⫾ 16 0.0042

83.9 ⫾ 6 78.9 ⫾ 6 63.1 ⫾ 16 63.1 ⫾ 16 0.0071

83.9 ⫾ 6 78.9 ⫾ 6 51.0 ⫾ 14 51.0 ⫾ 14 ⬍0.00005

83.9 ⫾ 6 78.9 ⫾ 6 64.3 ⫾ 14 60.7 ⫾ 16 0.0042

42.2 ⫾ 10 36.1 ⫾ 10 24.6 ⫾ 16 24.6 ⫾ 16 0.0521

42.8 ⫾ 10 36.7 ⫾ 10 40.5 ⫾ 14 27.0 ⫾ 24 0.7565

42.3 ⫾ 10 36.2 ⫾ 10 27.0 ⫾ 16 27.0 ⫾ 16 0.1408

41.2 ⫾ 10 35.2 ⫾ 10 17.0 ⫾ 12 17.0 ⫾ 12 0.0001

42.8 ⫾ 10 36.8 ⫾ 10 40.5 ⫾ 14 27.0 ⫾ 24 0.7565

S50

POSITIVE SURGICAL MARGINS IN RADICAL PROSTATECTOMY SPECIMENS TABLE 3. Multivariate analysis of pathological risk factors for disease recurrence

p Value: ⫹SM Gleason sum ECE SVI ⫹LN PSA AT Hazard ratio for ⫹SM 95% CI

Method 1

Method 2

Method 3

Method 4

Method 5

0.005 ⬍0.0005 ⬍0.0005 ⬍0.0005 ⬍0.0005 ⬍0.0005 – 1.66 1.17–2.38

0.014 ⬍0.0005 ⬍0.0005 ⬍0.0005 ⬍0.0005 ⬍0.0005 – 1.56 1.09–2.23

0.283 ⬍0.0005 ⬍0.0005 ⬍0.0005 ⬍0.0005 ⬍0.005 – 1.2 0.86–1.67

⬍0.0005 ⬍0.0005 ⬍0.0005 ⬍0.0005 ⬍0.0005 ⬍0.005 – 2.71 2.03–3.63

0.0021 ⬍0.0005 ⬍0.0005 ⬍0.0005 ⬍0.0005 ⬍0.0001 0.009 1.52 1.06–2.16

FIG. 2. PSA progression-free probability curves demonstrating difference in outcomes for patients with ECE (pT3a/b) with and without PSM (p⫽0.0065).

FIG. 3. PSA progression-free probability curves demonstrating difference in outcomes for patients with organ confined tumors (pT2) with and without PSM (p⫽0.2761).

22.5% for patients with organ confined disease.4 Improved preoperative methods of identifying the likely sites of ECE and appropriate adjustment of surgical technique with wider resection of surrounding tissues can decrease the likelihood of a PSM. Indeed our PSM rate in patients with ECE at our center during the last 3 years was 19% of 217 patients (PTS and JAE). Previous reports examining the impact of PSM on cancer control outcomes after RP excluded patients who received AT from analysis.14, 15 By doing so some patients with a PSM who were at high risk for recurrence were excluded from analysis, favorably distorting the recurrence rate of other patients with PSM. In the current study we assessed the significance of a PSM using multiple methods of analysis

FIG. 4. Trend in margin status and pathological stage during study period. Using logistic regression analysis year of surgery (p⫽0.02) and pathological stage (p⫽0.001) were significant suggesting change in surgical technique and favorable stage migration contributed to overall decrease in PSM.

accounting for the patients who received AT. To compare with previous reports we assessed 5 different methods of examining patients receiving AT: 1) exclusion from analysis, 2) inclusion in the analysis and ignoring that they received AT, 3) inclusion and censoring from analysis at the time AT was given, 4) treatment failure when AT was given and 5) considering AT a time dependent covariate. The initial 4 methods each bias the outcome for the remaining patients with PSMs. Clearly method 5, in which AT is considered a time dependent covariate, is the most appropriate means of assessing the overall prognostic significance of PSM. This statistical method includes all patients in the analysis and recognizes that the covariate (receiving AT) may change over time and incorporates these new values into an actuarial model. Followup was divided into time before AT and time after AT, thus appropriately recognizing the time of AT. By not excluding or censoring patients, this statistical method has the least potential for introducing bias into the analysis. Our study again confirms the adverse prognostic significance of a PSM, along with preoperative serum PSA, RP Gleason score, presence of ECE, SVI and LNI as adverse prognostic factors for biochemical recurrence after radical prostatectomy. In multivariate analysis a PSM was found to be significant in 4 of 5 methods of examining patients who received AT. A PSM was not significant in multivariate analysis using method 2, in which patients who received AT were included in the analysis and the effect of the AT was ignored. When considered as a time dependent covariate in method 5, adjuvant therapy was itself found to be a significant predictor of outcome (p⫽0.009), suggesting it is effective in delaying biochemical recurrence (table 2). This hypothesis has been given extra support by a recent article demonstrating the beneficial effect of adjuvant radiotherapy following radical prostatectomy.19 In our previous study3 a PSM was only significant in pa-

POSITIVE SURGICAL MARGINS IN RADICAL PROSTATECTOMY SPECIMENS

tients with ECE, not in those with organ confined cancer (pT2⫹) or advanced disease (positive seminal vesicle and/or lymph nodes). In the current series a PSM was significant in patients with extracapsular extension. The adverse impact of positive margins was less apparent in men with organ confined or advanced cancers. The strengths of the current study are that all specimens were examined by the same pathologist using the same pathological techniques, thereby eliminating variation in interpretation. The definition and diagnosis of a positive margin were uniform throughout the study, a factor lacking in most previous reports. Furthermore, the prognostic impact of PSM was examined using AT as a time dependent covariate. The data presented in this study support the growing body of evidence of the adverse impact of PSM and support its addition to the TNM staging system. As in most other studies we used biochemical recurrence as the reference point by which we measured the importance of PSM. This end point is the easiest to measure and requires less followup than disease specific survival or overall survival. Pound et al demonstrated that once biochemical recurrence occurred the most significant predictors of the development of metastases and of overall survival were time to biochemical progression, Gleason score and PSA doubling time.20 To further validate the significance of PSM, other objective end points such as the development of metastatic disease and disease specific survival should be analyzed. CONCLUSIONS

We demonstrated the significance of a PSM in the radical prostatectomy specimen when controlled for other clinical and pathological factors. Patients with positive surgical margins are at a significantly higher risk for disease progression than those without a PSM even in the presence of extraprostatic disease. Careful preoperative planning should allow surgeons to modify the technique for each individual patient’s cancer, reducing the likelihood of a PSM.

6. 7.

8. 9.

10.

11.

12.

13.

14.

15.

16.

REFERENCES

1. Kattan, M. W., Wheeler, T. M. and Scardino, P. T.: Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer. J Clin Oncol, 17: 1499, 1999 2. Hull, G. W., Rabbani, F., Abbas, F., Wheeler, T. M., Kattan, M. W. and Scardino, P. T.: Cancer control with radical prostatectomy alone in 1,000 consecutive patients. J Urol, 167: 528, 2002 3. Ohori, M., Wheeler, T. M., Kattan, M. W., Goto, Y. and Scardino, P. T.: Prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol, 154: 1818, 1995 4. Wieder, J. A. and Soloway, M. S.: Incidence, etiology, location, prevention and treatment of positive surgical margins after radical prostatectomy for prostate cancer. J Urol, 160: 299, 1998 5. Stamey, T. A., Villers, A. A., McNeal, J. E., Link, P. C. and Freiha, F. S.: Positive surgical margins at radical prostatec-

17.

18.

19.

20.

S51

tomy: importance of the apical dissection. J Urol, 143: 1166, 1990 Ohori, M. and Scardino, P. T.: Localized prostate cancer. Curr Probl Surg, 39: 833, 2002 Han, M., Partin, A. W., Pound, C. R. Epstein, J. I. and Walsh, P. C.: Long-term biochemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North Am, 28: 555, 2001 Epstein, J. I.: Pathologic assessment of the surgical specimen. Urol Clin North Am, 28: 567, 2001 Blute, M. L., Bostwick, D. G., Seay, T. M., Martin, S. K., Slezak, J. M., Bergstralh, E. J. et al: Pathologic classification of prostate carcinoma: the impact of margin status. Cancer, 82: 902, 1998 Epstein, J. I., Partin, A. W., Sauvageot, J. and Walsh, P. C.: Prediction of progression following radical prostatectomy. A multivariate analysis of 721 men with long-term follow-up. Am J Surg Pathol, 20: 286, 1996 Stamey, T. A., McNeal, J. E., Yemoto, C. M., Sigal, B. M. and Johnstone, I. M.: Biological determinants of cancer progression in men with prostate cancer. JAMA, 281: 1395, 1999 Graefen, M., Noldus, J., Pichlmeier, U., Haese, A., Hammerer, P., Fernandez, S. et al: Early prostate-specific antigen relapse after radical retropubic prostatectomy: prediction on the basis of preoperative and postoperative tumor characteristics. Eur Urol, 36: 21, 1999 Blute, M. L., Bostwick, D. G., Bergstralh, E. J., Slezak, J. M., Martin, S. K., Amling, C. L. et al: Anatomic site-specific positive margins in organ-confined prostate cancer and its impact on outcome after radical prostatectomy. Urology, 50: 733, 1997 Kausik, S. J., Blute, M. L., Sebo, T. J., Leibovich, B. C., Bergstralh, E. J., Slezak, J. et al: Prognostic significance of positive surgical margins in patients with extraprostatic carcinoma after radical prostatectomy. Cancer, 95: 1215, 2002 Cheng, L., Darson, M. F., Bergstralh, E. J., Slezak, J., Myers, R. P. and Bostwick, D. G.: Correlation of margin status and extraprostatic extension with progression of prostate carcinoma. Cancer, 86: 1775, 1999 Greene, D. R., Wheeler, T. M., Egawa, S., Dunn, J. K. and Scardino, P. T.: A comparison of the morphological features of cancer arising in the transition zone and in the peripheral zone of the prostate. J Urol, 146: 1069, 1991 Blute, M. L., Bergstralh, E. J., Iocca, A., Scherer, B. and Zincke, H.: Use of Gleason score, prostate specific antigen, seminal vesicle and margin status to predict biochemical failure after radical prostatectomy. J Urol, 165: 119, 2001 Eastham, J. A., Kattan, M. W., Riedel, E., Begg, C. B., Wheeler, T. M., Gerigk, C. et al: Variations among individual surgeons in the rate of positive surgical margins in radical prostatectomy specimens. J Urol, 170: 2292, 2003 Stephenson, A. J., Shariat, S. F., Zelefsky, M. J., Kattan, M. W., Butler, E. B., Teh, B. S. et al: Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA, 291: 1325, 2004 Pound, C. R., Partin, A. W., Eisenberger, M. A., Chan, D. W., Pearson, J. D. and Walsh, P. C.: Natural history of progression after PSA elevation following radical prostatectomy. JAMA, 281: 1591, 1999