Definition of Biochemical Recurrence After Radical Prostatectomy Does Not Substantially Impact Prognostic Factor Estimates

Definition of Biochemical Recurrence After Radical Prostatectomy Does Not Substantially Impact Prognostic Factor Estimates Angel M. Cronin, Guilherme Godoy and Andrew J. Vickers From the Department of Epidemiology and Biostatistics, and the Urology Service, Department of Surgery (GG), Memorial Sloan-Kettering Cancer Center, New York, New York

Abbreviations and Acronyms PSA ⫽ prostate specific antigen Submitted for publication June 29, 2009. Study received institutional review board approval.

Purpose: Biochemical recurrence serves as a surrogate end point after radical prostatectomy. Many definitions of biochemical recurrence are currently used in the research literature. We examined various definitions in a large clinical cohort to explore whether estimation differs by definition. Materials and Methods: The cohort included 5,473 patients who underwent radical prostatectomy from 1985 to 2007 at our cancer center. Separate analysis was done with 12 definitions of biochemical recurrence used in published studies. Cox regression was done to estimate HRs for established predictors. Predictive accuracy was determined using the concordance index. Results: Depending on the definition the recurrence-free probability was 86% to 91% at 3 years and 81% to 87% at 5 years. HRs tended to be smaller for the most inclusive definitions but were fairly similar across all definitions. The univariate HR was 2.1 to 2.4 for log prostate specific antigen, 2.4 to 2.6 for clinical stage T2b vs T2a or less and 9.8 to 15 for biopsy Gleason grade 8 or greater vs 6 or less. Multivariate HRs were more homogeneous across the definitions. The concordance index was 0.79 to 0.83 and 0.83 to 0.87 for the preoperative and postoperative nomograms, respectively. Conclusions: Estimates of risk ratios and predictive accuracy are generally robust to the biochemical recurrence definition. For clinical research, groups using different definitions will come to similar conclusions on prognostic factors. The definition should be factored into studies comparing overall recurrence probabilities. Key Words: prostate, prostatic neoplasms, prostatectomy, prostate-specific antigen, recurrence

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CLINICALLY relevant outcomes such as distant metastasis and death from prostate cancer do not occur for many years after radical prostatectomy.1,2 With the development of PSA as a marker in the mid 1980s came the concept of biochemical recurrence, an event that precedes clinical recurrence by many years and, thus, can function as a surrogate end point for treatment efficacy.3–5 The definition of this surrogate is open to discussion. PSA is a continuous variable and there is no clear

agreement on what level represents recurrence. Many definitions of biochemical recurrence have been published6,7 and they differ in various ways, such as in terms of level (eg 0.2 vs 0.4 ng/ml) and whether a single value indicates recurrence or a confirmatory test is required. When examining the prognostic significance of tertiary Gleason pattern 5 in Gleason 7 prostate cancer, Sim et al defined biochemical recurrence as serum PSA greater than 0.2 ng/ml, as confirmed by repeat measurement,8 but Hattab

0022-5347/10/1833-0984/0 THE JOURNAL OF UROLOGY® © 2010 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION

Vol. 183, 984-989, March 2010 Printed in U.S.A. DOI:10.1016/j.juro.2009.11.027

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et al explored the same issue but defined biochemical recurrence as 2 consecutive serum PSA measurements greater than 0.1 ng/ml.9 Biochemical recurrence is used for research and clinical purposes. Its predominant clinical use is to identify candidates for additional therapy who would benefit from early initiation of salvage treatment. The most useful definition has the optimal relationship with prostate cancer metastasis or death from prostate cancer, leading to a suitable balance between early treatment in a high proportion of men otherwise destined to have the worst oncological outcome (ie high sensitivity) without unnecessarily treating a large number who would not have clinical recurrence (ie good specificity). However, it is unclear whether the most clinically useful definition of biochemical recurrence would also be the most useful one for research purposes or whether different definitions would influence research results. We examined various biochemical recurrence definitions in a large clinical cohort to explore whether estimation for prognostic factors differs by the definition used.

MATERIALS AND METHODS We identified 6,545 patients who underwent primary radical prostatectomy from January 1985 to September 2007 at our cancer center. The 823 patients who received neoadjuvant therapy and 249 lost to followup on the surgery date were excluded from analysis. The final study cohort included 5,473 men (table 1). Patients were generally followed for disease recurrence postoperatively with serum PSA measurements and clinical assessments every 3 months for the first 3 years, semiannually during the next 2 years and annually thereafter. This study was approved by the institutional review board. We examined 12 definitions of biochemical recurrence that were previously used in published studies (table 2).6,7,10 –16 We also studied another definition that we constructed that has not been used in the literature, that is a single detectable postoperative PSA. This definition served as a positive control. If the results of this definition and more commonly used definitions did not differ, we would conclude that our study method was insensitive to determine differences between definitions. PSA assays used at our institution were Tandem®-E (lower detection limit 0.3 ng/ml) before 1996, AIA® (lower detection limit 0.05 ng/ml) from 1996 to 1997 and Immuno 1® (lower detection limit 0.05 ng/ml) since 1997. Patients were considered to have documented biochemical recurrence on the date on which they fulfilled the criteria or the date of the initiation of secondary therapy, whichever was earliest. Secondary therapy was given at the discretion of the treating physician and to a minority of patients before documented recurrence (table 2). Median followup in patients without recurrence according to the definition with the fewest events was 3 years and 1,612 men (29%) were followed at least 5 years. The probability of freedom from biochemical recurrence after radical prostatectomy was estimated using the Kaplan-Meier method. Univariate and multivariate Cox

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Table 1. Patient clinical and pathological characteristics Median age at surgery (IQR) Median ng/ml pretreatment PSA (IQR)* Median % nomogram 5-yr progression-free probability (IQR):† Preop Postop No. biopsy Gleason grade (%): 6 or Less 7 8 or Greater Unknown No. clinical stage (%): T2a or less T2b T2c or greater Unknown No. pathology Gleason grade (%): 6 or Less 7 8 or Greater Unknown No. extracapsular extension (%): No Yes Unknown No. seminal vesicle invasion (%): No Yes Unknown No. surgical margin status (%): Neg Pos Unknown No. lymph node involvement (%): Not determined No Yes

60 (55, 65) 5.77 (4.20, 8.30)

94 97

(88, 96) (92, 98)

2,946 1,585 353 589

(54) (29) (6) (11)

4,138 703 427 205

(76) (13) (8) (4)

1,967 2,835 377 294

(36) (52) (7) (5)

3,860 1,512 101

(71) (28) (2)

5,062 355 56

(92) (6) (1)

4,326 1,089 58

(79) (20) (1)

500 4,727 226

(9) (87) (4)

* Available in 5,299 patients. † Available in 4,525 and 4,870 patients preoperatively and postoperatively, respectively.

proportional hazards regression was used to estimate the HR with the 95% CI for established predictors such as PSA, stage, grade and positive surgical margins. The predictive accuracy of preoperative17 and postoperative18 nomograms was calculated using the concordance index, which is used to quantify the discriminative ability of a Cox regression model. Values are 0.5—lack of discrimination equivalent to a coin flip to 1.0 —perfect discrimination. Separate analysis was done for each definition. Patients were excluded from analysis if data were missing on predictor variables for that specific analysis. We performed sensitivity analysis in which patients who received secondary therapy before documented biochemical recurrence were censored at the date of secondary therapy. Although definition ordering by the least to the most number of events changed slightly, no trends observed were impacted (data not shown). All statistical analysis was done with Stata® 10.0.

RESULTS Table 2 lists estimated recurrence-free probability at 3 and 5 years for each definition. As expected,

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Table 2. Kaplan-Meier recurrence-free probability of biochemical recurrence definitions

Order*

Definition

No. Events

No. Secondary Therapy (%)†

1 2 3 4 5 6 7 8 9 10 11 12 13

PSA 0.4 ng/ml or greater ⫹ increasing6,7,10 Single PSA 0.6 ng/ml or greater6,7 PSA 0.2 ng/ml or greater ⫹ increasing6,7,11 3 Consecutive PSA increases7,12 2 Consecutive PSA values 0.2 ng/ml or greater6,13 Initial PSA 0.2 ng/ml or greater ⫹ successive PSA greater than 0.2 ng/ml6,‡ Single PSA 0.4 ng/ml or greater6,7,14 2 Successive PSA increases, final PSA 0.2 ng/ml or greater7 3 Successive PSA increases 0.1 ng/ml or greater7 PSA 0.1 ng/ml or greater ⫹ increasing7,15 3 Successive PSA increases7 Single PSA 0.2 ng/ml or greater6,7,16 Single detectable PSA

610 657 663 680 697 702 732 760 793 801 817 889 1,848

207 (34) 180 (27) 192 (29) 139 (20) 131 (19) 129 (18) 152 (21) 110 (14) 132 (17) 79 (10) 129 (16) 87 (10) 22 (1)

% Kaplan-Meier Recurrence-Free Probability (IQR) 3-Yr

5-Yr

91.1 (90.2, 91.9) 90.6 (89.7, 91.5) 90.4 (89.5, 91.3) 90.2 (89.3, 91.1) 89.9 (88.9, 90.7) 89.8 (88.8, 90.7) 89.4 (88.5, 90.3) 88.7 (87.7, 89.6) 88.3 (87.2, 89.2) 87.9 (86.9, 88.8) 88.0 (87.0, 88.9) 86.1 (85.0, 87.1) 70.3 (68.9, 71.7)

86.7 (85.4, 87.8) 85.7 (84.5, 86.9) 84.8 (83.5, 86.0) 85.1 (83.9, 86.3) 84.9 (83.6, 86.1) 84.8 (83.5, 85.9) 84.4 (83.1, 85.6) 83.5 (82.2, 84.7) 83.1 (81.7, 84.3) 82.4 (81.0, 83.6) 81.6 (80.2, 82.9) 80.6 (79.3, 81.9) 60.4 (58.7, 62.0)

* Definition 1—fewest to 13—most events. † Documented event was caused by initiation of secondary therapy. ‡ Definition recommended by American Urological Association Prostate Cancer Guidelines Panel.

univariate analysis, had similar HRs for each definition except the positive control. Risk factors with a large HR, eg biopsy Gleason grade 8 or greater vs 6 or less with a univariate HR of about 11 to 15, had fairly consistent HRs for each definition except the positive control. However, we observed more variability in these HRs with the higher HRs tending to occur with the more strict definitions. These differences were less on multivariate analysis. For example, the pathology Gleason grade 8 or greater vs 6 or less HR was 18 to 29 on univariate analysis and 6.3 to 10 on multivariate analysis, excluding the positive control. Table 4 shows the predictive accuracy of the preoperative and postoperative nomograms. These results were similar to that observed for multivariate regression. The concordance index was similar for

these estimates varied based on definition restrictiveness. At 3 years the recurrence-free probability was 91.1% vs 86.1% for the definition with the fewest vs the most events (PSA 0.4 ng/ml or greater and increasing vs a single PSA of 0.2 ng/ml). At 5 years the probability was 86.7% and 80.6%, respectively. The positive control showed much lower estimates with a 3 and 5-year recurrence-free probability of 70.3% and 60.4%, respectively. Tables 3 and 4 lists HRs for established prognostic factors. A few patterns were observed. 1) All univariate and multivariate associations were statistically significant and, thus, hypothesis testing was not affected by the definition in this cohort. 2) Risk factors with a moderate HR, eg clinical stage T2b vs T2a or less with an HR of about 2.5 on

Table 3. Univariate HR for various biochemical recurrence definitions Definition No.* Predictor

1 (95% CI)

2

3

4

5

6†

7

8

9

10

11

12

13

Log PSA Biopsy Gleason grade: 7 vs 6 or Less 8 or Greater vs 6 or less Clinical stage: T2b vs T2a or less T2c or greater vs T2a or less Pathology Gleason grade: 7 vs 6 or Less 8 or Greater vs 6 or less Extracapsular extension (yes vs no) Seminal vesicle invasion (yes vs no) Lymph node invasion (yes vs no/not determined) Pos surgical margin (yes vs no)

2.40 (2.14, 2.69)

2.42

2.32

2.40

2.42

2.40

2.31

2.34

2.17

2.36

2.10

2.23

1.54

3.89 (3.12, 4.87) 14.7 (11.5, 18.7)

3.81 13.4

3.77 12.0

3.88 13.3

3.89 13.1

3.87 13.1

3.52 11.9

3.73 12.5

3.38 11.1

3.73 12.3

3.21 9.79

3.32 10.5

1.72 3.69

2.53 (2.09, 3.06) 3.54 (2.86, 4.37)

2.63 3.69

2.49 3.45

2.48 3.41

2.52 3.48

2.52 3.44

2.39 3.37

2.43 3.29

2.42 3.11

2.35 3.21

2.39 2.97

2.46 3.25

1.60 2.19

5.15 (3.82, 6.96) 28.9 (21.1, 39.5) 4.55 (3.87, 5.36) 6.76 (5.64, 8.09) 9.54 (7.73, 11.8)

4.73 26.8 4.45 6.87 10.26

4.65 22.8 4.60 6.36 8.18

4.74 25.7 4.59 6.83 9.35

4.89 26.7 4.64 7.01 9.69

4.73 26.0 4.63 6.87 9.65

4.19 22.8 4.27 6.59 9.49

4.58 23.5 4.34 6.51 8.70

4.02 20.2 3.93 6.02 9.07

4.63 23.4 4.27 6.43 8.73

4.10 18.4 4.05 5.78 7.69

3.46 18.3 3.70 5.93 8.43

1.61 5.21 2.16 3.54 4.89

3.18 (2.71, 3.73)

3.09

2.96

3.18

3.15

3.13

2.98

3.12

2.89

3.14

2.89

2.99

2.05

All associations significant at p ⬍0.001. * Definition 1—fewest to 13—most events. † Definition recommended by American Urological Association Prostate Cancer Guidelines Panel.

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Table 4. Multivariate HR and concordance index in preoperative and postoperative models Definition No.*

Log PSA Biopsy Gleason grade: 7 vs 6 or Less 8 or Greater vs 6 or less Clinical stage: T2b vs T2a or less T2c or greater vs T2a or less Concordance index Log PSA Pathology Gleason grade: 7 vs 6 or Less 8 or Greater vs 6 or less Extracapsular extension (yes vs no) Seminal vesicle invasion (yes vs no) Lymph node invasion (yes vs no/not determined) Pos surgical margin (yes vs no) Concordance index

1 (95% CI)

2

3

4

5

2.07 (1.79, 2.38)

2.02

2.00

2.08

3.21 (2.55, 4.05) 10.7 (8.26, 13.9)

3.20 9.78

3.03 8.82

3.17 9.81

3.18 9.50

1.94 (1.55, 2.44) 2.09 (1.63, 2.68)

1.93 2.17

2.04 2.20

2.00 2.08

2.00 2.16

0.825

0.817

0.814

0.824

1.42 (1.23, 1.63)

1.42

3.47 (2.51, 4.79) 10.0 (6.99, 14.4)

6†

7

8

9

10

11

12

13

1.97

2.04

1.91

2.04

1.83

1.94

1.42

3.16 9.54

2.97 8.89

3.02 9.21

2.83 8.28

3.05 9.12

2.64 7.41

2.77 7.76

1.56 3.00

2.00 2.15

1.82 2.10

2.01 1.99

1.95 2.01

1.96 1.98

2.07 2.01

1.94 2.02

1.45 1.74

0.806

0.814

0.800

0.813

0.790

0.798

0.659

1.40

0.823 0.823 Postop model 1.45 1.46 1.46

1.41

1.44

1.39

1.44

1.31

1.45

1.20

3.10 9.25

3.03 7.87

3.15 8.73

3.27 9.14

3.14 8.89

2.80 8.13

3.07 8.04

2.77 7.52

3.12 8.07

2.78 6.75

2.29 6.34

1.29 2.61

2.08 (1.69, 2.55)

2.00

2.21

2.09

2.02

2.05

1.96

1.99

1.76

1.95

1.93

1.80

1.35

1.93 (1.54, 2.41)

2.02

1.88

1.97

2.01

1.98

2.00

1.96

1.89

1.89

1.81

1.96

1.71

2.50 (1.93, 3.23)

2.75

1.99

2.40

2.53

2.52

2.70

2.30

2.56

2.33

2.16

2.56

2.24

1.74 (1.44, 2.10)

1.67

1.69

1.79

1.74

1.74

1.65

1.79

1.68

1.78

1.73

1.79

1.52

0.872

0.861

0.858

0.868

0.869

0.868

0.850

0.857

0.842

0.855

0.834

0.833

0.686

Preop model 2.08 2.08

All associations significant at p ⬍0.001. * Definition 1—fewest to 13—most events. † Definition recommended by American Urological Association Prostate Cancer Guidelines Panel.

all definitions except the positive control. The preoperative nomogram had a concordance index of 0.66 for the positive control with a range of 0.79 to 0.83 for all other definitions. Postoperative nomogram values were 0.69 and 0.83 to 0.87, respectively. We then explored whether definitions with more events also had greater statistical power. Statistical significance in a Cox model is determined by the z score, calculated by dividing the estimated log HR by the SE of the estimate. Higher z scores in absolute value have lower p values. Although the numerator (log HR estimate) decreased with more events, the denominator (estimate SE) decreased more proportionately, resulting in a lower z score and a lower p value for the definition with more events. For example, the z score of pathology Gleason grade 8 or greater vs 6 or less was log(28.9)/0.16 ⫽ 21.0 for the definition with the fewest events and log(18.3)/0.12 ⫽ 24.2 for the definition with the most events.

DISCUSSION Biochemical recurrence has been widely used as an end point in studies of prognostic factors associated with disease progression after radical prostatectomy. However, the definition used in each study

varies, making the validity of comparisons among studies unclear. Less restrictive definitions of biochemical recurrence with a low trigger PSA or no required confirmatory increase naturally have a lower recurrence-free probability than more restrictive definitions. We noted that the biochemical recurrence definition did not have a large impact on estimated risk ratios such as HRs when the definition was reasonably chosen. We noted 2 general trends in our results. 1) HRs tended to be smaller for more inclusive definitions. A smaller risk ratio indicates a smaller relative separation in risk between those with and without the risk factor. With a more inclusive definition more patients meet recurrence criteria, which tends to have a disproportionate effect on risk estimates in those without the risk factor. Since patients without the risk factor are typically represented in the denominator of the risk ratio, more inclusive definitions have a smaller risk ratio. 2) Nomogram predictive accuracy tended to be higher for more restrictive definitions. This may be because worse events are easier to predict and meeting the criteria of more restrictive definitions typically indicates worse failure. A man with PSA 0.4

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ng/ml or greater with a confirmatory increase probably has more aggressive disease than a man with a single PSA of 0.2 ng/ml or greater. The concordance index was high (generally greater than 0.8) for each nomogram, primarily since 31% of patients were treated from 2005 to 2007. In a mature cohort we would expect the nomograms to have slightly lower predictive accuracy than that reported. With acknowledgment of these trends we also noted that RRs and HRs were fairly consistent among the 12 definitions examined. The univariate HR for positive surgical margins was about 3 and the univariate HR for clinical stage T2b vs T2a or less was about 2.5. The only definition to provide a substantially different result was the positive control, which lends support to our study method. In this large cohort statistical inferences on established prognostic factors were not impacted by the biochemical recurrence definition. We did not focus on this result because it is unlikely that hypothesis testing would be a problem in our setting. We analyzed strong predictors of outcome. The number of events was 600 to 800 and, thus, all definitions had high power to detect statistical differences. It is plausible that the biochemical recurrence definition would have an impact on hypothesis testing when examining a novel marker in a smaller data set, in which a statistically significant difference may be found using the most but not the least inclusive definition. This suggests that investigators should use a relatively inclusive but reasonable definition of biochemical recurrence when evaluating novel markers in small data sets. What a reasonable definition of biochemical recurrence would be is an area of debate that is beyond the scope of this study. An important distinction to make is between studies of prognostic factors such as molecular markers and studies of treatment for prostate cancer. In studies in which patients receive treatment after biochemical recurrence the definition should be based on treatment harms and benefits. A more liberal definition may be selected for a well tolerated treatment and a more restrictive one may be selected for a toxic treatment. Many investigators have examined the appropriate definition of biochemical recurrence for clinical purposes. The American Urological Association Prostate Cancer Guidelines Panel recommended defining biochemical recurrence after radical prostatectomy as initial serum PSA 0.2 ng/ml or greater with a second confirmatory PSA of greater than 0.2 ng/ml.6 This was based on a literature review of studies published from 2001 to 2004 but without any formal comparative statistical analysis. Stephenson et al subsequently examined the correlation among 10 definitions of biochemical recurrence with metastatic progression in a clinical cohort and proposed that biochemical recurrence should be defined as PSA greater than 0.4 ng/ml

with a confirmatory increase.7 Only 1 group has also examined the effects of the definition on clinical research. In a study of 2,782 men who underwent radical prostatectomy between 1987 and 1993 Amling et al assessed 5 biochemical recurrence definitions, and concluded that HRs and the statistical significance of Gleason grade, PSA doubling time, surgical margin status and seminal vesicle invasion were not impacted by the definition.19 Our study in more than 5,000 patients using 12 common definitions of biochemical recurrence and including other established prognostic factors such as pathological stage confirms the findings of Amling et al. A limitation of any study of recurrence definitions is secondary therapy. Depending on the biochemical recurrence definition 10% to 30% of patients received secondary therapy before the documented recurrence that was considered an event when secondary therapy began. This could have caused bias since they were not followed to the true failure time. However, HRs were fairly similar when comparing the results of the most and least inclusive definitions, corresponding to secondary therapy in 10% vs 30% of patients. Accordingly any bias is likely to be minimal. Other limitations are the retrospective nature of the data, the inherent inaccuracies and natural variability of serum PSA measurement, and the short followup. Longer followup may modify the results but any modification may be small since the data set included approximately 1,500 patients followed at least 5 years after surgery. The strength of our study is that we comprehensively examined 13 definitions of biochemical recurrence, including a positive control. Substantial differences in estimation were observed for the positive control. Thus, we are confident that we would have identified differences in estimation among the 12 reasonable definitions if true differences existed.

CONCLUSIONS Estimates of the risk ratio and predictive accuracy are generally robust to the definition of biochemical recurrence. These results do not imply that the clinical usefulness of the definitions is similar, only that research results do not differ importantly by definition. The biochemical recurrence definition used for clinical purposes should be based on clinical judgment with consideration of patient risk factors and after thorough discussion about the potential risks and benefits of treatment. For clinical research the definition of biochemical recurrence should be factored into comparative studies of overall recurrence probability but groups using different definitions will draw similar conclusions on prognostic factors. For trial design studies of prognostic factors are likely to have increased power when using a more inclusive but reasonable definition of biochemical recurrence.

BIOCHEMICAL RECURRENCE AFTER PROSTATECTOMY

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REFERENCES 1. Pound CR, Partin AW, Eisenberger MA et al: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999; 281: 1591. 2. Freedland SJ, Humphreys EB, Mangold LA et al: Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA 2005; 294: 433. 3. Kuriyama M, Wang MC, Lee CI et al: Use of human prostate-specific antigen in monitoring prostate cancer. Cancer Res 1981; 41: 3874. 4. Oesterling JE, Chan DW, Epstein JI et al: Prostate specific antigen in the preoperative and postoperative evaluation of localized prostatic cancer treated with radical prostatectomy. J Urol 1988; 139: 766. 5. Lange PH, Ercole CJ, Lightner DJ et al: The value of serum prostate specific antigen determinations before and after radical prostatectomy. J Urol 1989; 141: 873. 6. Cookson MS, Aus G, Burnett AL et al: Variation in the definition of biochemical recurrence in patients treated for localized prostate cancer: the American Urological Association Prostate Guidelines for Localized Prostate Cancer Update Panel report and recommendations for a standard in the reporting of surgical outcomes. J Urol 2007; 177: 540.

7. Stephenson AJ, Kattan MW, Eastham JA et al: Defining biochemical recurrence of prostate cancer after radical prostatectomy: a proposal for a standardized definition. J Clin Oncol 2006; 24: 3973. 8. Sim HG, Telesca D, Culp SH et al: Tertiary Gleason pattern 5 in Gleason 7 prostate cancer predicts pathological stage and biochemical recurrence. J Urol 2008; 179: 1775. 9. Hattab EM, Koch MO, Eble JN et al: Tertiary Gleason pattern 5 is a powerful predictor of biochemical relapse in patients with Gleason score 7 prostatic adenocarcinoma. J Urol 2006; 175: 1695. 10. Gomez CS, Gomez P, Knapp J et al: Hyaluronic acid and hyal-1 in prostate biopsy specimens: predictors of biochemical recurrence. J Urol 2009; 182: 1356. 11. Stephenson AJ, Wood DP, Kattan MW et al: Location, extent and number of positive surgical margins do not improve accuracy of predicting prostate cancer recurrence after radical prostatectomy. J Urol 2009; 182: 1357. 12. Abramowitz MC, Li T, Buyyounouski MK et al: The Phoenix definition of biochemical failure predicts for overall survival in patients with prostate cancer. Cancer 2008; 112: 55. 13. Cordon-Cardo C, Kotsianti A, Verbel DA et al: Improved prediction of prostate cancer recurrence

through systems pathology. J Clin Invest 2007; 117: 1876. 14. Shekarriz B, Upadhyay J, Bianco FJ Jr et al: Impact of preoperative serum PSA level from 0 to 10 ng/ml on pathological findings and diseasefree survival after radical prostatectomy. Prostate 2001; 48: 136. 15. Rabbani F, Vora KC, Yunis LH et al: Biochemical recurrence rate in patients with positive surgical margins at radical prostatectomy with further negative resected tissue. BJU Int 2009; 104: 605. 16. Laudano MA, Badani KK, McCann TR et al: Significant change in predicted risk of biochemical recurrence after radical prostatectomy more common in black than in white men. Urology 2009; 74: 660. 17. Stephenson AJ, Scardino PT, Eastham JA et al: Preoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J Natl Cancer Inst 2006; 98: 715. 18. Stephenson AJ, Scardino PT, Eastham JA et al: Postoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J Clin Oncol 2005; 23: 7005. 19. Amling CL, Bergstralh EJ, Blute ML et al: Defining prostate specific antigen progression after radical prostatectomy: what is the most appropriate cut point? J Urol 2001; 165: 1146.

EDITORIAL COMMENT These authors analyzed the large data set at their institution and reassure us that calculated HRs probably do not substantially depend on which of the 12 published definitions of post-prostatectomy PSA failure is applied, assuming that the data set used is reasonably large. For investigators using smaller data sets the practical advice is to consider a less restrictive definition of failure to increase the number of events and increase the power to detect differences. The authors do not address which definition is the best predictor of distant metastasis or prostate cancer specific mortality, which would be useful to study

as the database matures beyond its current 3-year followup. Of the cases 10% to 34% were scored as failures based on secondary therapy initiated before PSA crossed a failure threshold. This proportion will likely increase as groups at more institutions adopt ultrasensitive PSA, thereby artificially shortening time to PSA failure in future series. Paul L. Nguyen Dana-Farber Cancer Institute Brigham and Women’s Hospital Genitourinary Radiation Oncology Harvard Medical School Boston, Massachusetts