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Maximum Tumor Diameter and the Risk of Prostate-Specific Antigen Recurrence After Radical Prostatectomy
Original Study
Maximum Tumor Diameter and the Risk of Prostate-Specific Antigen Recurrence After Radical Prostatectomy Brent S. Rose,1 Ming-Hui Chen,2 Danjie Zhang,2 Michelle S. Hirsch,3 Jerome P. Richie,4 Stephen L. Chang,4 John V. Hegde,5 Marian J. Loffredo,6 Anthony V. D’Amico6 Abstract Multiple randomized controlled trials have demonstrated that adjuvant radiation therapy (ART) for men with pT3 or margin-positive disease reduces the risk of biochemical recurrence after radical prostatectomy (RP); however, overtreatment might occur. We used multivariable Cox regression to study 354 men with clinical T1c to T2 prostate cancer who underwent RP without adjuvant therapy to investigate whether the maximum tumor diameter (MTD) could identify men at low risk of prostate-specific antigen (PSA) recurrence. We found that men with an MTD £ median (1.2 cm) appear to be at low risk of PSA recurrence (< 10% at 5 years with a median follow-up of 4 years) despite adverse features at RP and might not benefit from ART. Introduction/Background: The aim of this study was to investigate whether the MTD could identify men at low risk of PSA recurrence after RP who might not benefit from ART despite other adverse features. Patients and Methods: The study cohort consisted of 354 men with T1c to T2 prostate cancer diagnosed between September 2001 and December 2008 who underwent RP without adjuvant therapy. Multivariable Cox regression was used to assess the effect of MTD on the risk of PSA recurrence (> 0.1 ng/mL and verified), adjusting for known predictors. Results: After a median follow-up of 4.0 years, 34 men (9.6%) experienced PSA failure. In multivariable analysis, increasing MTD was significantly associated with an increased PSA recurrence risk (hazard ratio, 2.74; 95% confidence interval, 1.236.10; P ¼ .01) within the interaction model. Estimates of PSA recurrence-free survival stratified around the median MTD value (1.2 cm) were significantly different in men with a pre-RP PSA > 4 ng/mL (P < .001; 5-year estimate: 74.5% vs. 99.0%) but not in men with PSA 4 ng/mL (P ¼ .59; 5-year estimate: 89.6% vs. 92.6%), consistent with the significant interaction (P ¼ .004) between PSA and MTD. Moreover, in men with a pre-RP PSA > 4 ng/mL these estimates were significantly different if at least 1 adverse feature (pT3, R1, or Gleason score 8) was present at RP (P ¼ .01; 5-year estimate: 46.6% vs. 100%) versus none (P ¼ .09; 5-year estimate: 93.4% vs. 98.9%). Conclusion: Men with a low MTD ( 1.2 cm) appear to be at low risk of PSA recurrence despite adverse features at RP and might not benefit from ART. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Adjuvant radiation therapy, Biochemical recurrence, Over treatment, Prostate cancer, Risk stratification
Introduction More than 78,000 men undergo radical prostatectomy (RP) for the treatment of prostate cancer in the United States, annually.1 Although RP is an effective primary treatment for localized 1
Harvard Radiation Oncology Program, Boston, MA Department of Statistics, University of Connecticut, Storrs, CT Department of Pathology, Brigham and Women’s Hospital, Boston, MA 4 Division of Urology, Brigham and Women’s Hospital, Boston, MA 5 Harvard Medical School, Boston, MA 6 Department of Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, MA 2 3
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2014.03.008
prostate cancer, a subset of men are found to have adverse prognostic features on pathologic examination. The number of men with high-risk features is expected to increase as more men with high-risk disease are treated with RP. Approximately half of men with positive Submitted: Jan 20, 2014; Revised: Mar 4, 2014; Accepted: Mar 11, 2014 Address for correspondence: Brent S. Rose, MD, Department of Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, 75 Francis St, Boston, MA 02215 Fax: 617-264-5242; e-mail contact: [email protected]
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MTD and the Risk of PSA Recurrence surgical margins, extraprostatic extension, or seminal vesicle invasion will experience prostate-specific antigen (PSA) recurrence within 5 years.2-4 Multiple randomized controlled trials (RCTs) have demonstrated that adjuvant radiation therapy (ART) for men with pT3 or marginpositive (R1) disease reduces the risk of biochemical recurrence after RP.2-6 However, because of conflicting results of RCTs with respect to the effect of ART on the time to metastasis, prostate cancer, and all-cause mortality,2-6 it is unclear the extent to which ART can affect the rate of metastases or improve cancer-specific and overall survival.5,6 Furthermore, many men who undergo PSA surveillance after RP and show pT3 and/or R1 disease will not experience PSA recurrence with more than a decade of follow-up.7 In addition, it remains to be determined whether receipt of radiation therapy (RT) at the time of an increasing PSA (early salvage RT) portends a worse prognosis than ART in men with high-risk features. This question is currently being tested in the RADICALS (Radiation Therapy and Androgen Deprivation Therapy in Treating Patients Who Have Undergone Surgery for Prostate Cancer) study (NCT00541047). As a result, ART might lead to overtreatment and the potential for unnecessary toxicity in some men. The question remains, however, how best to identify the men who would require subsequent ART after RP. McNeal originally suggested that the biologic aggressiveness of prostate cancer is related to its volume.8 The clinical use of tumor volume is limited because the technique requires examining the entire RP specimen which is labor-intensive and expensive. Renshaw has proposed that the maximum tumor dimension (MTD) can be used as a simple and effective proxy for tumor volume.9 Early investigation by several groups found that increasing MTD was associated with PSA recurrence after RP alone.10-14 However, some have questioned whether the MTD or tumor volume are independent predictors when controlling for other measures of disease burden, such as PSA level, Gleason score, and tumor (T) category.15,16 Therefore, we investigated whether MTD was independently associated with time to PSA recurrence adjusting for known prognostic factors to differentiate men who can be observed with PSA surveillance after RP and those in whom the increased risk of PSA recurrence merits consideration of adjuvant treatment.
Patients and Methods
brief, the apical and basal margins were amputated to a thickness of up to 5 mm and sectioned parasagittally in a direction perpendicular to the initial transverse incision at approximately 3-mm intervals. The base of the seminal vesicles was amputated and the basal cross section submitted. The prostate was then sectioned perpendicularly to the long axis (apical to basal) of the gland as thinly as possible which is typically at approximately 3-mm intervals, with most specimens requiring 4 to 7 cross sections to be entirely sectioned. For each cross section, a single section each of the right and left posterior region was submitted, with most cases entirely submitting the posterior zone. Finally, at least 1 section of the midanterior prostate was also submitted, although frequently > 1 section was submitted for histology analysis. The correlation of this method with entirely submitted sectioning has been previously detailed.9 The prostatectomy Gleason score was determined using a primary and secondary Gleason grade a tertiary pattern as per the 2005 International Society of Urological Pathology Consensus statement.17 All RP specimens were rereviewed following the 2005 recommendations and all reporting criteria were consistent with this report. The MTD was extracted from the pathology report and recorded as the maximal linear dimension of the largest single focus of tumor from all sections of the tumor, and was determined by marking both ends of the tumor with a pen and measuring this distance directly from the glass slide with a ruler. Contiguous tumor from adjacent corresponding sections of the posterior zone (ie, left and right sections with tumor that extends to the midline in the posterior zone) from the same cross section was added for a single maximum MTD.
Definition of PSA Failure and Follow-Up Prostate-specific antigen failure was defined as a PSA value > 0.10 ng/mL which was confirmed with another elevated value at least 1 month after the initial PSA value. This definition differs from the consensus threshold of 0.2 ng/mL because ultrasensitive PSA testing is performed at our institution to allow for an assessment and confirmation of an upward PSA trend18 (eg, 0.01, 0.04, 0.09, and then 0.11, at which point PSA failure would be defined). At each follow-up, serial PSA measurements followed by a digital rectal examination were performed every 3 months for 2 years, then every 6 months for an additional 3 years, and annually thereafter.
Patient Population and Treatment The study cohort consisted of 354 men with clinically localized prostate cancer diagnosed between September 2001 and December 2008 using a median of 12-cores via a transrectal ultrasound-guided biopsy who underwent open RP and pelvic lymph node dissection at the Brigham and Women’s Hospital. No patients were treated with ART or hormonal therapy before PSA recurrence. Men with positive pelvic lymph nodes were excluded from this analysis. This study and the prospective acquisition of the data were approved by the Dana Farber Cancer Institute Institutional Review Board.
Processing of the RP Specimen and Definition of the MTD
2
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The prostatectomy specimens were submitted and processed using a previously documented submission protocol for seminal vesicle invasion, extraprostatic extension, and margin status.9 In
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Statistical Methods Description of Study Cohort. Descriptive statistics were used to characterize the baseline patient and tumor characteristics stratified according to normal ( 4 ng/mL) versus abnormal PSA level (> 4 ng/mL) and the median value of MTD (1.2 cm). The distributions of these characteristics were compared using a Mantel-Haenszel c2 metric19 for categorical factors and a nonparametric Wilcoxon statistic20 for continuous covariates (Table 1). Fisher exact test19 was used in the case of small sample cell size. Time to PSA Failure Analyses. The primary end point of this study was time to PSA failure. Cox regression analyses21 were performed to assess the effect of increasing MTD as a continuous variable on the risk of PSA failure adjusting for known predictors. Continuous covariates adjusted for in the model included age and PSA level
Table 1 Comparison of the Distribution of Patient and Cancer Characteristics at the Time of RP Stratified According to > and < a Normal PSA Value and the Median Maximum Tumor Diameter Stratification Using PSA Cut Point of 4 ng/mL and Maximum Tumor Diameter Using the Median Value of 1.2 cm PSA £4 ng/mL Patient or Cancer Characteristic Median Age At Time of RP (IQR), Years Median PSA at Time of Presentation (IQR), ng/mL pT2, n (%) pT3a, n (%) pT3b/4, n (%) pGleason Score 6 or less, n (%) pGleason Score 3D4, n (%) pGleason Score 4D3, n (%) pGleason Score 8 to 10, n (%) Positive Margin, n (%) Negative Margin, n (%) Prostate Gland Volume (IQR), cc
Maximum Tumor Diameter £1.2 cm (n [ 80) 58.63 3.0 79 1 0 53 24 3 0 4 76 49.0
(52.16-62.96) (2.5-3.6) (98.75) (1.25) (0.00) (66.25) (30.00) (3.75) (0.00) (5.00) (95.00) (41.3-58.0)
PSA >4 ng/mL
Maximum Tumor Diameter >1.2 cm (n [ 37) 59.06 3.5 28 5 4 15 15 0 7 4 33 50.5
(54.08-63.47) (2.8-3.8) (75.68) (13.51) (10.81) (40.54) (40.54) (0) (18.92) (10.81) (89.19) (42.0-62.9)
P .44 .13 <.001b
<.001b
.26b .56
Maximum Tumor Diameter £1.2 cm (n [ 110)a 60.24 5.2 103 6 1 67 31 8 4 9 101 57.4
(57.41-64.48) (4.7-6.5) (93.64) (5.45) (0.91) (60.91) (28.18) (7.27) (3.64) (8.18) (91.82) (45.3-69.5)
Maximum Tumor Diameter >1.2 cm (n [ 127)a 59.14 5.6 92 29 6 27 63 20 17 19 108 51.0
(53.43-63.85) (4.8-8.1) (72.44) (22.83) (4.72) (21.26) (49.61) (15.75) (13.39) (14.96) (85.04) (44.5-59.0)
P .05 .09 <.001b
<.001b
.16b .03
Brent S. Rose et al
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Abbreviations: IQR ¼ interquartile range; MTD ¼ maximum tumor diameter; p ¼ prostatectomy; PSA ¼ prostate-specific antigen; RP ¼ radical prostatectomy. a Number of men with at least 1 risk factor (pT3-4, pGleason score of 8-10, or positive margins) for men with MTD the median (1.2 cm) and MTD > the median is 15/110 and 50/127, respectively (Fig. 3). b Fisher exact test.
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MTD and the Risk of PSA Recurrence at diagnosis, and prostatectomy-defined prostate gland volume. Categorical covariates included prostatectomy tumor category (T3b/T4 vs. T3a vs. T2 as baseline), margin status (R1 vs. R0 as baseline), and prostatectomy Gleason score (8-10 vs. 4þ3 vs. 3þ4 or less as baseline). Unadjusted and adjusted hazard ratios (AHRs) with 95% confidence intervals (CIs) and 2-sided P values were calculated. Because PSA is associated with tumor volume at PSA levels > normal (ie, 4 ng/mL) but not necessarily when PSA is < 4 ng/mL, we included an interaction term between PSA levels and MTD in the model. Estimates of PSA Failure-Free Survival. For the purpose of illustration, Kaplan-Meier plots of PSA failure-free survival stratified according to the median MTD were produced for the following groups: (1) all men with PSA > 4 ng/mL; (2) all men with PSA 4 ng/mL; (3) men with a PSA > 4 ng/mL and at least 1 adverse pathologic factor (ie, pT3/4 or R1 or Gleason score 8-10); (4) men with PSA > 4 ng/mL and no adverse pathologic factors (ie, pT2 and R0 and Gleason score 7). Kaplan-Meier estimates of PSA failurefree survival22 were compared with the log rank test.23 A Bonferroni correction was applied for multiple comparisons.24 SAS version 9.3 was used for all statistical analyses (SAS Institute, Cary, NC).
Results Description of Study Cohort In men with a normal PSA ( 4 ng/mL), an MTD greater than the median (1.2 cm) compared with less than or equal to the median was significantly associated with more advanced pathologic T stage (P < .001) and increased prostatectomy Gleason score (P < .001). For men with an elevated PSA (> 4 ng/mL), an MTD greater than the median was also significantly associated with more advanced T stage (P < .001) and increased prostatectomy Gleason score (P < .001). Men with an elevated PSA and an MTD greater than the median were also more likely to have a smaller prostate gland volume (51.0 cc vs. 57.4 cc; P ¼ .03), suggesting that the increase in PSA in men with an MTD greater than the median is
more likely to be related to the tumor rather than from benign prostatic hyperplasia.
Time to PSA Failure Analyses After a median follow-up of 4.0 years (interquartile range, 1.9-5.0 years), 34 men (9.6%) experienced a PSA recurrence. In multivariable analysis, increasing MTD in cm was significantly associated with an increased risk of PSA failure (AHR, 2.74; 95% CI, 1.236.10; P ¼ .014) after adjusting for pre-RP PSA, pathologic T stage, Gleason score, and positive margins as shown in Table 2. The MTD was particularly important in men with an increased PSA as indicated by the significant interaction between PSA level in ng/mL and the MTD value in cm (P interaction ¼ .004). Other significant factors associated with the time to PSA failure in multivariable analysis were increasing presenting PSA level (AHR, 1.21; 95% CI, 1.09-1.35; P < .001), pT3a (AHR, 2.68; 95% CI, 1.11-6.49; P ¼ .029), prostatectomy Gleason score 4þ3 (AHR, 6.30; 95% CI, 2.41-16.48; P < .001), prostatectomy Gleason score 8 to 10 (AHR, 12.10; 95% CI, 4.82-30.40; P < .001), and R1 disease (AHR, 4.74; 95% CI, 1.90-11.82; P < .001). Pathologic T3b/4 was significantly associated with the risk of PSA failure in univariable but not multivariable analysis. However, there were only 11 men with T3b/4 cancer, and multicollinearity was noted between T3b/4, Gleason score 8 to 10, and PSA recurrence. Five of the 6 men with both risk factors experienced PSA failure, causing Gleason score 8 to 10 but not T3b/4 to be significantly associated with an increased risk of PSA failure in multivariable analysis.
Estimates of PSA Failure-Free Survival We constructed Kaplan-Meier plots to illustrate the clinical significance of the prognostic effect of MTD in addition to known predictors of PSA failure from the multivariable model (ie, Gleason score at time of prostatectomy [pGleason] 8 to 10, and positive surgical margins) in addition to accepted factors for recommending
Table 2 Unadjusted and Adjusted HRs of PSA Failure for Patient and Cancer Characteristics at the Time of RP Unadjusted Analysis Patient or Cancer Characteristic Age at Time of RP, Years Presenting PSA, ng/mL Maximum Tumor Diameter, cm Maximum Tumor Diameter Measured as cm 3 PSA level, ng/mL pT2 pT3a pT3b/4 pGleason Score £3D4 pGleason Score 4D3 pGleason Score 8-10 Negative Margin Positive Margin Prostatectomy-Defined Prostate Gland Volume, cc
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Men, n
PSA Failure, n
354 354 354 354
34 34 34 34
302 41 11 295 31 28 318 36 354
16 11 7 10 9 15 19 15 34
HR (95% CI) 0.99 1.17 3.49 0.95
(0.95-1.04) (1.06-1.29) (1.97-6.20) (0.91-0.996)
1.0 (Ref) 6.64 (3.07-14.34) 13.93 (5.69-34.06) 1.0 (Ref) 9.37 (3.79-23.16) 22.39 (10.04-49.93) 1.0 (Ref) 8.34 (4.23-16.64) 0.98 (0.96-1.01)
P .801 .002 <.001 .034 NA <.001 <.001 NA <.001 <.001 NA <.001 .146
Adjusted Analysis AHR (95% CI) 1.02 1.21 2.74 0.92
(0.96-1.08) (1.09-1.35) (1.23-6.10) (0.87-0.97)
1.0 (Ref) 2.68 (1.11-6.49) 1.15 (0.28-4.70) 1.0 (Ref) 6.30 (2.41-16.48) 12.10 (4.82-30.40) 1.0 (Ref) 4.74 (1.90-11.82) 0.98 (0.95-1.01)
Abbreviations: AHR ¼ adjusted hazard ratio; HR ¼ hazard ratio; p ¼ prostatectomy; PSA ¼ prostate-specific antigen; Ref ¼ reference group; RP ¼ radical prostatectomy.
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P .591 <.001 .014 .004 NA .029 .850 NA <.001 <.001 NA <.001 .169
Brent S. Rose et al the use of ART (ie, pT3). As shown in Figures 1 and 2, PSA failurefree survival stratified according to the median MTD value was significantly different in men with an increased PSA (Fig. 1; P < .001) but not in men with a normal PSA (Fig. 2; P ¼ .59). When restricting attention to men with an abnormal PSA as shown in Figures 3 and 4, PSA failure-free survival stratified according to the median MTD was significantly different in men with at least 1 adverse feature (Fig. 3; P ¼ .01) but not in men with no adverse features (Fig. 4; P ¼ .09). Specifically, estimates of PSA failure-free survival at 5 years for men with an increased PSA and an MTD > and < the median were 74.5% (95% CI, 62.9%-83.0%) and 99.0% (95% CI, 93.2%99.9%), respectively (Fig. 1). These respective estimates were 89.6% (95% CI, 70.1%-96.7%) and 92.6% (95% CI, 78.7%97.6%), for men with normal PSA (Fig. 2). Restricting attention to men with an increased PSA, the 5-year PSA failure-free survival for men with at least 1 adverse pathologic factor and an MTD > and < the median was 46.6% (95% CI, 27.6%-63.5%) and 100% (95% CI, 100%-100%), respectively (Fig. 3). These respective estimates were 93.4% (95% CI, 78.8%-98.1%) and 98.9% (95% CI, 92.4%-99.8%), for men with no adverse pathologic factors (Fig. 4).
Figure 2 Kaplan-Meier Plot of Prostate-Specific Antigen (PSA) Failure-Free Survival Stratified According to the Median Maximum Tumor Diameter (1.2 cm) for All Men With PSA £ 4 ng/mL (P [ .59)
Discussion In this study we found that the MTD, a simple, inexpensive, and readily available metric at the time of pathologic sectioning of the RP specimen, was associated with an increased risk of early PSA failure after RP in men who received no adjuvant or neoadjuvant therapies after adjusting for known predictors of PSA failure. Moreover, in men with an increased preoperative PSA (> 4 ng/mL) and at least 1 adverse pathologic factor (pT3, R1or pGleason 8), we observed clinically significant differences in the estimates of PSA failure when stratified around the median MTD of 1.2 cm.
Figure 1 Kaplan-Meier Plot of Prostate-Specific Antigen (PSA) Failure-Free Survival Stratified According to the Median Maximum Tumor Diameter (1.2 cm) for All Men With PSA > 4 ng/mL (P < .001)
Specifically, as shown in Figure 3, there was a 53.4% difference (46.6% vs. 100%) in the rate of PSA failure-free survival 5 years after RP in men with at least 1 adverse feature and an MTD > versus < the median, respectively. The clinical significance of these findings is that in light of the controversy surrounding the clinical utility of ART,25 the MTD value appears to be able to identify men at low risk for early PSA Figure 3 Kaplan-Meier Plot of Prostate-Specific Antigen (PSA) Failure-Free Survival Stratified According to the Median Maximum Tumor Diameter (1.2 cm) for Men With PSA > 4 ng/mL and at Least 1 Adverse Pathologic Factor (ie, pT3/4 or R1 or Gleason Score of 8-10) (P [ .01)
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MTD and the Risk of PSA Recurrence Figure 4 Kaplan-Meier Plot of Prostate-Specific Antigen (PSA) Failure-Free Survival Stratified According to the Median Maximum Tumor Diameter (1.2 cm) for Men With PSA > 4 ng/mL and No Adverse Pathologic Factor (ie, pT2 and R0 and Gleason Score of 7 or Less) (P [ .09)
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failure permitting the more judicious use of ART. Specifically, as shown in Figure 3, from the number of men assessable after RP, 15 of 65 or 23.1% of men with unfavorable pathologic findings at RP can be identified based on the MTD value as having a low risk of PSA failure within 5 years after RP permitting one to tailor the recommendation for ART to a more select population which can decrease overtreatment. When limiting the unfavorable pathologic finding to those eligible for ART (namely pT3 or R1) based on the previous RCT results,2-4 this ratio is 12 of 54 (22.2%). Therefore, although the actual sample of men with an MTD 1.2 cm and at least 1 adverse factor at the time of RP (pT3-4, pGleason score 810, or positive margins) was only 15, it appears that using the MTD value could improve our selection of men for ART by reducing the eligible men by approximately 25% and thereby reduce the potential for overtreatment. Conversely, the high rate of PSA failure for men with adverse pathologic findings and large MTD (> 1.2 cm) suggests that these men are unlikely to be overtreated with ART. Furthermore, results of a recently published study from the University of Michigan were that a larger MTD (> 1.4 cm) at the time of RP was associated with a greater risk of PSA failure and prostate cancer-specific mortality after salvage radiotherapy.26 Together these data suggest adjuvant rather than salvage radiotherapy might be more appropriate treatment for these men at very high risk of PSA recurrence. It remains to be studied, however, whether ART is sufficient to effect cure in men with a large MTD or whether these men would benefit further from supplemental adjuvant suppression therapy considering the known synergy of this combination on survival in the de novo setting for men with high risk features. The ongoing RAVES (Radiotherapy - Adjuvant Versus Early Salvage; NCT00860652; a RCT of adjuvant vs. early salvage RT) and RADICALS (NCT00541047; a RCT of adjuvant vs. early
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salvage RT with a second randomization to 0, 6, or 24 months of androgen deprivation therapy) trials might be able to retrieve MTD data to answer this question for these men. Several points require further discussion. First, because this analysis is retrospective, the prognostic significance of the MTD is hypothesis-generating and will require prospective validation. Second, the prognostic significance of the MTD appears to be limited to men with an abnormal PSA level (> 4 ng/mL) as shown in Figures 1 and 2, and the significant interaction term in the multivariable model. In the setting of an increased PSA, it appears that the MTD adds additional prognostic significance to a given PSA level, presumably by differentiating men who have an abnormal PSA based on a greater degree of benign prostatic hyperplasia from those with an increased PSA from a larger tumor as illustrated in Figure 1. It might be that the lack of an increased PSA implies a favorable prognosis regardless of the MTD. Further follow-up is needed to ascertain if this lack of early PSA failure is maintained because a median follow-up of approximately 4 years might not be adequate to ascertain the prognostic significance of the MTD in a cohort of men with a favorable prognosis based on the low PSA value as shown in Figure 2. Third, as shown in Figure 4, although no PSA failures have been noted in men with a pre-RP PSA > 4 ng/mL and at least 1 unfavorable pathologic finding at RP, and a low MTD after a median follow-up of approximately 4 years, longer follow-up will be needed to verify that PSA failure rates remain low in these men. Finally, longer follow-up from this study and future prospective studies that include other known predictors of PSA failure such as the length, Gleason score, and location of the positive margin27-30 will be necessary to evaluate the prognostic effect of the MTD on longterm end points including time to metastasis, castrate-resistant prostate cancer, prostate cancer death, and all-cause mortality.
Conclusion It appears that the MTD value is a clinically significant parameter that might be able to identify men at low risk of early PSA failure who might not benefit from ART despite adverse features (pT3 or R1) at the time of RP.
Clinical Practice Points The maximum tumor diameter is a simple, inexpensive, and
readily available metric at the time of pathologic sectioning of the radical prostatectomy specimen. Several groups have found that increasing MTD was associated with PSA recurrence after RP alone. However, others have questioned whether the MTD is an independent predictor when controlling for other measures of disease burden. In multivariable analysis, increasing MTD was significantly associated with an increased risk of PSA recurrence after adjusting for pre-RP PSA, pathologic T stage, Gleason Score and positive surgical margins. Estimates of PSA failure-free survival at 5 years for men with an increased PSA and an MTD > and < the median were 74.5% (95% CI, 62.9%-83.0%) and 99.0% (95% CI, 93.2%-99.9%), respectively.
Brent S. Rose et al Restricting attention to men with an increased PSA and at least 1
adverse pathologic factor, the 5-year PSA failure-free survival for men with an MTD > and < the median was 46.6% (95% CI, 27.6%-63.5%) and 100% (95% CI, 100%-100%), respectively. It appears that the MTD value is a clinically significant parameter that might be able to identify men at low risk of early PSA failure who might not benefit from ART despite adverse features (pT3 or R1) at the time of RP.
Disclosure The authors have stated that they have no conflicts of interest to report.
References 1. U.S. Department of Health and Human Services. Agency for Healthcare Research and Quality. Welcome to HCUPnet. Available at: http://hcupnet.ahrq.gov/. Accessed May 7, 2013. 2. Thompson IM Jr, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA 2006; 296:2329-35. 3. Bolla M, van Poppel H, Collette L, et al. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet 2005; 366:572-8. 4. Wiegel T, Bottke D, Steiner U, et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 9602/AUO AP 09/95. J Clin Oncol 2009; 27:2924-30. 5. Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term follow-up of a randomized clinical trial. J Urol 2009; 181:956-62. 6. Bolla M, van Poppel H, Tombal B, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet 2012; 380:2018-27. 7. Roehl KA, Han M, Ramos CG, et al. Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: long-term results. J Urol 2004; 172:910-4. 8. McNeal JE. Cancer volume and site of origin of adenocarcinoma in the prostate: relationship to local and distant spread. Hum Pathol 1992; 23:258-66. 9. Renshaw AA. An abbreviated protocol for processing radical prostatectomy specimens: analysis of grade, stage, margin status, and volume. J Urol Pathol 1996; 5:183-92. 10. Renshaw AA, Richie JP, Loughlin KR, et al. Maximum diameter of prostatic carcinoma is a simple, inexpensive, and independent predictor of prostate-specific antigen failure in radical prostatectomy specimens. Validation in a cohort of 434 patients. Am J Clin Pathol 1999; 111:641-4.
11. Dvorak T, Chen MH, Renshaw AA, et al. Maximal tumor diameter and the risk of PSA failure in men with specimen-confined prostate cancer. Urology 2005; 66: 1024-8. 12. Fukuhara H, Kume H, Suzuki M, et al. Maximum tumor diameter: a simple independent predictor for biochemical recurrence after radical prostatectomy. Prostate Cancer Prostatic Dis 2010; 13:244-7. 13. Mizuno R, Nakashima J, Mukai M, et al. Tumour length of the largest focus predicts prostate-specific antigen-based recurrence after radical prostatectomy in clinically localized prostate cancer. BJU Int 2009; 104:1215-8. 14. Eichelberger LE, Koch MO, Eble JN, et al. Maximum tumor diameter is an independent predictor of prostate-specific antigen recurrence in prostate cancer. Mod Pathol 2005; 18:886-90. 15. van Oort IM, Witjes JA, Kok DE, et al. Maximum tumor diameter is not an independent prognostic factor in high-risk localized prostate cancer. World J Urol 2008; 26:237-41. 16. Porten SP, Cooperberg MR, Carroll PR. The independent value of tumour volume in a contemporary cohort of men treated with radical prostatectomy for clinically localized disease. BJU Int 2010; 105:472-5. 17. Epstein JI, Allsbrook WC Jr, Amin MB, et al. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol 2005; 29:1228-42. 18. Valicenti RK, Thompson I Jr, Albertsen P, et al. Adjuvant and salvage radiation therapy after prostatectomy: American Society for Radiation Oncology/American Urological Association guidelines. Int J Radiat Oncol Biol Phys 2013; 86:822-8. 19. Agresti A. Categorical Data Analysis. 2nd ed. New York: John Wiley & Sons; 2002. 20. Hollander M, Wolfe DA. Nonparametric Statistical Methods. 2nd ed. New York: John Wiley & Sons; 1999. 21. Cox DR. Regression models and life-tables (with discussion). J R Stat Soc Ser B Meth 1972; 34:187-202. 22. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:457-81. 23. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50:163-70. 24. Shaffer JP. Multiple hypothesis testing. Annu Rev Psychol 1995; 46:571-84. 25. Stephenson AJ, Bolla M, Briganti A, et al. Postoperative radiation therapy for pathologically advanced prostate cancer after radical prostatectomy. Eur Urol 2012; 61:443-51. 26. Johnson SB, Hamstra DA, Jackson WC, et al. Larger maximum tumor diameter at radical prostatectomy is associated with increased biochemical failure, metastasis, and death from prostate cancer after salvage radiation for prostate cancer. Int J Radiat Oncol Biol Phys 2013; 87:275-81. 27. Cao D, Humphrey PA, Gao F, Tao Y, Kibel AS. Ability of linear length of positive margin in radical prostatectomy specimens to predict biochemical recurrence. Urology 2011; 77:1409-14. 28. Cao D, Kibel AS, Gao F, Tao Y, Humphrey PA. The Gleason score of tumor at the margin in radical prostatectomy is predictive of biochemical recurrence. Am J Surg Pathol 2010; 34:994-1001. 29. Brimo F, Partin AW, Epstein JI. Tumor grade at margins of resection in radical prostatectomy specimens is an independent predictor of prognosis. Urology 2010; 76:1206-9. 30. Kordan Y, Salem S, Chang SS, et al. Impact of positive apical surgical margins on likelihood of biochemical recurrence after radical prostatectomy. J Urol 2009; 182: 2695-701.
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Maximum Tumor Diameter and the Risk of Prostate-Specific Antigen Recurrence After Radical Prostatectomy Brent S. Rose,1 Ming-Hui Chen,2 Danjie Zhang,2 Michelle S. Hirsch,3 Jerome P. Richie,4 Stephen L. Chang,4 John V. Hegde,5 Marian J. Loffredo,6 Anthony V. D’Amico6 Abstract Multiple randomized controlled trials have demonstrated that adjuvant radiation therapy (ART) for men with pT3 or margin-positive disease reduces the risk of biochemical recurrence after radical prostatectomy (RP); however, overtreatment might occur. We used multivariable Cox regression to study 354 men with clinical T1c to T2 prostate cancer who underwent RP without adjuvant therapy to investigate whether the maximum tumor diameter (MTD) could identify men at low risk of prostate-specific antigen (PSA) recurrence. We found that men with an MTD £ median (1.2 cm) appear to be at low risk of PSA recurrence (< 10% at 5 years with a median follow-up of 4 years) despite adverse features at RP and might not benefit from ART. Introduction/Background: The aim of this study was to investigate whether the MTD could identify men at low risk of PSA recurrence after RP who might not benefit from ART despite other adverse features. Patients and Methods: The study cohort consisted of 354 men with T1c to T2 prostate cancer diagnosed between September 2001 and December 2008 who underwent RP without adjuvant therapy. Multivariable Cox regression was used to assess the effect of MTD on the risk of PSA recurrence (> 0.1 ng/mL and verified), adjusting for known predictors. Results: After a median follow-up of 4.0 years, 34 men (9.6%) experienced PSA failure. In multivariable analysis, increasing MTD was significantly associated with an increased PSA recurrence risk (hazard ratio, 2.74; 95% confidence interval, 1.236.10; P ¼ .01) within the interaction model. Estimates of PSA recurrence-free survival stratified around the median MTD value (1.2 cm) were significantly different in men with a pre-RP PSA > 4 ng/mL (P < .001; 5-year estimate: 74.5% vs. 99.0%) but not in men with PSA 4 ng/mL (P ¼ .59; 5-year estimate: 89.6% vs. 92.6%), consistent with the significant interaction (P ¼ .004) between PSA and MTD. Moreover, in men with a pre-RP PSA > 4 ng/mL these estimates were significantly different if at least 1 adverse feature (pT3, R1, or Gleason score 8) was present at RP (P ¼ .01; 5-year estimate: 46.6% vs. 100%) versus none (P ¼ .09; 5-year estimate: 93.4% vs. 98.9%). Conclusion: Men with a low MTD ( 1.2 cm) appear to be at low risk of PSA recurrence despite adverse features at RP and might not benefit from ART. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Adjuvant radiation therapy, Biochemical recurrence, Over treatment, Prostate cancer, Risk stratification
Introduction More than 78,000 men undergo radical prostatectomy (RP) for the treatment of prostate cancer in the United States, annually.1 Although RP is an effective primary treatment for localized 1
Harvard Radiation Oncology Program, Boston, MA Department of Statistics, University of Connecticut, Storrs, CT Department of Pathology, Brigham and Women’s Hospital, Boston, MA 4 Division of Urology, Brigham and Women’s Hospital, Boston, MA 5 Harvard Medical School, Boston, MA 6 Department of Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, MA 2 3
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2014.03.008
prostate cancer, a subset of men are found to have adverse prognostic features on pathologic examination. The number of men with high-risk features is expected to increase as more men with high-risk disease are treated with RP. Approximately half of men with positive Submitted: Jan 20, 2014; Revised: Mar 4, 2014; Accepted: Mar 11, 2014 Address for correspondence: Brent S. Rose, MD, Department of Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, 75 Francis St, Boston, MA 02215 Fax: 617-264-5242; e-mail contact: [email protected]
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MTD and the Risk of PSA Recurrence surgical margins, extraprostatic extension, or seminal vesicle invasion will experience prostate-specific antigen (PSA) recurrence within 5 years.2-4 Multiple randomized controlled trials (RCTs) have demonstrated that adjuvant radiation therapy (ART) for men with pT3 or marginpositive (R1) disease reduces the risk of biochemical recurrence after RP.2-6 However, because of conflicting results of RCTs with respect to the effect of ART on the time to metastasis, prostate cancer, and all-cause mortality,2-6 it is unclear the extent to which ART can affect the rate of metastases or improve cancer-specific and overall survival.5,6 Furthermore, many men who undergo PSA surveillance after RP and show pT3 and/or R1 disease will not experience PSA recurrence with more than a decade of follow-up.7 In addition, it remains to be determined whether receipt of radiation therapy (RT) at the time of an increasing PSA (early salvage RT) portends a worse prognosis than ART in men with high-risk features. This question is currently being tested in the RADICALS (Radiation Therapy and Androgen Deprivation Therapy in Treating Patients Who Have Undergone Surgery for Prostate Cancer) study (NCT00541047). As a result, ART might lead to overtreatment and the potential for unnecessary toxicity in some men. The question remains, however, how best to identify the men who would require subsequent ART after RP. McNeal originally suggested that the biologic aggressiveness of prostate cancer is related to its volume.8 The clinical use of tumor volume is limited because the technique requires examining the entire RP specimen which is labor-intensive and expensive. Renshaw has proposed that the maximum tumor dimension (MTD) can be used as a simple and effective proxy for tumor volume.9 Early investigation by several groups found that increasing MTD was associated with PSA recurrence after RP alone.10-14 However, some have questioned whether the MTD or tumor volume are independent predictors when controlling for other measures of disease burden, such as PSA level, Gleason score, and tumor (T) category.15,16 Therefore, we investigated whether MTD was independently associated with time to PSA recurrence adjusting for known prognostic factors to differentiate men who can be observed with PSA surveillance after RP and those in whom the increased risk of PSA recurrence merits consideration of adjuvant treatment.
Patients and Methods
brief, the apical and basal margins were amputated to a thickness of up to 5 mm and sectioned parasagittally in a direction perpendicular to the initial transverse incision at approximately 3-mm intervals. The base of the seminal vesicles was amputated and the basal cross section submitted. The prostate was then sectioned perpendicularly to the long axis (apical to basal) of the gland as thinly as possible which is typically at approximately 3-mm intervals, with most specimens requiring 4 to 7 cross sections to be entirely sectioned. For each cross section, a single section each of the right and left posterior region was submitted, with most cases entirely submitting the posterior zone. Finally, at least 1 section of the midanterior prostate was also submitted, although frequently > 1 section was submitted for histology analysis. The correlation of this method with entirely submitted sectioning has been previously detailed.9 The prostatectomy Gleason score was determined using a primary and secondary Gleason grade a tertiary pattern as per the 2005 International Society of Urological Pathology Consensus statement.17 All RP specimens were rereviewed following the 2005 recommendations and all reporting criteria were consistent with this report. The MTD was extracted from the pathology report and recorded as the maximal linear dimension of the largest single focus of tumor from all sections of the tumor, and was determined by marking both ends of the tumor with a pen and measuring this distance directly from the glass slide with a ruler. Contiguous tumor from adjacent corresponding sections of the posterior zone (ie, left and right sections with tumor that extends to the midline in the posterior zone) from the same cross section was added for a single maximum MTD.
Definition of PSA Failure and Follow-Up Prostate-specific antigen failure was defined as a PSA value > 0.10 ng/mL which was confirmed with another elevated value at least 1 month after the initial PSA value. This definition differs from the consensus threshold of 0.2 ng/mL because ultrasensitive PSA testing is performed at our institution to allow for an assessment and confirmation of an upward PSA trend18 (eg, 0.01, 0.04, 0.09, and then 0.11, at which point PSA failure would be defined). At each follow-up, serial PSA measurements followed by a digital rectal examination were performed every 3 months for 2 years, then every 6 months for an additional 3 years, and annually thereafter.
Patient Population and Treatment The study cohort consisted of 354 men with clinically localized prostate cancer diagnosed between September 2001 and December 2008 using a median of 12-cores via a transrectal ultrasound-guided biopsy who underwent open RP and pelvic lymph node dissection at the Brigham and Women’s Hospital. No patients were treated with ART or hormonal therapy before PSA recurrence. Men with positive pelvic lymph nodes were excluded from this analysis. This study and the prospective acquisition of the data were approved by the Dana Farber Cancer Institute Institutional Review Board.
Processing of the RP Specimen and Definition of the MTD
2
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The prostatectomy specimens were submitted and processed using a previously documented submission protocol for seminal vesicle invasion, extraprostatic extension, and margin status.9 In
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Statistical Methods Description of Study Cohort. Descriptive statistics were used to characterize the baseline patient and tumor characteristics stratified according to normal ( 4 ng/mL) versus abnormal PSA level (> 4 ng/mL) and the median value of MTD (1.2 cm). The distributions of these characteristics were compared using a Mantel-Haenszel c2 metric19 for categorical factors and a nonparametric Wilcoxon statistic20 for continuous covariates (Table 1). Fisher exact test19 was used in the case of small sample cell size. Time to PSA Failure Analyses. The primary end point of this study was time to PSA failure. Cox regression analyses21 were performed to assess the effect of increasing MTD as a continuous variable on the risk of PSA failure adjusting for known predictors. Continuous covariates adjusted for in the model included age and PSA level
Table 1 Comparison of the Distribution of Patient and Cancer Characteristics at the Time of RP Stratified According to > and < a Normal PSA Value and the Median Maximum Tumor Diameter Stratification Using PSA Cut Point of 4 ng/mL and Maximum Tumor Diameter Using the Median Value of 1.2 cm PSA £4 ng/mL Patient or Cancer Characteristic Median Age At Time of RP (IQR), Years Median PSA at Time of Presentation (IQR), ng/mL pT2, n (%) pT3a, n (%) pT3b/4, n (%) pGleason Score 6 or less, n (%) pGleason Score 3D4, n (%) pGleason Score 4D3, n (%) pGleason Score 8 to 10, n (%) Positive Margin, n (%) Negative Margin, n (%) Prostate Gland Volume (IQR), cc
Maximum Tumor Diameter £1.2 cm (n [ 80) 58.63 3.0 79 1 0 53 24 3 0 4 76 49.0
(52.16-62.96) (2.5-3.6) (98.75) (1.25) (0.00) (66.25) (30.00) (3.75) (0.00) (5.00) (95.00) (41.3-58.0)
PSA >4 ng/mL
Maximum Tumor Diameter >1.2 cm (n [ 37) 59.06 3.5 28 5 4 15 15 0 7 4 33 50.5
(54.08-63.47) (2.8-3.8) (75.68) (13.51) (10.81) (40.54) (40.54) (0) (18.92) (10.81) (89.19) (42.0-62.9)
P .44 .13 <.001b
<.001b
.26b .56
Maximum Tumor Diameter £1.2 cm (n [ 110)a 60.24 5.2 103 6 1 67 31 8 4 9 101 57.4
(57.41-64.48) (4.7-6.5) (93.64) (5.45) (0.91) (60.91) (28.18) (7.27) (3.64) (8.18) (91.82) (45.3-69.5)
Maximum Tumor Diameter >1.2 cm (n [ 127)a 59.14 5.6 92 29 6 27 63 20 17 19 108 51.0
(53.43-63.85) (4.8-8.1) (72.44) (22.83) (4.72) (21.26) (49.61) (15.75) (13.39) (14.96) (85.04) (44.5-59.0)
P .05 .09 <.001b
<.001b
.16b .03
Brent S. Rose et al
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Abbreviations: IQR ¼ interquartile range; MTD ¼ maximum tumor diameter; p ¼ prostatectomy; PSA ¼ prostate-specific antigen; RP ¼ radical prostatectomy. a Number of men with at least 1 risk factor (pT3-4, pGleason score of 8-10, or positive margins) for men with MTD the median (1.2 cm) and MTD > the median is 15/110 and 50/127, respectively (Fig. 3). b Fisher exact test.
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MTD and the Risk of PSA Recurrence at diagnosis, and prostatectomy-defined prostate gland volume. Categorical covariates included prostatectomy tumor category (T3b/T4 vs. T3a vs. T2 as baseline), margin status (R1 vs. R0 as baseline), and prostatectomy Gleason score (8-10 vs. 4þ3 vs. 3þ4 or less as baseline). Unadjusted and adjusted hazard ratios (AHRs) with 95% confidence intervals (CIs) and 2-sided P values were calculated. Because PSA is associated with tumor volume at PSA levels > normal (ie, 4 ng/mL) but not necessarily when PSA is < 4 ng/mL, we included an interaction term between PSA levels and MTD in the model. Estimates of PSA Failure-Free Survival. For the purpose of illustration, Kaplan-Meier plots of PSA failure-free survival stratified according to the median MTD were produced for the following groups: (1) all men with PSA > 4 ng/mL; (2) all men with PSA 4 ng/mL; (3) men with a PSA > 4 ng/mL and at least 1 adverse pathologic factor (ie, pT3/4 or R1 or Gleason score 8-10); (4) men with PSA > 4 ng/mL and no adverse pathologic factors (ie, pT2 and R0 and Gleason score 7). Kaplan-Meier estimates of PSA failurefree survival22 were compared with the log rank test.23 A Bonferroni correction was applied for multiple comparisons.24 SAS version 9.3 was used for all statistical analyses (SAS Institute, Cary, NC).
Results Description of Study Cohort In men with a normal PSA ( 4 ng/mL), an MTD greater than the median (1.2 cm) compared with less than or equal to the median was significantly associated with more advanced pathologic T stage (P < .001) and increased prostatectomy Gleason score (P < .001). For men with an elevated PSA (> 4 ng/mL), an MTD greater than the median was also significantly associated with more advanced T stage (P < .001) and increased prostatectomy Gleason score (P < .001). Men with an elevated PSA and an MTD greater than the median were also more likely to have a smaller prostate gland volume (51.0 cc vs. 57.4 cc; P ¼ .03), suggesting that the increase in PSA in men with an MTD greater than the median is
more likely to be related to the tumor rather than from benign prostatic hyperplasia.
Time to PSA Failure Analyses After a median follow-up of 4.0 years (interquartile range, 1.9-5.0 years), 34 men (9.6%) experienced a PSA recurrence. In multivariable analysis, increasing MTD in cm was significantly associated with an increased risk of PSA failure (AHR, 2.74; 95% CI, 1.236.10; P ¼ .014) after adjusting for pre-RP PSA, pathologic T stage, Gleason score, and positive margins as shown in Table 2. The MTD was particularly important in men with an increased PSA as indicated by the significant interaction between PSA level in ng/mL and the MTD value in cm (P interaction ¼ .004). Other significant factors associated with the time to PSA failure in multivariable analysis were increasing presenting PSA level (AHR, 1.21; 95% CI, 1.09-1.35; P < .001), pT3a (AHR, 2.68; 95% CI, 1.11-6.49; P ¼ .029), prostatectomy Gleason score 4þ3 (AHR, 6.30; 95% CI, 2.41-16.48; P < .001), prostatectomy Gleason score 8 to 10 (AHR, 12.10; 95% CI, 4.82-30.40; P < .001), and R1 disease (AHR, 4.74; 95% CI, 1.90-11.82; P < .001). Pathologic T3b/4 was significantly associated with the risk of PSA failure in univariable but not multivariable analysis. However, there were only 11 men with T3b/4 cancer, and multicollinearity was noted between T3b/4, Gleason score 8 to 10, and PSA recurrence. Five of the 6 men with both risk factors experienced PSA failure, causing Gleason score 8 to 10 but not T3b/4 to be significantly associated with an increased risk of PSA failure in multivariable analysis.
Estimates of PSA Failure-Free Survival We constructed Kaplan-Meier plots to illustrate the clinical significance of the prognostic effect of MTD in addition to known predictors of PSA failure from the multivariable model (ie, Gleason score at time of prostatectomy [pGleason] 8 to 10, and positive surgical margins) in addition to accepted factors for recommending
Table 2 Unadjusted and Adjusted HRs of PSA Failure for Patient and Cancer Characteristics at the Time of RP Unadjusted Analysis Patient or Cancer Characteristic Age at Time of RP, Years Presenting PSA, ng/mL Maximum Tumor Diameter, cm Maximum Tumor Diameter Measured as cm 3 PSA level, ng/mL pT2 pT3a pT3b/4 pGleason Score £3D4 pGleason Score 4D3 pGleason Score 8-10 Negative Margin Positive Margin Prostatectomy-Defined Prostate Gland Volume, cc
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Men, n
PSA Failure, n
354 354 354 354
34 34 34 34
302 41 11 295 31 28 318 36 354
16 11 7 10 9 15 19 15 34
HR (95% CI) 0.99 1.17 3.49 0.95
(0.95-1.04) (1.06-1.29) (1.97-6.20) (0.91-0.996)
1.0 (Ref) 6.64 (3.07-14.34) 13.93 (5.69-34.06) 1.0 (Ref) 9.37 (3.79-23.16) 22.39 (10.04-49.93) 1.0 (Ref) 8.34 (4.23-16.64) 0.98 (0.96-1.01)
P .801 .002 <.001 .034 NA <.001 <.001 NA <.001 <.001 NA <.001 .146
Adjusted Analysis AHR (95% CI) 1.02 1.21 2.74 0.92
(0.96-1.08) (1.09-1.35) (1.23-6.10) (0.87-0.97)
1.0 (Ref) 2.68 (1.11-6.49) 1.15 (0.28-4.70) 1.0 (Ref) 6.30 (2.41-16.48) 12.10 (4.82-30.40) 1.0 (Ref) 4.74 (1.90-11.82) 0.98 (0.95-1.01)
Abbreviations: AHR ¼ adjusted hazard ratio; HR ¼ hazard ratio; p ¼ prostatectomy; PSA ¼ prostate-specific antigen; Ref ¼ reference group; RP ¼ radical prostatectomy.
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P .591 <.001 .014 .004 NA .029 .850 NA <.001 <.001 NA <.001 .169
Brent S. Rose et al the use of ART (ie, pT3). As shown in Figures 1 and 2, PSA failurefree survival stratified according to the median MTD value was significantly different in men with an increased PSA (Fig. 1; P < .001) but not in men with a normal PSA (Fig. 2; P ¼ .59). When restricting attention to men with an abnormal PSA as shown in Figures 3 and 4, PSA failure-free survival stratified according to the median MTD was significantly different in men with at least 1 adverse feature (Fig. 3; P ¼ .01) but not in men with no adverse features (Fig. 4; P ¼ .09). Specifically, estimates of PSA failure-free survival at 5 years for men with an increased PSA and an MTD > and < the median were 74.5% (95% CI, 62.9%-83.0%) and 99.0% (95% CI, 93.2%99.9%), respectively (Fig. 1). These respective estimates were 89.6% (95% CI, 70.1%-96.7%) and 92.6% (95% CI, 78.7%97.6%), for men with normal PSA (Fig. 2). Restricting attention to men with an increased PSA, the 5-year PSA failure-free survival for men with at least 1 adverse pathologic factor and an MTD > and < the median was 46.6% (95% CI, 27.6%-63.5%) and 100% (95% CI, 100%-100%), respectively (Fig. 3). These respective estimates were 93.4% (95% CI, 78.8%-98.1%) and 98.9% (95% CI, 92.4%-99.8%), for men with no adverse pathologic factors (Fig. 4).
Figure 2 Kaplan-Meier Plot of Prostate-Specific Antigen (PSA) Failure-Free Survival Stratified According to the Median Maximum Tumor Diameter (1.2 cm) for All Men With PSA £ 4 ng/mL (P [ .59)
Discussion In this study we found that the MTD, a simple, inexpensive, and readily available metric at the time of pathologic sectioning of the RP specimen, was associated with an increased risk of early PSA failure after RP in men who received no adjuvant or neoadjuvant therapies after adjusting for known predictors of PSA failure. Moreover, in men with an increased preoperative PSA (> 4 ng/mL) and at least 1 adverse pathologic factor (pT3, R1or pGleason 8), we observed clinically significant differences in the estimates of PSA failure when stratified around the median MTD of 1.2 cm.
Figure 1 Kaplan-Meier Plot of Prostate-Specific Antigen (PSA) Failure-Free Survival Stratified According to the Median Maximum Tumor Diameter (1.2 cm) for All Men With PSA > 4 ng/mL (P < .001)
Specifically, as shown in Figure 3, there was a 53.4% difference (46.6% vs. 100%) in the rate of PSA failure-free survival 5 years after RP in men with at least 1 adverse feature and an MTD > versus < the median, respectively. The clinical significance of these findings is that in light of the controversy surrounding the clinical utility of ART,25 the MTD value appears to be able to identify men at low risk for early PSA Figure 3 Kaplan-Meier Plot of Prostate-Specific Antigen (PSA) Failure-Free Survival Stratified According to the Median Maximum Tumor Diameter (1.2 cm) for Men With PSA > 4 ng/mL and at Least 1 Adverse Pathologic Factor (ie, pT3/4 or R1 or Gleason Score of 8-10) (P [ .01)
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MTD and the Risk of PSA Recurrence Figure 4 Kaplan-Meier Plot of Prostate-Specific Antigen (PSA) Failure-Free Survival Stratified According to the Median Maximum Tumor Diameter (1.2 cm) for Men With PSA > 4 ng/mL and No Adverse Pathologic Factor (ie, pT2 and R0 and Gleason Score of 7 or Less) (P [ .09)
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failure permitting the more judicious use of ART. Specifically, as shown in Figure 3, from the number of men assessable after RP, 15 of 65 or 23.1% of men with unfavorable pathologic findings at RP can be identified based on the MTD value as having a low risk of PSA failure within 5 years after RP permitting one to tailor the recommendation for ART to a more select population which can decrease overtreatment. When limiting the unfavorable pathologic finding to those eligible for ART (namely pT3 or R1) based on the previous RCT results,2-4 this ratio is 12 of 54 (22.2%). Therefore, although the actual sample of men with an MTD 1.2 cm and at least 1 adverse factor at the time of RP (pT3-4, pGleason score 810, or positive margins) was only 15, it appears that using the MTD value could improve our selection of men for ART by reducing the eligible men by approximately 25% and thereby reduce the potential for overtreatment. Conversely, the high rate of PSA failure for men with adverse pathologic findings and large MTD (> 1.2 cm) suggests that these men are unlikely to be overtreated with ART. Furthermore, results of a recently published study from the University of Michigan were that a larger MTD (> 1.4 cm) at the time of RP was associated with a greater risk of PSA failure and prostate cancer-specific mortality after salvage radiotherapy.26 Together these data suggest adjuvant rather than salvage radiotherapy might be more appropriate treatment for these men at very high risk of PSA recurrence. It remains to be studied, however, whether ART is sufficient to effect cure in men with a large MTD or whether these men would benefit further from supplemental adjuvant suppression therapy considering the known synergy of this combination on survival in the de novo setting for men with high risk features. The ongoing RAVES (Radiotherapy - Adjuvant Versus Early Salvage; NCT00860652; a RCT of adjuvant vs. early salvage RT) and RADICALS (NCT00541047; a RCT of adjuvant vs. early
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salvage RT with a second randomization to 0, 6, or 24 months of androgen deprivation therapy) trials might be able to retrieve MTD data to answer this question for these men. Several points require further discussion. First, because this analysis is retrospective, the prognostic significance of the MTD is hypothesis-generating and will require prospective validation. Second, the prognostic significance of the MTD appears to be limited to men with an abnormal PSA level (> 4 ng/mL) as shown in Figures 1 and 2, and the significant interaction term in the multivariable model. In the setting of an increased PSA, it appears that the MTD adds additional prognostic significance to a given PSA level, presumably by differentiating men who have an abnormal PSA based on a greater degree of benign prostatic hyperplasia from those with an increased PSA from a larger tumor as illustrated in Figure 1. It might be that the lack of an increased PSA implies a favorable prognosis regardless of the MTD. Further follow-up is needed to ascertain if this lack of early PSA failure is maintained because a median follow-up of approximately 4 years might not be adequate to ascertain the prognostic significance of the MTD in a cohort of men with a favorable prognosis based on the low PSA value as shown in Figure 2. Third, as shown in Figure 4, although no PSA failures have been noted in men with a pre-RP PSA > 4 ng/mL and at least 1 unfavorable pathologic finding at RP, and a low MTD after a median follow-up of approximately 4 years, longer follow-up will be needed to verify that PSA failure rates remain low in these men. Finally, longer follow-up from this study and future prospective studies that include other known predictors of PSA failure such as the length, Gleason score, and location of the positive margin27-30 will be necessary to evaluate the prognostic effect of the MTD on longterm end points including time to metastasis, castrate-resistant prostate cancer, prostate cancer death, and all-cause mortality.
Conclusion It appears that the MTD value is a clinically significant parameter that might be able to identify men at low risk of early PSA failure who might not benefit from ART despite adverse features (pT3 or R1) at the time of RP.
Clinical Practice Points The maximum tumor diameter is a simple, inexpensive, and
readily available metric at the time of pathologic sectioning of the radical prostatectomy specimen. Several groups have found that increasing MTD was associated with PSA recurrence after RP alone. However, others have questioned whether the MTD is an independent predictor when controlling for other measures of disease burden. In multivariable analysis, increasing MTD was significantly associated with an increased risk of PSA recurrence after adjusting for pre-RP PSA, pathologic T stage, Gleason Score and positive surgical margins. Estimates of PSA failure-free survival at 5 years for men with an increased PSA and an MTD > and < the median were 74.5% (95% CI, 62.9%-83.0%) and 99.0% (95% CI, 93.2%-99.9%), respectively.
Brent S. Rose et al Restricting attention to men with an increased PSA and at least 1
adverse pathologic factor, the 5-year PSA failure-free survival for men with an MTD > and < the median was 46.6% (95% CI, 27.6%-63.5%) and 100% (95% CI, 100%-100%), respectively. It appears that the MTD value is a clinically significant parameter that might be able to identify men at low risk of early PSA failure who might not benefit from ART despite adverse features (pT3 or R1) at the time of RP.
Disclosure The authors have stated that they have no conflicts of interest to report.
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