Long-term survival after radical prostatectomy for men with high Gleason sum in pathologic specimen.
Journal: 2010/October - Urology
ISSN: 1527-9995
Abstract:
OBJECTIVE
To evaluate the long-term outcomes of patients with high Gleason sum 8-10 at radical prostatectomy (RP) and to identify the predictors of prostate cancer-specific survival (CSS) in this cohort.
METHODS
The institutional RP database was queried. A total of 9381 patients with complete follow-up underwent RP from 1982 to 2008. Of these 9381 patients, 1061 had pathologic Gleason sum 8-10 cancer. The patient and prostate cancer characteristics were evaluated. Survival analyses were performed using the Kaplan-Meier method. Univariate and multivariate proportional hazard regression models were created to evaluate the pertinent predictors of CSS (death from, or attributed to, prostate cancer).
RESULTS
The median preoperative prostate-specific antigen level was 7.6 ng/mL; 435 men had clinical Stage T1 tumor, 568 had Stage T2, and 36 had Stage T3. The biopsy Gleason sum was <7, 7, and >7 in 244 (22.3%), 406 (37.2%), and 425 (38.9%) patients, respectively. The median follow-up was 5 years (range 1-23). The actuarial 15-year recurrence-free survival, CSS, and overall survival rate was 20.7%, 57.4%, and 45.4%, respectively. On multivariate analysis, the predictors of poor CSS were pathologic Gleason sum 9-10 and seminal vesicle and lymph node involvement. Patients with pathologic Gleason sum 8 and organ-confined disease had a CSS rate of 89.9% at 15 years.
CONCLUSIONS
The results of our study have shown that 80% of the men with Gleason sum 8-10 who undergo RP will have experienced biochemical recurrence by 15 years. However, the CSS rate approached 90% for men with pathologic organ-confined disease. Higher pathologic Gleason sum 9-10 and seminal vesicle and lymph node involvement were independent predictors of worse CSS.
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Urology 76(3): 715-721

Long-Term Survival after Radical Prostatectomy for men with High Gleason Sum in the Pathological Specimen

Objective

To evaluate long-term outcomes of patients with high Gleason sum (8–10) at radical prostatectomy (RP) and to identify predictors of prostate cancer-specific survival (CSS) in this cohort.

Methods

The Institutional RP Database was queried. 9,381 patients with complete follow-up underwent RP from 1982 to 2008; 1,061 patients had pathologic Gleason sum 8–10. Patient and prostate cancer characteristics were evaluated. Survival analyses were performed using Kaplan-Meier method. Univariate and multivariate proportional hazard regression models were created to evaluate pertinent predictors of CSS (death from or attributed to prostate cancer).

Results

Median pre-operative PSA was 7.6 ng/mL; 435 men had clinical stage T1 tumor, 568 had T2, and 36 had T3. Biopsy Gleason sum was <7, =7 and >7 in 244 (22.3%), 406 (37.2%) and 425 (38.9%) patients, respectively. Median follow-up was five years (range 1–23 years). Actuarial 15-year recurrence-free survival, CSS and overall survival rates were 20.7%, 57.4% and 45.4%, respectively. In multivariate analysis, predictors of poor CSS were pathological Gleason sum of 9–10, seminal vesicle and lymph node involvement. Patients with pathological Gleason sum 8 and organ confined disease experienced a CSS of 89.9% at 15 years.

Conclusions

80% of men with Gleason sum 8–10 who undergo RP will experience biochemical recurrence at 15 years. However, CSS approached 90% in men with pathologic organ-confined disease. Higher pathological Gleason sum (9–10), seminal vesicle and lymph node involvement are independent predictors of worse CSS.

INTRODUCTION

The majority of newly diagnosed prostate cancers in the United States present with low-risk disease (non-palpable tumors, PSA<10ng/mL and Gleason sum (GS) <7) and demonstrate favorable outcomes regardless of initial definitive treatment modality.12 Predictive models have been generated to forecast the outcomes of patients after radical prostatectomy (RP) based on both pre- and post-operative clinical and pathological variables. 35 In pre-operative models, clinical stage, PSA and GS are associated with an increased risk of recurrence; PSA, pathological GS, surgical margin status, seminal vesicle (SV) and lymph node (LN) involvement are all excellent predictors of biochemical recurrence and death from cancer in post-operative models. GS is believed to be the strongest predictor of outcome in pre- and post-operative models, reflecting the adverse pathologic characteristics of the cancer. 67 Biochemical recurrence rates for patients with a tumor of GS less than seven is approximately 25% at 10-years 7 and is 77% for patients with high-risk GS (8–10) tumors over the same time period. 7 It has been suggested that select patients with GS 8–10 may benefit from surgery 8 with delayed adjuvant therapies as necessary, 9 while others may best be treated with radiation with systemic therapies (hormone deprivation therapy, chemotherapy).10

A recent study that included our institution examined the outcomes of patients with high biopsy GS and determined that the majority of men with a biopsy GS of eight or greater have unfavorable pathological disease and quickly experience disease-progression following surgery.11 While men with large burden, high GS disease on prostate biopsy may be expected to have a worse outcome, it is not clear whether a hastened time to biochemical recurrence necessarily translates into a worse cancer-specific or overall survival. In addition, many men undergo RP with a low to intermediate-risk GS (seven or less) on biopsy and are upgraded at pathological analysis. 12 Therefore, we sought to determine the long-term outcomes of men with high GS disease (8–10) at RP to identify predictors of favorable CSS among this cohort.

MATERIALS AND METHODS

The Institutional RP Database of approximately 17,000 men since 1982 who underwent open retropubic, laparoscopic or robot-assisted laparoscopic RP was queried; 9,381 were identified with complete follow-up. Of those men, 1,061 were identified with pathologic GS of 8 to 10. The database is an Institutional Review Board approved and catalogues demographic, pathological and follow-up data for each patient. Prostatectomy specimens were serially sectioned and totally submitted for histological analysis as previously described. 13

Patient and prostate cancer characteristics were evaluated using student’s t-test, chi-squared analysis and analysis of variance (ANOVA) when appropriate. Prostate cancer recurrence-free survival (RFS) was defined as survival from either a biochemical recurrence after RP (PSA ≥0.2ng/mL) or the presence of local or metastatic disease confirmed by physical examination or radiological study. Prostate cancer-specific survival (CSS) was defined as survival from death due to or attributed to complications of prostate cancer. Overall survival (OS) was defined as survival from any mortality. Mortality data was collected from the Social Security Administration (SSA) Death Index and cause of death was confirmed by the Center for Disease Control (CDC) National Death Index information. Survival analyses were performed using Kaplan-Meier method with log-rank test. Univariate and multivariate proportional hazards models were created to evaluate pertinent predictors of CSS. Models were fit with age, preoperative PSA, year of surgery classified as prior to or during the contemporary PSA era (prior to and after 1993 based on institutional data and the emergence and full incorporation of the Partin tables into clinical practice at our institution),514 biopsy GS, pathological GS, clinical stage, diagnostic biopsy characteristics (number of positive cores, maximum percentage core involvement) and pathologic stage (organ-confined (OC) versus extra-prostatic extension (EPE), SV invasion and LN involvement) to evaluate demographic and pathological predictors of CSS.

A secondary analysis was designed to investigate era-specific clinical and pathological characteristics of patients undergoing RP and subsequent outcomes. Based on year of surgery, the cohort was split into two groups: pre-PSA era (before 1993) and the contemporary PSA-era (1993 to present). Biochemical RFS and CSS were evaluated by era for changes in clinical and pathological staging.

RESULTS

Patient Demographics

Patient demographics and prostate cancer characteristics are detailed in Table 1. Of note, average age was 59.8 years, most men had palpable disease on digital rectal examination (T2 or greater, 57.2%), and 49.5% had a PSA in the range of 4–10 ng/mL. Biopsy GS was <7, =7 and >7 in 244 (22.3%), 406 (37.2%) and 425 (38.9%) patients, respectively. Two-hundred forty-four patients (22.3%) with a low-risk biopsy GS (<7), and 406 patients (37.2%) with an intermediate risk GS (=7) were upgraded to GS 8–10 at pathology.

Table 1

Patient and prostate cancer characteristics.

Patient
Characteristics:Value/NumberRange/Percentage
Median Age, years60(36–76)
Clinical Stage
T1a–b11(1.0%)
T1c446(40.8%)
T2a277(25.4%)
T2b231(21.2%)
T2c67(6.1%)
T336(3.3%)
Race
African-American81(7.4%)
Asian8(0.7%)
Caucasian961(88.0%)
Other42(3.8%)
Median PSA, ng/mL7.6(0.1–129)
PSA 0–4135(12.4%)
PSA 4–10540(49.5%)
PSA 10–20228(20.9%)
PSA >20124(11.4%)
Pathological
Variables:
Biopsy Gleason Sum
<7244(22.3%)
=7406(37.2%)
8296(27.1%)
9122(11.2%)
107(0.6%)
Pathological Gleason
Sum
8662(60.6%)
9423(38.7%)
107(0.6%)
Pathological Stage
OC (EPE−, SV−, LN−)270(24.7%)
EPE+ (SV−, LN−)463(42.4%)
SV+ (EPE+/−, LN−)200(18.3%)
LN+ (EPE+/−, SV+/−)159(14.6%)

N=l,061 except where specified.

Survival Analysis

RFS, CSS and OS were 20.7%, 57.4% and 45.4% at 15 years with a median follow-up of six years (range 1–25 years) (Figure 1). Four-hundred ten (38.4%) patients experienced prostate cancer recurrence, all manifest by an elevation in PSA; 70 (17.1%) and 187 (45.6%) had local and metastatic recurrences respectively. Median time to biochemical and metastatic recurrence was 3 and 12 years respectively.

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Kaplan-Meier actuarial PSA recurrence- free survival, Prostate Cancer-specific Survival and Overall Survival.

Predictors of Cancer-specific Survival

In univariate analyses, significant predictors of poor CSS included year of surgery, palpable (T2) and extraprostatic (T3) clinical stage, biopsy GS greater than seven, pathologic GS of nine or ten, SV and LN involvement (Table 2). PSA was not a statistically significant predictor of CSS among this high-risk cohort. Non-significant predictors of outcome in the univariate model were not included in the multivariate model (number of positive biopsy cores and maximum core positivity) with the exception of age and preoperative PSA, as they are established predictors of outcome in historical models. Pathological GS of nine or ten, SV invasion and LN involvement were significant predictors of poor CSS in multivariate analysis (Table 2).

Table 2

Univariate and Multivariate Cox Regression Models predicting CSS

UNIVARIATE
Hazard Ratio
MULTIVARIATE
Hazard Ratio
Variable(95%CI)p-value(95%CI)p-value

Preoperative Variables
Age, years1.0 (0.97–1.03)0.861.0 (0.97–1.03)0.96
PSA (ng/mL)1.01 (1.00–1.02)0.150.99 (0.97–1.004)0.15
PSA era (1993)0.84 (0.60–1.17)0.301.16 (.073–1.85)0.53
Clinical Stage T2*1.57 (0.98–2.52)0.0591.16 (.068–1.98)0.59
Clinical Stage T3*1.54 (0.71–3.37)0.280.82 (0.33–2.03)0.68
Biopsy Variables
Biopsy Gleason 7**1.68 (0.98–2.88)0.061.39 (0.73–2.65)0.31
Biopsy Gleason 8 or greater**2.52 (1.52–4.20)<0.0012.12 (1.14–3.93)0.02
>3 Positive Biopsy Cores0.45 (0.04–5.03)0.51-
>50% maximum Core Positivity0.23 (0.02–2.65)0.02-
Pathologic Variables
Pathological Gleason 9–10***2.19 (1.52–3.15)<0.0011.85 (1.21–2.85)0.005
EPE+ (SV−, LN−)****2.23 (0.79–6.34)0.131.52 (0.52–4.44)0.44
SV+ (EPE+/−, LN−)****6.71 (2.37–18.99)<0.0014.08 (1.38–12.02)0.01
LN+ (EPE+/−, SV+/−)****7.78 (2.81–21.51)<0.0015.98 (2.06–17.34)0.001

Referent variable is Clinical Stage T1 (*),

Biopsy Gleason sum six or less (**),

pathological Gleason sum eight (***) and

organ confined disease (EPE(−), SV(−), LN(−)) (****).

HR = Hazard Ratio, 95% CI = 95% Confidence Interval.

CSS in relation to pathologic GS and stage are demonstrated in Table 3. Patients with OC disease experienced a durable CSS of 95.9% and 89.7% at 15 years for patients with GS 8 and 9–10, respectively. Patients with Gleason 9–10 had consistently worse CSS by stage when compared to patients with Gleason 8 disease (p<0.001). There was not a significant difference in CSS among men with Gleason 9–10 with SV involvement and LN invasion (p=0.62).

Table 3

Prostate cancer-specific survival at 5,10 and 15 years in relation to Pathologic Gleason Sum and Pathologic Stage.

Gleason 8
Gleason 9–10
Pathologic Stagen5 y10 y15 yn5 y10 y15 y


OC (EPE−, SV−, LN−)17899.295.995.963100.089.789.7
EPE+ (SV−, LN−)26798.093.186.115393.883.576.5
SV+ (EPE+/−, LN−)8394.883.873.18689.767.737.0
LN+ (EPE+/−, SV+/−)7291.775.450.37877.556.946.0

PSA- era Specific Analysis of Cancer-specific Survival

The secondary analysis revealed 246 (22.5%) patients who underwent RP prior to 1993 and 846 (77.5%), since 1993, in the contemporary PSA-era (Table 4). Of note, prostate cancer was OC in only 7.9% of pre-PSA era patients, while 30.3% of patients had OC disease in the contemporary PSA-era (p<0.001). Biochemical RFS at 15 years was 22.4% and 26.0% for the pre- and contemporary PSA-era groups, respectively (p=0.53). CSS at 15 years was 64.2% and 78.0% for the pre- and contemporary PSA-era groups, respectively (p<0.001). PSA-era was not a significant predictor of BFS (not shown) or CSS (Table 2) in the multivariable proportional hazard model.

Table 4

Era-specific analysis of clinical and pathological prostate cancer characteristics.

Pre-PSA EraContemporary-PSA Era
Patient Characteristics:Value/NumberRange/PercentageValue/NumberRange/Percentagep-value
Median Age, years61(38–76)60(36–74)0.001
Clinical Stage<0.001
Tl35(14.6%)422(50.9%)
T2183(76.6%)392(47.3%)
T321(8.8%)15(1.8%)
Median PSA, ng/mL10.4(0.6–129)6.8(0.1–84.1)<0.001
Biopsy Gleason Sum<0.001
<782(34.3%)162(19.5%)
=772(30.1%)334(40.3%)
>780(33.5%)345(41.6%)
Pathological Gleason
Sum0.85
8146(61.1%)516(62.2%)
998(41.0%)325(39.2%)
102(0.8%)5(0.6%)
Pathological Stage<0.001
OC (EPE−, SV−, LN−)19(7.9%)251(30.3%)
EPE+ (SV−, LN−)106(44.4%)357(43.1%)
SV+ (EPE+/−, LN−)51(21.3%)149(18.0%)
LN+ (EPE+/−, SV+/−)70(29.3%)89(10.7%)

Pre-PSA era = prior to 1993, Contemporary PSA-era = 1993 to present.

Additional Therapies after RP

Of 634 men with complete data regarding additional therapies, 310 (48.9%) patients received neoadjuvant, adjuvant or salvage therapy. Thirty-three (5.2%) received neoadjuvant hormones. Eleven (1.7%) received adjuvant therapy, defined as treatment within the first year of RP without a biochemical recurrence; 6, 6 and 3 received hormones, radiation and chemotherapy (or a combination of therapies) respectively. In total, 266 (42.1%), 111 (17.7%) and 73 (12.8%) received salvage hormone, radiation and chemotherapy (or a combination thereof). One hundred twenty men received early hormones before the presence of metastatic disease; 122 received delayed hormones after metastatic recurrence.

Patient Demographics

Patient demographics and prostate cancer characteristics are detailed in Table 1. Of note, average age was 59.8 years, most men had palpable disease on digital rectal examination (T2 or greater, 57.2%), and 49.5% had a PSA in the range of 4–10 ng/mL. Biopsy GS was <7, =7 and >7 in 244 (22.3%), 406 (37.2%) and 425 (38.9%) patients, respectively. Two-hundred forty-four patients (22.3%) with a low-risk biopsy GS (<7), and 406 patients (37.2%) with an intermediate risk GS (=7) were upgraded to GS 8–10 at pathology.

Table 1

Patient and prostate cancer characteristics.

Patient
Characteristics:Value/NumberRange/Percentage
Median Age, years60(36–76)
Clinical Stage
T1a–b11(1.0%)
T1c446(40.8%)
T2a277(25.4%)
T2b231(21.2%)
T2c67(6.1%)
T336(3.3%)
Race
African-American81(7.4%)
Asian8(0.7%)
Caucasian961(88.0%)
Other42(3.8%)
Median PSA, ng/mL7.6(0.1–129)
PSA 0–4135(12.4%)
PSA 4–10540(49.5%)
PSA 10–20228(20.9%)
PSA >20124(11.4%)
Pathological
Variables:
Biopsy Gleason Sum
<7244(22.3%)
=7406(37.2%)
8296(27.1%)
9122(11.2%)
107(0.6%)
Pathological Gleason
Sum
8662(60.6%)
9423(38.7%)
107(0.6%)
Pathological Stage
OC (EPE−, SV−, LN−)270(24.7%)
EPE+ (SV−, LN−)463(42.4%)
SV+ (EPE+/−, LN−)200(18.3%)
LN+ (EPE+/−, SV+/−)159(14.6%)

N=l,061 except where specified.

Survival Analysis

RFS, CSS and OS were 20.7%, 57.4% and 45.4% at 15 years with a median follow-up of six years (range 1–25 years) (Figure 1). Four-hundred ten (38.4%) patients experienced prostate cancer recurrence, all manifest by an elevation in PSA; 70 (17.1%) and 187 (45.6%) had local and metastatic recurrences respectively. Median time to biochemical and metastatic recurrence was 3 and 12 years respectively.

An external file that holds a picture, illustration, etc.
Object name is nihms175770f1.jpg

Kaplan-Meier actuarial PSA recurrence- free survival, Prostate Cancer-specific Survival and Overall Survival.

Predictors of Cancer-specific Survival

In univariate analyses, significant predictors of poor CSS included year of surgery, palpable (T2) and extraprostatic (T3) clinical stage, biopsy GS greater than seven, pathologic GS of nine or ten, SV and LN involvement (Table 2). PSA was not a statistically significant predictor of CSS among this high-risk cohort. Non-significant predictors of outcome in the univariate model were not included in the multivariate model (number of positive biopsy cores and maximum core positivity) with the exception of age and preoperative PSA, as they are established predictors of outcome in historical models. Pathological GS of nine or ten, SV invasion and LN involvement were significant predictors of poor CSS in multivariate analysis (Table 2).

Table 2

Univariate and Multivariate Cox Regression Models predicting CSS

UNIVARIATE
Hazard Ratio
MULTIVARIATE
Hazard Ratio
Variable(95%CI)p-value(95%CI)p-value

Preoperative Variables
Age, years1.0 (0.97–1.03)0.861.0 (0.97–1.03)0.96
PSA (ng/mL)1.01 (1.00–1.02)0.150.99 (0.97–1.004)0.15
PSA era (1993)0.84 (0.60–1.17)0.301.16 (.073–1.85)0.53
Clinical Stage T2*1.57 (0.98–2.52)0.0591.16 (.068–1.98)0.59
Clinical Stage T3*1.54 (0.71–3.37)0.280.82 (0.33–2.03)0.68
Biopsy Variables
Biopsy Gleason 7**1.68 (0.98–2.88)0.061.39 (0.73–2.65)0.31
Biopsy Gleason 8 or greater**2.52 (1.52–4.20)<0.0012.12 (1.14–3.93)0.02
>3 Positive Biopsy Cores0.45 (0.04–5.03)0.51-
>50% maximum Core Positivity0.23 (0.02–2.65)0.02-
Pathologic Variables
Pathological Gleason 9–10***2.19 (1.52–3.15)<0.0011.85 (1.21–2.85)0.005
EPE+ (SV−, LN−)****2.23 (0.79–6.34)0.131.52 (0.52–4.44)0.44
SV+ (EPE+/−, LN−)****6.71 (2.37–18.99)<0.0014.08 (1.38–12.02)0.01
LN+ (EPE+/−, SV+/−)****7.78 (2.81–21.51)<0.0015.98 (2.06–17.34)0.001

Referent variable is Clinical Stage T1 (*),

Biopsy Gleason sum six or less (**),

pathological Gleason sum eight (***) and

organ confined disease (EPE(−), SV(−), LN(−)) (****).

HR = Hazard Ratio, 95% CI = 95% Confidence Interval.

CSS in relation to pathologic GS and stage are demonstrated in Table 3. Patients with OC disease experienced a durable CSS of 95.9% and 89.7% at 15 years for patients with GS 8 and 9–10, respectively. Patients with Gleason 9–10 had consistently worse CSS by stage when compared to patients with Gleason 8 disease (p<0.001). There was not a significant difference in CSS among men with Gleason 9–10 with SV involvement and LN invasion (p=0.62).

Table 3

Prostate cancer-specific survival at 5,10 and 15 years in relation to Pathologic Gleason Sum and Pathologic Stage.

Gleason 8
Gleason 9–10
Pathologic Stagen5 y10 y15 yn5 y10 y15 y


OC (EPE−, SV−, LN−)17899.295.995.963100.089.789.7
EPE+ (SV−, LN−)26798.093.186.115393.883.576.5
SV+ (EPE+/−, LN−)8394.883.873.18689.767.737.0
LN+ (EPE+/−, SV+/−)7291.775.450.37877.556.946.0

PSA- era Specific Analysis of Cancer-specific Survival

The secondary analysis revealed 246 (22.5%) patients who underwent RP prior to 1993 and 846 (77.5%), since 1993, in the contemporary PSA-era (Table 4). Of note, prostate cancer was OC in only 7.9% of pre-PSA era patients, while 30.3% of patients had OC disease in the contemporary PSA-era (p<0.001). Biochemical RFS at 15 years was 22.4% and 26.0% for the pre- and contemporary PSA-era groups, respectively (p=0.53). CSS at 15 years was 64.2% and 78.0% for the pre- and contemporary PSA-era groups, respectively (p<0.001). PSA-era was not a significant predictor of BFS (not shown) or CSS (Table 2) in the multivariable proportional hazard model.

Table 4

Era-specific analysis of clinical and pathological prostate cancer characteristics.

Pre-PSA EraContemporary-PSA Era
Patient Characteristics:Value/NumberRange/PercentageValue/NumberRange/Percentagep-value
Median Age, years61(38–76)60(36–74)0.001
Clinical Stage<0.001
Tl35(14.6%)422(50.9%)
T2183(76.6%)392(47.3%)
T321(8.8%)15(1.8%)
Median PSA, ng/mL10.4(0.6–129)6.8(0.1–84.1)<0.001
Biopsy Gleason Sum<0.001
<782(34.3%)162(19.5%)
=772(30.1%)334(40.3%)
>780(33.5%)345(41.6%)
Pathological Gleason
Sum0.85
8146(61.1%)516(62.2%)
998(41.0%)325(39.2%)
102(0.8%)5(0.6%)
Pathological Stage<0.001
OC (EPE−, SV−, LN−)19(7.9%)251(30.3%)
EPE+ (SV−, LN−)106(44.4%)357(43.1%)
SV+ (EPE+/−, LN−)51(21.3%)149(18.0%)
LN+ (EPE+/−, SV+/−)70(29.3%)89(10.7%)

Pre-PSA era = prior to 1993, Contemporary PSA-era = 1993 to present.

Additional Therapies after RP

Of 634 men with complete data regarding additional therapies, 310 (48.9%) patients received neoadjuvant, adjuvant or salvage therapy. Thirty-three (5.2%) received neoadjuvant hormones. Eleven (1.7%) received adjuvant therapy, defined as treatment within the first year of RP without a biochemical recurrence; 6, 6 and 3 received hormones, radiation and chemotherapy (or a combination of therapies) respectively. In total, 266 (42.1%), 111 (17.7%) and 73 (12.8%) received salvage hormone, radiation and chemotherapy (or a combination thereof). One hundred twenty men received early hormones before the presence of metastatic disease; 122 received delayed hormones after metastatic recurrence.

COMMENT

In a select population of high-risk prostate cancer patients with pathologic GS eight to ten, CSS following surgery is 57% at 15 years. This represents, to our knowledge, the longest reported comprehensive follow-up of high-risk patients after RP. These data can be interpreted in a positive or negative fashion depending on the perspective – proponents of RP may interpret these data as promising while advocates of non-surgical management of aggressive disease can highlight studies with alternative treatment modalities. For instance, long-term studies of all patients undergoing RP demonstrate a CSS on the order of 90 percent at 15 years, setting the benchmark for cancer-specific outcome.1 The survival statistics in these studies are skewed by the large-percentage of patients with favorable characteristics (only 4 to 12 percent have GS 8–10 disease).815 The historical 10-year CSS and metastasis-free survival rates for men with high-Gleason disease are closer to 80% and 50% respectively. 16 However, the CSS in our study indicates that select patients with high-risk disease who undergo RP may experience a survival benefit.8 Those patients with OC, GS 8–10 – although only 25% of the cohort – experienced a durable cancer-specific survival of 94%, achieving the benchmark of 90% for low- or intermediate-risk prostate cancer described by Han et al and Zincke et al.117 In addition, the actuarial metastasis-free survival in this study was 45.7% at 15 years, a marked improvement from 8-year rates between 27% and 40% and 10 year rates of 38% from prior surgical follow-up studies.78 In fact, greater than half of the high-risk population in this study achieved 15 year survival, meeting the average life expectancy of 75–78 years for American men, and surpassing the predicted life expectancy of many men with high-Gleason disease.

Our analyses demonstrate that GS is the most important predictor of CSS in these patients with high-grade disease. It deserves mention that the vast majority of men had Gleason 8–9 disease; only seven men had Gleason ten disease. While pathological variables like EPE, LN involvement and SV invasion remained important predictors of outcome, pre-operative variables such as clinical stage, positive biopsy cores and maximum core percent positivity were not significant predictor of CSS. This may imply that tumor volume is not as important in high-Gleason disease as it is in lower-risk forms of the disease. In low-risk disease, large tumors manifested by a palpable abnormality on digital rectal examination, a high number of positive biopsy cores or a large percentage of core positivity are believed to indicate bulky and worse disease and poor prognosis. In high-risk disease, an increasing GS is believed to portend a worse prognosis due to aggressive biological behavior and the risk of occult systemic disease, with series demonstrating positive LN in 40 to 100 percent of patients with GS 8–10.1819 Therefore, traditional preoperative predictors of outcome for low-risk disease may not apply to high-risk disease.

In this study, of only men with high-risk disease, preoperative PSA was not a significant predictor of CSS. Previous studies demonstrated that poorly differentiated tumors are not effective in producing PSA and therefore, patients with high-risk GSs may have relatively lower serum PSA levels. 20 In addition, EPE (including positive surgical margins) was not predictive of CSS while LN and SV involvement were predictors of worse survival outcome. This may reflect that EPE has a minimal impact in an already aggressive form of prostate cancer or the benefit of adjuvant therapies, as these patients are more likely to progress to biochemical recurrence and adjuvant or rescue therapies early.

Most importantly, patient survival following surgery for pathologic Gleason 8–10 disease decreased precipitously with worse pathological stage (Table 3). The majority of patients (67.1%) without SV involvement or LN invasion experienced a 15-year survival of 50% or better, indicating that many patients with high-risk GS (8–10) could experience a reasonable long-term CSS. However, patients with SV involvement or LN invasion experienced a drastically lower long-term CSS rate. It deserves mention that the CSS for men with LN invasion approached 50% at 15-years, possibly indicating the benefit of extended pelvic LN dissection in these patients. This study accentuates the importance of developing methods and models to aid in identifying those patients who have extensive disease and high number of adverse features, so that they may be better counseled regarding systemic and multimodality neoadjuvant and adjuvant treatments. To date, neither molecular markers nor advanced imaging (i.e. MRI or MRI spectroscopy) have proven capable of consistently detecting locally advanced prostate cancer; leaving vast opportunities for advances in research in the future.

As a final point, PSA-era was not a significant predictor of BFS or CSS in this analysis. This finding was previously reported by Boorjian et al., where they similarly noted an increase in the rate of OC disease from 23 to 35% in the early to contemporary PSA era.21 However, they did not notice an improvement in BFS or CSS at 7 years. In our study, over longer follow-up period, an increase from 8 to 30% in OC disease resulted in a significant improvement in CSS from 64 to 78% (p<0.001). The improvement in CSS can be attributed to an improvement in pathological stage subsequent to improved prostate cancer detection via PSA testing. Not only does this demonstrate the utility of PSA screening, but highlights the importance of early detection and treatment for prostate cancer for men with high-grade disease.

Quality-of-life is important to prostate cancer patients as surgical technique and medical therapies have improved. The majority of patients in this cohort did experience a biochemical recurrence with less than 20 percent remaining completely disease-free at 20 years. At the same time, nearly 70 percent of patients were free from local recurrence and 45 percent were metastases free. However 70 (17.1%) and 187 (45.6%) experienced local and metastatic recurrence and may have suffered a decrease in quality of life due to either the symptoms of metastatic (specifically osseous) disease or the subsequent effects of adjuvant or salvage therapies. Nearly a third of this cohort underwent radiation, chemo- and/or hormone therapy. While adjuvant and salvage therapies are patient and surgeon specific, in general, we support the use of adjuvant radiation only in patients with positive surgical margins without seminal vesicle invasion. 2223 In addition, we recommend the use of androgen deprivation therapy only upon clinical recurrence as immediate hormone therapy has not been proven to extend overall survival following RP. 2425 As we improve upon our ability to identify those patients who will benefit from RP, we need to be mindful of those patients who will recur and undergo further treatments, and most importantly, how those consequences will affect their quality-of-life.

There are several potential limitations of this study. Any retrospective analysis of surgical patients is fraught will selection bias; predictably, those patients who are excellent surgical candidates are destined to have better outcomes than those unable to undergo surgery. As such, only seven men had Gleason ten disease on biopsy and 36 men had clinical stage T3 disease, highlighting that aggressive forms of prostate cancer are often advanced and unresectable. This does not, however, preclude valuable information from being extracted from these studies. Survival information on patients with high-Gleason disease who underwent non-surgical treatment would offer a valuable comparator group for the patients in this cohort. Also, death due to malignancy is often under-reported. To prevent gross overestimation of CSS we utilize both the SSA and CDC death indices to query and verify causes of death. In addition, this study would be strengthened by controlling the survival analyses for neoadjuvant, adjuvant and salvage therapies.21 Drawing significant conclusions from the analysis of additional therapies, adjuvant specifically, is difficult given that the patients who receive additional therapy often have worse pre-operative and pathological features and are therefore destined to do worse. While this would provide valuable information regarding the efficacy and timing of these therapies, neither limitation detracts from the overall message of this study – that there are select patients with high-Gleason disease who experience extended CSS.

CONCLUSIONS

Select patients with high GS (8–10) will experience a prolonged CSS. For example, CSS is 90% in men with pathologic OC disease. A pathologic GS of nine or ten, SV invasion and LN involvement are significant predictors of poor CSS.

Acknowledgments

This study was supported by SPORE grant P50CA58236 from the National institutes of Health Cancer Institute.

Corresponding Author: Phillip M. Pierorazio, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, 600 N. Wolfe Street, Marburg 134, Baltimore, Maryland 21287, ude.imhj@oizaroreiplihp, (410) 955-0351 phone, (410) 614-3695 fax
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Abstract

Objective

To evaluate long-term outcomes of patients with high Gleason sum (8–10) at radical prostatectomy (RP) and to identify predictors of prostate cancer-specific survival (CSS) in this cohort.

Methods

The Institutional RP Database was queried. 9,381 patients with complete follow-up underwent RP from 1982 to 2008; 1,061 patients had pathologic Gleason sum 8–10. Patient and prostate cancer characteristics were evaluated. Survival analyses were performed using Kaplan-Meier method. Univariate and multivariate proportional hazard regression models were created to evaluate pertinent predictors of CSS (death from or attributed to prostate cancer).

Results

Median pre-operative PSA was 7.6 ng/mL; 435 men had clinical stage T1 tumor, 568 had T2, and 36 had T3. Biopsy Gleason sum was <7, =7 and >7 in 244 (22.3%), 406 (37.2%) and 425 (38.9%) patients, respectively. Median follow-up was five years (range 1–23 years). Actuarial 15-year recurrence-free survival, CSS and overall survival rates were 20.7%, 57.4% and 45.4%, respectively. In multivariate analysis, predictors of poor CSS were pathological Gleason sum of 9–10, seminal vesicle and lymph node involvement. Patients with pathological Gleason sum 8 and organ confined disease experienced a CSS of 89.9% at 15 years.

Conclusions

80% of men with Gleason sum 8–10 who undergo RP will experience biochemical recurrence at 15 years. However, CSS approached 90% in men with pathologic organ-confined disease. Higher pathological Gleason sum (9–10), seminal vesicle and lymph node involvement are independent predictors of worse CSS.

Keywords: Prostate cancer, High-Risk, Gleason sum
Abstract

KEY OF ABBREVIATIONS

ANOVAAnalysis of Variance
CDCCenter for Disease Control
CSSProstate cancer-specific survival
EPEExtra-prostatic extension
GSGleason sum
LNLymph node
OCOrgan-confined
OSOverall survival
PSAProstate-specific antigen
RFSRecurrence-free survival
RPRadical prostatectomy
SSASocial Security Adminstration
KEY OF ABBREVIATIONS

Footnotes

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Footnotes

REFERENCES

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