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New Prostate Cancer Grading System Predicts Long-term Survival Following Surgery for Gleason Score 8–10 Prostate Cancer
EURURO-7133; No. of Pages 6 EUROPEAN UROLOGY XXX (2016) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Prostate Cancer Editorial by XXX on pp. x–y of this issue
New Prostate Cancer Grading System Predicts Long-term Survival Following Surgery for Gleason Score 8–10 Prostate Cancer Won Sik Ham a,y, Heather J. Chalfin a, Zhaoyong Feng a, Bruce J. Trock a, Jonathan I. Epstein a,b, Carling Cheung a, Elizabeth Humphreys a, Alan W. Partin a, Misop Han a,* a
Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; b Department of Pathology,
Johns Hopkins Medical Institutions, Baltimore, MD, USA
Article info
Abstract
Article history: Accepted November 4, 2016
Background: The newly proposed five-tiered prostate cancer grading system (PCGS) divides Gleason score (GS) 8–10 disease into GS 8 and GS 9–10 on the basis of biochemical recurrence (BCR) following radical prostatectomy (RP) as an outcome. However, BCR does not necessarily portend worse survival outcomes. Objective: To assess the significance of distinguishing GS 8 versus 9–10 disease in terms of long-term survival outcomes for both the preoperative setting using biopsy (Bx) GS and the postoperative setting with RP GS. Design, setting, and participants: Of 23 918 men who underwent RP between 1984 and 2014, there were 721 men with biopsy GS 8–10, and 1047 men with RP GS 8–10. Outcome measures and statistical analysis: Clinicopathologic characteristics were compared between men with GS 8 and those with GS 9–10. We compared all-cause mortality (ACM) and prostate cancer–specific mortality (PCSM) risk between the groups using Cox regression and competing-risks analyses, adjusting for other perioperative variables and death from other causes as the competing event. Results and limitations: Compared to men with GS 8, men with GS 9–10 had later RP year and higher pathologic stage. Among men with Bx GS 8–10, 115 died (82 due to PC) with median follow-up of 3 yr (interquartile range [IQR] 1–7) for both overall and cancer-specific survival. Of men with RP GS 8–10, 221 died (151 due to PC) with median follow-up of 4 yr (IQR 2–8) and 4 yr (IQR 2–9) for overall and cancer-specific survival, respectively. PC-specific survival rates were significantly lower for men with GS 9–10 compared to men with GS 8 for both Bx (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.37–3.30; p < 0.01) and RP GS (HR 2.38, 95% CI 1.74–3.28; p < 0.01). This association persisted in multivariable models after adjusting for perioperative variables. Conclusions: Men with GS 9–10 had higher ACM and PCSM rates compared to those with GS 8. GS 8 and GS 9–10 PC should be considered separately in both the preoperative and postoperative setting as suggested by the new PCGS. Patient summary: The prostate cancer grading system can predict mortality risk after radical prostatectomy (RP) for men with Gleason score 8–10 disease based on both biopsy and RP Gleason scores. There are significant differences in all-cause mortality and prostate cancer–specific mortality following surgery between men with Gleason score 8 and those with Gleason score 9–10 disease. # 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: Giacomo Novara Keywords: Mortality Prostate cancer Gleason score
y Present address: Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea. * Corresponding author. E-mail address: [email protected] (M. Han).
http://dx.doi.org/10.1016/j.eururo.2016.11.006 0302-2838/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Ham WS, et al. New Prostate Cancer Grading System Predicts Long-term Survival Following Surgery for Gleason Score 8–10 Prostate Cancer. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.11.006
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1.
value of the new grading system in two clinical settings: preoperative (biopsy) GS and postoperative (RP) GS.
Introduction
In 1974, Gleason and Mellinger proposed the prostate cancer (PC) grading system as the sum of the two most common grade patterns [1]. Since then, there have been two major updates owing to the evolving diagnosis and treatment of PC [2,3]. For example, Gleason score (GS) 2–5 distinctions are no longer used. In addition, certain patterns such as poorly formed glands and cribriform glomeruloid cancers are now considered Gleason pattern 4 [2–4]. Compared to other clinicopathologic factors and molecular markers, GS remains the single most powerful predictor of PC outcomes [4]. Although various GS groupings have been used in clinical practice [5–12], most researchers have combined GS 8 and GS 9–10 into a single high-grade entity [9,13–15]. In the new five-tiered prostate cancer grading system (PCGS) proposed by Epstein and colleagues [16], the high-grade entity (GS 8) is divided into GS 8 and GS 9–10 because men with GS 9–10 had a much higher likelihood of biochemical recurrence (BCR) following radical prostatectomy (RP) than those with GS 8. Recently, this new PCGS was validated using multi-institutional and multimodal therapy data with BCR as an endpoint [17,18]. However, BCR does not necessarily portend worse survival outcomes [19,20]. In this study, we assessed long-term survival outcomes (prostate cancer–specific mortality [PCSM] and all-cause mortality [ACM]) following RP for GS 8 versus GS 9–10 disease using data for a large cohort of RP patients at a single institution. Specifically, we investigated the prognostic
2.
Patients and methods
Following institutional review board approval at Johns Hopkins, we reviewed data for 23 918 men who underwent RP at our institution between 1984 and 2014. After excluding patients with biopsy (Bx) GS < 8 and RP GS < 8, incomplete clinicopathologic or follow-up data, or a history of neoadjuvant treatment, there were 721 men with Bx GS 8–10 and 1047 men with RP GS 8–10 (Fig. 1). Most men were treated only with RP until BCR. Clinical and pathologic stages were assigned in accordance with the American Joint Committee on Cancer staging system [21]. One of the authors of the current article led a consensus on updating the Gleason grading system in 2004 [2]. Men with GS < 8 were appropriately reclassified since 2004, while men with GS 8–10 were properly classified since 1984. Therefore, we decided to perform long-term survival analyses solely evaluating men with GS 8–10, and to focus on the distinction of GS 8 disease from the former ‘‘high-risk’’ clump of GS 8–10. Baseline characteristics and pathologic outcomes were compared between men with GS 8 and GS 9–10 using x2 tests for categorical data and Student’s t-test or the nonparametric alternative Wilcoxon sum rank test for continuous data. Information on survival status and cause of death was obtained from patient follow-up, the Social Security Administration Death Index, and the Centers for Disease Control National Death Index. PCSM was designated when the underlying cause of death was PC or the patient had castration-resistant PC at the time of death. PCSM was calculated for men with GS 8 versus GS 9–10, and PCSM estimates were compared between the groups using a competing-risks model. A cumulative incidence function was also generated for each
n = 23 918 Men who underwent RP (1984–2014) n = 13 198, Excluded for biopsy GS <8 and radical prostatectomy GS <8 n = 8952, Excluded for: incompleteclinicpathological data, follow-up informaon, or history of neoadjuvant treatment n = 1303 Men with Bx GS 810 or RP GS 8–10
n = 721
n = 1047
Men with biopsy GS 8–10
Men with radical prostatectomy GS 8–10
n = 490
n = 231
n = 574
n = 473
Bx GS 8
Bx GS 9–10
RP GS 8
RP GS 9–10
Included in analysis
Fig. 1 – Flowchart for study inclusion. RP = radical prostatectomy; GS = Gleason score; Bx = biopsy.
Please cite this article in press as: Ham WS, et al. New Prostate Cancer Grading System Predicts Long-term Survival Following Surgery for Gleason Score 8–10 Prostate Cancer. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.11.006
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Table 1 – Clinicopathologic characteristics for men with Gleason score 8 and 9–10 prostate cancer Parameter
Age (yr) Mean (SD) Median (IQR) Race, n (%) White Black Others Year of surgery Median (IQR) PSA (ng/ml) Mean (SD) Median (IQR) Clinical stage, n (%) T1–T2a T2b–T2c T3a–T4 Pathologic stage, n (%) Organ-confined Extraprostatic extension Seminal vesicle invasion Lymph node invasion PSM, n (%) Follow-up (yr) Mean (SD) Median (IQR) PCSM, n (%) All-cause mortality, n (%)
Biopsy GS 8–10 (n = 721) GS 8
GS 9–10
(n = 490)
(n = 231)
RP GS 8–10 (n = 1047) p value
GS 8
GS 9–10
(n = 574)
(n = 473)
0.2 60.4 (6.5) 61 (9)
0.2
61.0 (6.8) 61 (10)
59.9 (6.5) 60 (10)
60.4 (6.6) 61 (9)
0.8 410 (84) 53 (11) 27 (5.1)
0.6
195 (84) 26 (11) 10 (4.3)
481 (84) 61 (11) 32 (5.6)
408 (86) 42 (8.9) 23 (4.9)
2003 (12)
2006 (11)
<0.0001 2006 (11)
2008 (9)
<0.0001
0.9 7.4 (6.8) 5.6 (5.1)
0.1
7.6 (7.9) 5.7 (5.2)
7.6 (7.3) 5.9 (5.5)
8.8 (8.8) 6.2 (7.3)
0.9 370 (76) 107 (22) 13 (2.7)
0.2
171 (74) 53 (23) 7 (3.0)
435 (76) 127 (22) 12 (2.1)
339 (72) 119 (25) 15 (3.2)
202 225 90 57 141
109 170 92 102 146
0.0002 201 190 55 44 111
(41) (39) (11) (9.0) (23)
6.1 (5.6) 4.0 (7) 49 (10.0) 72 (15)
70 81 39 41 53
(30) (35) (17) (18) (23)
0.9 0.033
4.9 (4.5) 3 (4) 33 (14) 43 (19)
0.091 0.2
p value
<0.0001 (35) (39) (16) (9.9) (25)
7.4 (6.4) 6 (9) 62 (11) 108 (19)
(23) (36) (20) (22) (31)
6.1 (5.2) 5 (6) 89 (19) 113 (24)
0.02 0.010
0.0002 0.045
GS = Gleason score; IQR = interquartile range; PCSM = prostate cancer–specific mortality; PSA = prostate-specific antigen; PSM = positive surgical margin; RP = radical prostatectomy; SD = standard deviation.
Gleason group. Multivariable Cox regression analysis was used to determine ACM as a function of GS 8 versus GS 9–10. Multivariable competing-risks regression analysis was performed for PCSM with death from other causes as the competing event [22]. For our primary endpoint analyses, GS 8 disease was defined as the reference group. Preoperative variables (preoperative prostate-specific antigen [PSA] level, clinical stage) were adjusted for multivariable analyses between Bx GS 8 and GS 9–10, whereas postoperative variables (age, year of surgery, preoperative PSA level, pathologic stage, and positive surgical margins [PSMs]) were used for multivariable analyses between RP GS 8 and GS 9–10. The level of significance was set at 0.05 in all analyses. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).
3.
Results
Men with both Bx and RP GS 9–10 disease had later RP year and higher pathologic stage compared to men with GS 8 disease (p < 0.01 for all; Table 1). There were no significant differences in age, race, preoperative PSA level, or clinical stage between men with GS 8 and men with GS 9–10. There was a significant difference in PSM rate between RP GS 8 and GS 9–10. Among 721 men with Bx GS 8–10, 115 men died (82 of PC) during median follow-up of 3 yr (interquartile range [IQR] 1–7) for overall and cancer-specific survival. Of 1047 men with RP GS 8–10, 221 died (151 of PC) during median follow-up of 4 yr (IQR 2–8) for overall survival and 4 yr (IQR 2–9) for cancer-specific survival. Among men with
Bx GS 8–10, the respective 10-yr estimates of ACM and PCSM rate were 17% and 12% for Bx GS 8, and 36% and 32% for Bx GS 9–10. For men with RP GS 8–10, these were 17% and 8.9% for RP GS 8, and 37% and 29% for RP GS 9–10, respectively. PC-specific survival rates were significantly lower for men with both Bx GS 9–10 (Fig. 2; p < 0.01) and RP GS 9–10 (Fig. 3; p < 0.01) compared to men with GS 8. On multivariable analysis, ACM was higher for men with GS 9–10 (adjusted HR [AHR] 1.93, 95% CI 1.32–2.84, p = 0.001 for Bx GS; AHR 1.65, 95% CI 1.25–2.18, p = 0.0004 for RP GS) (Table 2). PCSM was also significantly higher for men with GS 9–10 (AHR 2.09, 95% CI 1.33–3.28, p = 0.001 for Bx GS; AHR 2.20, 95% CI 1.58–3.05, p < 0.0001 for RP GS) after adjusting for preoperative and postoperative variables (Table 3). 4.
Discussion
The new five-tiered PCGS proposes that GS 8–10 disease should not be viewed as a single high-grade entity but should be subdivided into GS 8 and GS 9–10 on the basis of differences in BCR [16,17]. The proposed system was more recently validated by Tsao et al [23] and Loeb et al [18]. However, these studies were based on BCR as an outcome measure, and there has been no validation in terms of long-term survival outcomes such as PCSM. The new PCGS is poised to become the universal risk grouping
Please cite this article in press as: Ham WS, et al. New Prostate Cancer Grading System Predicts Long-term Survival Following Surgery for Gleason Score 8–10 Prostate Cancer. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.11.006
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Table 2 – Cox regression analyses of predictors for all-cause mortality Variable
Univariable model HR (95% CI)
Preoperative variablesa Prostate-specific antigen Clinical stage T1–T2a (reference) T2b–T2c T3a–T4 Biopsy Gleason score 8 (reference) 9–10 Postoperative variablesb Age Year of surgery Prostate-specific antigen RP Gleason score 8 (reference) 9–10 Pathologic stage Organ-confined (reference) Extraprostatic extension Seminal vesicle invasion Lymph node invasion Positive surgical margins Negative (reference) Positive
Multivariable model p value
AHR (95% CI)
1.00 (0.98–1.02)
0.8
1.00 (0.98–1.02), 0.8
1 1.64 (1.11–2.44) 1.19 (0.54–2.62)
0.013 0.7
1 1.60 (1.08–2.38), 0.020 1.25 (0.56–2.80), 0.6
1 1.96 (1.34–2.88)
0.001
1 1.93 (1.32–2.84), 0.001
1.03 (1.01–1.05) 0.98 (0.96–1.01) 1.00 (0.98–1.01)
0.007 0.2 0.6
1.03 (1.01–1.06), 0.003 0.99 (0.97–1.02), 0.7 0.98 (0.96–0.99), 0.002
1 1.79 (1.37–2.34)
<0.0001
1 1.65 (1.25–2.18), 0.0004
1 2.31 (1.35–3.97) 4.51 (2.58–7.88) 6.02 (3.51–10.33)
0.002 <0.0001 <0.0001
1 2.09 (1.20–3.62) 3.88 (2.18–6.89) 5.76 (3.27–10.14)
1 1.82 (1.38–2.39)
<0.0001
1 1.42 (1.08–1.88)
p value
0.009 <0.0001 0.0001
0.014
ACM = all cause mortality; AHR = adjusted hazard ratio; CI = confidence interval; HR = hazard ratio; RP = radical prostatectomy. Preoperative variables (preoperative prostate-specific antigen level, clinical stage) were adjusted for multivariate analyses between biopsy Gleason score 8 versus 9–10. b Postoperative variables (age, year of surgery, preoperative prostate-specific antigen level, pathologic stage, and positive surgical margins) were adjusted for multivariable analyses between RP Gleason score 8 versus 9–10. a
Table 3 – Competing-risks analyses of predictors of prostate cancer–specific mortality Variable
Univariable model HR (95% CI)
Preoperative variablesa Prostate-specific antigen Clinical stage T1–2a (reference) T2b–c T3a–4 Biopsy Gleason score 8 (reference) 9–10 Postoperative variablesb Age Year of surgery Prostate-specific antigen RP Gleason score 8 (reference) 9–10 Pathologic stage Organ-confined (reference) Extraprostatic extension Seminal vesicle invasion Lymph node invasion Positive surgical margins Negative (reference) Positive
Multivariable model p value
AHR (95% CI)
p value
1.01 (0.99–1.03)
0.2
1.01 (0.99–1.03)
0.5
1 2.12 (1.35–3.34) 1.37 (0.60–3.15)
0.001 0.5
1 2.04 (1.28–3.24) 1.35 (0.58–3.14)
0.003 0.5
1 2.13 (1.37–3.30)
0.001
1 2.09 (1.33–3.28)
0.001
0.99 (0.97–1.02) 0.96 (0.94–0.99) 1.00 (0.98–1.02)
0.6 0.007 1.0
0.99 (0.97–1.02) 0.97 (0.95–0.99) 0.97 (0.96–0.99)
0.7 0.035 0.002
1 2.39 (1.74–3.28)
<0.0001
1 2.20 (1.58–3.05)
<0.0001
1 2.92 (1.32–6.48) 7.63 (3.46–16.88) 10.26 (4.72–22.32)
0.008 <0.0001 <0.0001
1 2.43 (1.08–5.50) 6.02 (2.66–13.63) 7.99 (3.56–17.96)
0.032 <0.0001 <0.0001
1 1.93 (1.41–2.64)
<0.0001
1 1.42 (1.03–1.96)
0.034
AHR = adjusted hazard ratio; CI = confidence interval; HR = hazard ratio; RP = radical prostatectomy. Preoperative variables (preoperative prostate-specific antigen level, clinical stage) were adjusted for multivariate analyses between biopsy Gleason score 8 versus 9–10. b Postoperative variables (age, year of surgery, preoperative prostate-specific antigen level, pathologic stage, and positive surgical margins) were adjusted for multivariable analyses between RP Gleason score 8 versus 9–10. a
Please cite this article in press as: Ham WS, et al. New Prostate Cancer Grading System Predicts Long-term Survival Following Surgery for Gleason Score 8–10 Prostate Cancer. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.11.006
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1 Bx GS 8 vs. 9–10 (HR = 2.13, 95% CI: 1.37–3.30; p = 0.001) Cancer-specific motality
0.8
0.6
0.4
0.2 BxGS8
BxGS9–10
15
20
25
13 7
3 1
0 0
5
10
Time [years aer surgery] At risk: Bx GS 8 Bx GS 9–10
490 231
233 95
115 30
50 9
Fig. 2 – Cumulative incidence functions for prostate cancer–specific mortality for biopsy (Bx) Gleason score (GS) 8 versus 9–10. HR = hazard ratio; CI = confidence interval.
Cancer-specific mortality
0.8
RP GS 8 vs. 9–10 (HR = 2.38, 95% CI: 1.74–3.28; p < 0.001)
0.6
5
the more restrictive definition of grade pattern 3 [2,3], resulting in better prognosis for updated GS 6 disease. Likewise, updated GS 8 disease may have a better prognosis today, as some cases of GS 7 disease might have shifted up to GS 8 disease. However, Gleason pattern 5 has remained unchanged in the updated PC grading system [4], so we were able to study Gleason 8–10 disease. Another limitation of the study is the retrospective data collection at a single institution, so the results are sensitive to selection bias and may not be generalizable. In addition, information about adjuvant and salvage therapy was not included in the multivariable analysis. Notably, only 4.0% of our cohort received adjuvant therapy as we did not routinely offer this intervention at our center. Approximately 30% of the cohort did receive salvage therapy. When salvage and adjuvant information are included in multivariable models, they act as indicators for disease progression, and take away prognostic significance from the other indicators. Next, the Charlson comorbidity index or other indicator of comorbidity was not included in the model. Finally, our study is based on outcomes after radical prostatectomy, yet radiation therapy is another primary management strategy and future study may be warranted to investigate outcomes after primary RT.
0.4
5. 0.2
RP GS8
RP GS9–10
15
20
25
38 16
8 2
0 0
5
10
Time [years aer surgery] At risk: RP GS 8 RP GS 9–10
574 473
319 244
180 97
86 39
Fig. 3 – Cumulative incidence functions for prostate cancer–specific mortality for radical prostatectomy (RP) Gleason score (GS) 8 versus 9–10. HR = hazard ratio; CI = confidence interval.
Conclusions
The new PCGS can predict the risk of mortality after RP for men with GS 8–10 prostate cancer. Men with GS 8 have significantly better ACM and PCSM following RP compared to those with GS 9–10. Author contributions: Misop Han had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Han. Acquisition of data: Epstein, Humphreys, Partin. Analysis and interpretation of data: Feng, Trock, Humphreys.
for men with prostate cancer. Current guidelines and treatment recommendations rely heavily on the formerly accepted high-risk grouping of GS 8–10 (most popularly known as the D’Amico high-risk stratification) [9,13–15, 24,25]. Thus, it is crucial to evaluate the new PCGS grouping using PCSM and ACM as outcomes. In the present study, we evaluated the Gleason grouping in both preoperative and postoperative settings using Bx and RP GS. Men with Bx and RP GS 9–10 had higher ACM and PCSM rates following RP compared to those with GS 8, even after adjustment for perioperative variables. The present study focuses on the high-risk grouping because we are unable to accurately study men with GS <8 because cases before 2004 were not reclassified in accordance with the updated Gleason grading system. These updates occurred in 2005 and 2014 by the International Society of Urological Pathology [2,3]. Many studies have demonstrated improved correlation between Bx and RP grade pattern, stage, and postoperative progression with this updated system [26–28]. A major change was
Drafting of the manuscript: Ham. Critical revision of the manuscript for important intellectual content: Ham, Chalfin, Epstein, Cheung, Partin. Statistical analysis: Feng, Trock. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Partin, Han. Other: None. Financial disclosures: Misop Han certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
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Platinum Priority – Prostate Cancer Editorial by XXX on pp. x–y of this issue
New Prostate Cancer Grading System Predicts Long-term Survival Following Surgery for Gleason Score 8–10 Prostate Cancer Won Sik Ham a,y, Heather J. Chalfin a, Zhaoyong Feng a, Bruce J. Trock a, Jonathan I. Epstein a,b, Carling Cheung a, Elizabeth Humphreys a, Alan W. Partin a, Misop Han a,* a
Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; b Department of Pathology,
Johns Hopkins Medical Institutions, Baltimore, MD, USA
Article info
Abstract
Article history: Accepted November 4, 2016
Background: The newly proposed five-tiered prostate cancer grading system (PCGS) divides Gleason score (GS) 8–10 disease into GS 8 and GS 9–10 on the basis of biochemical recurrence (BCR) following radical prostatectomy (RP) as an outcome. However, BCR does not necessarily portend worse survival outcomes. Objective: To assess the significance of distinguishing GS 8 versus 9–10 disease in terms of long-term survival outcomes for both the preoperative setting using biopsy (Bx) GS and the postoperative setting with RP GS. Design, setting, and participants: Of 23 918 men who underwent RP between 1984 and 2014, there were 721 men with biopsy GS 8–10, and 1047 men with RP GS 8–10. Outcome measures and statistical analysis: Clinicopathologic characteristics were compared between men with GS 8 and those with GS 9–10. We compared all-cause mortality (ACM) and prostate cancer–specific mortality (PCSM) risk between the groups using Cox regression and competing-risks analyses, adjusting for other perioperative variables and death from other causes as the competing event. Results and limitations: Compared to men with GS 8, men with GS 9–10 had later RP year and higher pathologic stage. Among men with Bx GS 8–10, 115 died (82 due to PC) with median follow-up of 3 yr (interquartile range [IQR] 1–7) for both overall and cancer-specific survival. Of men with RP GS 8–10, 221 died (151 due to PC) with median follow-up of 4 yr (IQR 2–8) and 4 yr (IQR 2–9) for overall and cancer-specific survival, respectively. PC-specific survival rates were significantly lower for men with GS 9–10 compared to men with GS 8 for both Bx (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.37–3.30; p < 0.01) and RP GS (HR 2.38, 95% CI 1.74–3.28; p < 0.01). This association persisted in multivariable models after adjusting for perioperative variables. Conclusions: Men with GS 9–10 had higher ACM and PCSM rates compared to those with GS 8. GS 8 and GS 9–10 PC should be considered separately in both the preoperative and postoperative setting as suggested by the new PCGS. Patient summary: The prostate cancer grading system can predict mortality risk after radical prostatectomy (RP) for men with Gleason score 8–10 disease based on both biopsy and RP Gleason scores. There are significant differences in all-cause mortality and prostate cancer–specific mortality following surgery between men with Gleason score 8 and those with Gleason score 9–10 disease. # 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: Giacomo Novara Keywords: Mortality Prostate cancer Gleason score
y Present address: Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea. * Corresponding author. E-mail address: [email protected] (M. Han).
http://dx.doi.org/10.1016/j.eururo.2016.11.006 0302-2838/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Ham WS, et al. New Prostate Cancer Grading System Predicts Long-term Survival Following Surgery for Gleason Score 8–10 Prostate Cancer. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.11.006
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1.
value of the new grading system in two clinical settings: preoperative (biopsy) GS and postoperative (RP) GS.
Introduction
In 1974, Gleason and Mellinger proposed the prostate cancer (PC) grading system as the sum of the two most common grade patterns [1]. Since then, there have been two major updates owing to the evolving diagnosis and treatment of PC [2,3]. For example, Gleason score (GS) 2–5 distinctions are no longer used. In addition, certain patterns such as poorly formed glands and cribriform glomeruloid cancers are now considered Gleason pattern 4 [2–4]. Compared to other clinicopathologic factors and molecular markers, GS remains the single most powerful predictor of PC outcomes [4]. Although various GS groupings have been used in clinical practice [5–12], most researchers have combined GS 8 and GS 9–10 into a single high-grade entity [9,13–15]. In the new five-tiered prostate cancer grading system (PCGS) proposed by Epstein and colleagues [16], the high-grade entity (GS 8) is divided into GS 8 and GS 9–10 because men with GS 9–10 had a much higher likelihood of biochemical recurrence (BCR) following radical prostatectomy (RP) than those with GS 8. Recently, this new PCGS was validated using multi-institutional and multimodal therapy data with BCR as an endpoint [17,18]. However, BCR does not necessarily portend worse survival outcomes [19,20]. In this study, we assessed long-term survival outcomes (prostate cancer–specific mortality [PCSM] and all-cause mortality [ACM]) following RP for GS 8 versus GS 9–10 disease using data for a large cohort of RP patients at a single institution. Specifically, we investigated the prognostic
2.
Patients and methods
Following institutional review board approval at Johns Hopkins, we reviewed data for 23 918 men who underwent RP at our institution between 1984 and 2014. After excluding patients with biopsy (Bx) GS < 8 and RP GS < 8, incomplete clinicopathologic or follow-up data, or a history of neoadjuvant treatment, there were 721 men with Bx GS 8–10 and 1047 men with RP GS 8–10 (Fig. 1). Most men were treated only with RP until BCR. Clinical and pathologic stages were assigned in accordance with the American Joint Committee on Cancer staging system [21]. One of the authors of the current article led a consensus on updating the Gleason grading system in 2004 [2]. Men with GS < 8 were appropriately reclassified since 2004, while men with GS 8–10 were properly classified since 1984. Therefore, we decided to perform long-term survival analyses solely evaluating men with GS 8–10, and to focus on the distinction of GS 8 disease from the former ‘‘high-risk’’ clump of GS 8–10. Baseline characteristics and pathologic outcomes were compared between men with GS 8 and GS 9–10 using x2 tests for categorical data and Student’s t-test or the nonparametric alternative Wilcoxon sum rank test for continuous data. Information on survival status and cause of death was obtained from patient follow-up, the Social Security Administration Death Index, and the Centers for Disease Control National Death Index. PCSM was designated when the underlying cause of death was PC or the patient had castration-resistant PC at the time of death. PCSM was calculated for men with GS 8 versus GS 9–10, and PCSM estimates were compared between the groups using a competing-risks model. A cumulative incidence function was also generated for each
n = 23 918 Men who underwent RP (1984–2014) n = 13 198, Excluded for biopsy GS <8 and radical prostatectomy GS <8 n = 8952, Excluded for: incompleteclinicpathological data, follow-up informaon, or history of neoadjuvant treatment n = 1303 Men with Bx GS 810 or RP GS 8–10
n = 721
n = 1047
Men with biopsy GS 8–10
Men with radical prostatectomy GS 8–10
n = 490
n = 231
n = 574
n = 473
Bx GS 8
Bx GS 9–10
RP GS 8
RP GS 9–10
Included in analysis
Fig. 1 – Flowchart for study inclusion. RP = radical prostatectomy; GS = Gleason score; Bx = biopsy.
Please cite this article in press as: Ham WS, et al. New Prostate Cancer Grading System Predicts Long-term Survival Following Surgery for Gleason Score 8–10 Prostate Cancer. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.11.006
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Table 1 – Clinicopathologic characteristics for men with Gleason score 8 and 9–10 prostate cancer Parameter
Age (yr) Mean (SD) Median (IQR) Race, n (%) White Black Others Year of surgery Median (IQR) PSA (ng/ml) Mean (SD) Median (IQR) Clinical stage, n (%) T1–T2a T2b–T2c T3a–T4 Pathologic stage, n (%) Organ-confined Extraprostatic extension Seminal vesicle invasion Lymph node invasion PSM, n (%) Follow-up (yr) Mean (SD) Median (IQR) PCSM, n (%) All-cause mortality, n (%)
Biopsy GS 8–10 (n = 721) GS 8
GS 9–10
(n = 490)
(n = 231)
RP GS 8–10 (n = 1047) p value
GS 8
GS 9–10
(n = 574)
(n = 473)
0.2 60.4 (6.5) 61 (9)
0.2
61.0 (6.8) 61 (10)
59.9 (6.5) 60 (10)
60.4 (6.6) 61 (9)
0.8 410 (84) 53 (11) 27 (5.1)
0.6
195 (84) 26 (11) 10 (4.3)
481 (84) 61 (11) 32 (5.6)
408 (86) 42 (8.9) 23 (4.9)
2003 (12)
2006 (11)
<0.0001 2006 (11)
2008 (9)
<0.0001
0.9 7.4 (6.8) 5.6 (5.1)
0.1
7.6 (7.9) 5.7 (5.2)
7.6 (7.3) 5.9 (5.5)
8.8 (8.8) 6.2 (7.3)
0.9 370 (76) 107 (22) 13 (2.7)
0.2
171 (74) 53 (23) 7 (3.0)
435 (76) 127 (22) 12 (2.1)
339 (72) 119 (25) 15 (3.2)
202 225 90 57 141
109 170 92 102 146
0.0002 201 190 55 44 111
(41) (39) (11) (9.0) (23)
6.1 (5.6) 4.0 (7) 49 (10.0) 72 (15)
70 81 39 41 53
(30) (35) (17) (18) (23)
0.9 0.033
4.9 (4.5) 3 (4) 33 (14) 43 (19)
0.091 0.2
p value
<0.0001 (35) (39) (16) (9.9) (25)
7.4 (6.4) 6 (9) 62 (11) 108 (19)
(23) (36) (20) (22) (31)
6.1 (5.2) 5 (6) 89 (19) 113 (24)
0.02 0.010
0.0002 0.045
GS = Gleason score; IQR = interquartile range; PCSM = prostate cancer–specific mortality; PSA = prostate-specific antigen; PSM = positive surgical margin; RP = radical prostatectomy; SD = standard deviation.
Gleason group. Multivariable Cox regression analysis was used to determine ACM as a function of GS 8 versus GS 9–10. Multivariable competing-risks regression analysis was performed for PCSM with death from other causes as the competing event [22]. For our primary endpoint analyses, GS 8 disease was defined as the reference group. Preoperative variables (preoperative prostate-specific antigen [PSA] level, clinical stage) were adjusted for multivariable analyses between Bx GS 8 and GS 9–10, whereas postoperative variables (age, year of surgery, preoperative PSA level, pathologic stage, and positive surgical margins [PSMs]) were used for multivariable analyses between RP GS 8 and GS 9–10. The level of significance was set at 0.05 in all analyses. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).
3.
Results
Men with both Bx and RP GS 9–10 disease had later RP year and higher pathologic stage compared to men with GS 8 disease (p < 0.01 for all; Table 1). There were no significant differences in age, race, preoperative PSA level, or clinical stage between men with GS 8 and men with GS 9–10. There was a significant difference in PSM rate between RP GS 8 and GS 9–10. Among 721 men with Bx GS 8–10, 115 men died (82 of PC) during median follow-up of 3 yr (interquartile range [IQR] 1–7) for overall and cancer-specific survival. Of 1047 men with RP GS 8–10, 221 died (151 of PC) during median follow-up of 4 yr (IQR 2–8) for overall survival and 4 yr (IQR 2–9) for cancer-specific survival. Among men with
Bx GS 8–10, the respective 10-yr estimates of ACM and PCSM rate were 17% and 12% for Bx GS 8, and 36% and 32% for Bx GS 9–10. For men with RP GS 8–10, these were 17% and 8.9% for RP GS 8, and 37% and 29% for RP GS 9–10, respectively. PC-specific survival rates were significantly lower for men with both Bx GS 9–10 (Fig. 2; p < 0.01) and RP GS 9–10 (Fig. 3; p < 0.01) compared to men with GS 8. On multivariable analysis, ACM was higher for men with GS 9–10 (adjusted HR [AHR] 1.93, 95% CI 1.32–2.84, p = 0.001 for Bx GS; AHR 1.65, 95% CI 1.25–2.18, p = 0.0004 for RP GS) (Table 2). PCSM was also significantly higher for men with GS 9–10 (AHR 2.09, 95% CI 1.33–3.28, p = 0.001 for Bx GS; AHR 2.20, 95% CI 1.58–3.05, p < 0.0001 for RP GS) after adjusting for preoperative and postoperative variables (Table 3). 4.
Discussion
The new five-tiered PCGS proposes that GS 8–10 disease should not be viewed as a single high-grade entity but should be subdivided into GS 8 and GS 9–10 on the basis of differences in BCR [16,17]. The proposed system was more recently validated by Tsao et al [23] and Loeb et al [18]. However, these studies were based on BCR as an outcome measure, and there has been no validation in terms of long-term survival outcomes such as PCSM. The new PCGS is poised to become the universal risk grouping
Please cite this article in press as: Ham WS, et al. New Prostate Cancer Grading System Predicts Long-term Survival Following Surgery for Gleason Score 8–10 Prostate Cancer. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.11.006
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Table 2 – Cox regression analyses of predictors for all-cause mortality Variable
Univariable model HR (95% CI)
Preoperative variablesa Prostate-specific antigen Clinical stage T1–T2a (reference) T2b–T2c T3a–T4 Biopsy Gleason score 8 (reference) 9–10 Postoperative variablesb Age Year of surgery Prostate-specific antigen RP Gleason score 8 (reference) 9–10 Pathologic stage Organ-confined (reference) Extraprostatic extension Seminal vesicle invasion Lymph node invasion Positive surgical margins Negative (reference) Positive
Multivariable model p value
AHR (95% CI)
1.00 (0.98–1.02)
0.8
1.00 (0.98–1.02), 0.8
1 1.64 (1.11–2.44) 1.19 (0.54–2.62)
0.013 0.7
1 1.60 (1.08–2.38), 0.020 1.25 (0.56–2.80), 0.6
1 1.96 (1.34–2.88)
0.001
1 1.93 (1.32–2.84), 0.001
1.03 (1.01–1.05) 0.98 (0.96–1.01) 1.00 (0.98–1.01)
0.007 0.2 0.6
1.03 (1.01–1.06), 0.003 0.99 (0.97–1.02), 0.7 0.98 (0.96–0.99), 0.002
1 1.79 (1.37–2.34)
<0.0001
1 1.65 (1.25–2.18), 0.0004
1 2.31 (1.35–3.97) 4.51 (2.58–7.88) 6.02 (3.51–10.33)
0.002 <0.0001 <0.0001
1 2.09 (1.20–3.62) 3.88 (2.18–6.89) 5.76 (3.27–10.14)
1 1.82 (1.38–2.39)
<0.0001
1 1.42 (1.08–1.88)
p value
0.009 <0.0001 0.0001
0.014
ACM = all cause mortality; AHR = adjusted hazard ratio; CI = confidence interval; HR = hazard ratio; RP = radical prostatectomy. Preoperative variables (preoperative prostate-specific antigen level, clinical stage) were adjusted for multivariate analyses between biopsy Gleason score 8 versus 9–10. b Postoperative variables (age, year of surgery, preoperative prostate-specific antigen level, pathologic stage, and positive surgical margins) were adjusted for multivariable analyses between RP Gleason score 8 versus 9–10. a
Table 3 – Competing-risks analyses of predictors of prostate cancer–specific mortality Variable
Univariable model HR (95% CI)
Preoperative variablesa Prostate-specific antigen Clinical stage T1–2a (reference) T2b–c T3a–4 Biopsy Gleason score 8 (reference) 9–10 Postoperative variablesb Age Year of surgery Prostate-specific antigen RP Gleason score 8 (reference) 9–10 Pathologic stage Organ-confined (reference) Extraprostatic extension Seminal vesicle invasion Lymph node invasion Positive surgical margins Negative (reference) Positive
Multivariable model p value
AHR (95% CI)
p value
1.01 (0.99–1.03)
0.2
1.01 (0.99–1.03)
0.5
1 2.12 (1.35–3.34) 1.37 (0.60–3.15)
0.001 0.5
1 2.04 (1.28–3.24) 1.35 (0.58–3.14)
0.003 0.5
1 2.13 (1.37–3.30)
0.001
1 2.09 (1.33–3.28)
0.001
0.99 (0.97–1.02) 0.96 (0.94–0.99) 1.00 (0.98–1.02)
0.6 0.007 1.0
0.99 (0.97–1.02) 0.97 (0.95–0.99) 0.97 (0.96–0.99)
0.7 0.035 0.002
1 2.39 (1.74–3.28)
<0.0001
1 2.20 (1.58–3.05)
<0.0001
1 2.92 (1.32–6.48) 7.63 (3.46–16.88) 10.26 (4.72–22.32)
0.008 <0.0001 <0.0001
1 2.43 (1.08–5.50) 6.02 (2.66–13.63) 7.99 (3.56–17.96)
0.032 <0.0001 <0.0001
1 1.93 (1.41–2.64)
<0.0001
1 1.42 (1.03–1.96)
0.034
AHR = adjusted hazard ratio; CI = confidence interval; HR = hazard ratio; RP = radical prostatectomy. Preoperative variables (preoperative prostate-specific antigen level, clinical stage) were adjusted for multivariate analyses between biopsy Gleason score 8 versus 9–10. b Postoperative variables (age, year of surgery, preoperative prostate-specific antigen level, pathologic stage, and positive surgical margins) were adjusted for multivariable analyses between RP Gleason score 8 versus 9–10. a
Please cite this article in press as: Ham WS, et al. New Prostate Cancer Grading System Predicts Long-term Survival Following Surgery for Gleason Score 8–10 Prostate Cancer. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.11.006
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1 Bx GS 8 vs. 9–10 (HR = 2.13, 95% CI: 1.37–3.30; p = 0.001) Cancer-specific motality
0.8
0.6
0.4
0.2 BxGS8
BxGS9–10
15
20
25
13 7
3 1
0 0
5
10
Time [years aer surgery] At risk: Bx GS 8 Bx GS 9–10
490 231
233 95
115 30
50 9
Fig. 2 – Cumulative incidence functions for prostate cancer–specific mortality for biopsy (Bx) Gleason score (GS) 8 versus 9–10. HR = hazard ratio; CI = confidence interval.
Cancer-specific mortality
0.8
RP GS 8 vs. 9–10 (HR = 2.38, 95% CI: 1.74–3.28; p < 0.001)
0.6
5
the more restrictive definition of grade pattern 3 [2,3], resulting in better prognosis for updated GS 6 disease. Likewise, updated GS 8 disease may have a better prognosis today, as some cases of GS 7 disease might have shifted up to GS 8 disease. However, Gleason pattern 5 has remained unchanged in the updated PC grading system [4], so we were able to study Gleason 8–10 disease. Another limitation of the study is the retrospective data collection at a single institution, so the results are sensitive to selection bias and may not be generalizable. In addition, information about adjuvant and salvage therapy was not included in the multivariable analysis. Notably, only 4.0% of our cohort received adjuvant therapy as we did not routinely offer this intervention at our center. Approximately 30% of the cohort did receive salvage therapy. When salvage and adjuvant information are included in multivariable models, they act as indicators for disease progression, and take away prognostic significance from the other indicators. Next, the Charlson comorbidity index or other indicator of comorbidity was not included in the model. Finally, our study is based on outcomes after radical prostatectomy, yet radiation therapy is another primary management strategy and future study may be warranted to investigate outcomes after primary RT.
0.4
5. 0.2
RP GS8
RP GS9–10
15
20
25
38 16
8 2
0 0
5
10
Time [years aer surgery] At risk: RP GS 8 RP GS 9–10
574 473
319 244
180 97
86 39
Fig. 3 – Cumulative incidence functions for prostate cancer–specific mortality for radical prostatectomy (RP) Gleason score (GS) 8 versus 9–10. HR = hazard ratio; CI = confidence interval.
Conclusions
The new PCGS can predict the risk of mortality after RP for men with GS 8–10 prostate cancer. Men with GS 8 have significantly better ACM and PCSM following RP compared to those with GS 9–10. Author contributions: Misop Han had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Han. Acquisition of data: Epstein, Humphreys, Partin. Analysis and interpretation of data: Feng, Trock, Humphreys.
for men with prostate cancer. Current guidelines and treatment recommendations rely heavily on the formerly accepted high-risk grouping of GS 8–10 (most popularly known as the D’Amico high-risk stratification) [9,13–15, 24,25]. Thus, it is crucial to evaluate the new PCGS grouping using PCSM and ACM as outcomes. In the present study, we evaluated the Gleason grouping in both preoperative and postoperative settings using Bx and RP GS. Men with Bx and RP GS 9–10 had higher ACM and PCSM rates following RP compared to those with GS 8, even after adjustment for perioperative variables. The present study focuses on the high-risk grouping because we are unable to accurately study men with GS <8 because cases before 2004 were not reclassified in accordance with the updated Gleason grading system. These updates occurred in 2005 and 2014 by the International Society of Urological Pathology [2,3]. Many studies have demonstrated improved correlation between Bx and RP grade pattern, stage, and postoperative progression with this updated system [26–28]. A major change was
Drafting of the manuscript: Ham. Critical revision of the manuscript for important intellectual content: Ham, Chalfin, Epstein, Cheung, Partin. Statistical analysis: Feng, Trock. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Partin, Han. Other: None. Financial disclosures: Misop Han certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
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