Radical prostatectomy represents an effective treatment in patients with specimen-confined high pathological Gleason score prostate cancer

Authors


Correspondence: Giovanni Lughezzani, San Raffaele Turro, Via Stamira D'Ancona 20, 20127 Milano, Italia.

e-mail: lughezzani.giovanni@hsr.it

Abstract

What's known on the subject? and What does the study add?

  • To date, only a few studies have addressed the long-term oncological outcomes of radical prostatectomy (RP) in patients with pathological Gleason score ≥ 8 prostate cancer. According to these reports, some individuals with pathological Gleason score ≥ 8 may benefit from RP, with cancer-control outcomes comparable with those of patients with low- and intermediate-risk prostate cancer.
  • The presence of pathological Gleason score 8–10 represents a poor prognostic factor in the outcome of men with prostate cancer. However, in patients with specimen-confined disease, RP and bilateral PLND provided long-term cancer-control outcomes similar to those of patients with more favourable disease characteristics.

Objectives

  • To evaluate the outcomes of patients with pathological Gleason score 8–10 prostate cancer subjected to radical prostatectomy (RP).
  • To determine the prognostic factors associated with cancer-specific survival (CSS) in this subset of patients.

Patients and Methods

  • The study included 580 consecutive patients with pathological Gleason sum 8–10 prostate cancer treated with RP and pelvic lymph node dissection (PLND) at a single European institution between July 1988 and April 2010. All patients had detailed pathological and follow-up data.
  • Pathological Gleason score was determined by a single expert genitourinary pathologist. Biochemical recurrence (BCR) was defined PSA concentration of ≥0.2 ng/mL and rising.
  • Kaplan–Meier plots were used to graphically explore BCR-free survival as well as CSS and overall survival (OS) rates. Moreover, univariable and multivariable Cox regression models were fitted to test the predictors of CSS.

Results

  • The mean (median, range) age at surgery was 66.1 (66.4, 41–85) years. The mean (median, range) total PSA concentration was 29.6 (11.1, 0.5–1710) ng/mL.
  • Pathological Gleason score was 8 in 238 (41.0%), 9 in 330 (56.9%) and 10 in 12 (2.1%) patients. Overall, 119 (20.5%), 124 (21.4%), 281 (48.4%) and 56 (9.7%) patients had pT2, pT3a, pT3b and pT4 prostate cancer, respectively. Overall, 275 (47.4%) had LN invasion, while 150 (25.1%) patients had specimen-confined disease (defined as pT2cR0 pN0 or pT3aR0 pN0 prostate cancer).
  • The mean (median, range) follow-up was 53 (47, 1–226) months. At 5 and 10 years after RP, BCR-free survival was 76.7% and 49.6%, respectively. Similarly, the 5- and 10-year CSS rates were 87.3% and 69.5%, respectively.
  • Patients with specimen-confined disease (P < 0.001) and patients with negative LNs (P = 0.012) had significantly better CSS rates than their counterparts with less favourable pathological characteristics. In multivariable Cox regression models, only the presence of specimen-confined disease achieved independent predictor status (P = 0.001).

Conclusion

  • Presence of high Gleason score at RP represents a poor prognostic factor in the outcome of patients with prostate cancer.
  • However, RP provides excellent long-term cancer control outcomes in the subset of patients with specimen-confined disease.
Abbreviations
CSS

cancer-specific survival

RP

radical prostatectomy

PLND

pelvic lymph node dissection

LN

lymph node

BCR

biochemical recurrence

OS

overall survival

ECE

extracapsular extension

Introduction

Pathological Gleason score represents an important predictor of disease progression and cancer-specific survival (CSS) in patients with prostate cancer treated with radical prostatectomy (RP) [1, 2]. While most men in the PSA era present with favourable pathological characteristics, a not trivial proportion of men still harbour Gleason score ≥ 8 disease at final pathology [3]. The best treatment strategy for these patients is still a matter of debate. Androgen-deprivation therapy plus external-beam radiotherapy are the most frequently recommended treatment strategies for patients with high-risk prostate cancer, and only a minority of cases are initially treated with RP [4]. To date, the long-term oncological outcomes of RP in patients with pathological Gleason score ≥ 8 has only been addressed a few studies [5-9]. According to these reports, at least a group of individuals with pathological Gleason score ≥ 8 may benefit from RP, with cancer-control outcomes comparable to those of patients with low- and intermediate-risk prostate cancer [5-9].

Based on the paucity of data on this topic and since there is no consensus about the role of RP in this group of patients, we decided to explore the outcomes of 580 consecutive men with pathological Gleason sum 8–10 treated with RP and bilateral pelvic lymph node dissection (PLND) at our single tertiary Department of Urology between July 1988 and April 2010. Our hypothesis was that RP may be an effective treatment option in selected patients with high pathological Gleason score prostate cancer.

Patients and Methods

The study included 580 consecutive patients with pathological Gleason sum 8–10 prostate cancer who were treated with RP and bilateral PLND at our tertiary care centre between July 1988 and April 2010. Detailed pathological and oncological follow-up data were available for all patients. Conversely, clinical stage and prostate biopsy Gleason score were available only in a subgroup of 398 patients. A single expert genito-urinary pathologist reviewed all prostate specimens. Specimens were surface-inked and the pathological assessment was performed according to the Stanford protocol, with serial step sections at 3 mm [10]. Tumour differentiation was assigned according to the Gleason system [11]. As previously reported, specimen-confined prostate cancer was defined as no tumour extending beyond the cut margins (negative surgical margins, seminal vesicles, and lymph nodes [LNs]; pT2R0pN0 and pT3aR0pN0) [12].

PSA concentrations were measured quarterly in the first year, followed by bi-annual measurements thereafter. Biochemical recurrence (BCR) was defined as two consecutive postoperative PSA concentrations of ≥0.2 ng/mL and rising. Patients without BCR were censored at the time of last follow-up. Of 460 individuals with available data on adjuvant therapy administration, 350 patients received adjuvant radiotherapy and/or hormonal therapy. The potential benefits and side-effects of each adjuvant treatment were carefully discussed with patients before any decision was undertaken.

Estimates of the probability of remaining free from BCR, CSS and overall survival (OS) were calculated using the Kaplan–Meier method. Differences among groups were assessed using the pairwise log-rank test. Univariable and multivariable Cox proportional hazards regression analyses tested the relationship between the predictor variables and CSS. Predictor variables consisted of either preoperative variables (patient age, prostate volume, preoperative PSA concentrations) or pathological variables (presence or absence of specimen-confined disease, presence or absence of LN invasion, and pathological Gleason score). The same analyses were then performed in the subgroup of patients with available data on adjuvant therapy administration.

All tests were two-sided with a significance level set at 0.05.

Results

The descriptive characteristics of the study cohort are shown in Table 1. The mean (median, range) age at surgery was 66.1 (66.4, 41–85) years. The mean (median, range) preoperative total PSA concentration was 29.6 (11.1, 0.5–1710) ng/mL. Clinical stage was cT1 in 143 (33.9%), cT2 in 155 (36.7%) and cT3 in 124 (29.4%) patients. Biopsy Gleason score was ≤6 in 109 (24.2%), 7 in 170 (37.8%) and ≥8 in 172 (38.1%) patients. The mean (median, range) prostate volume was 48.6 (43; 17–210) mL. Pathological Gleason score was 8 in 238 (41.0%), 9 in 330 (56.9%) and 10 in 12 (2.1%). Overall, 119 (20.5%), 124 (21.4%), 281 (48.4%) and 56 (9.7%) patients had pT2, pT3a, pT3b and pT4 prostate cancer, respectively. Finally, 275 (47.4%) had LN invasion (pN1). It is noteworthy that, in the subset of patients with available data on adjuvant therapy (460 patients), pathological stage was an important determinant of the use of radiotherapy or hormonal therapy, with 44.5% of patients with specimen-confined disease receiving adjuvant treatment relative to 86.0% of patients who did not have specimen-confined disease.

Table 1. Descriptive characteristics of the study population
VariablesOverallSpecimen-confined diseaseNot specimen-confined diseaseP
  1. *Missing in 158 patients; °missing in 122 patients; †defined as pT2R0 pN0 or pT3aR0 pN0 prostate cancer.
Total number of patients580150430
Mean (median, range):    
age, years66.1 (66.4, 41–85)66.1 (67.2, 41–78)66.1 (66.6, 44–85)0.996
preoperative total PSA, ng/mL29.6 (11.1, 0.5–171012.1 (7.3, 0.8–90)35.6 (12.8, 0.5–1710)<0.001
prostate volume, mL48.6 (43.0, 17.6–210)46.5 (41.0, 18.0–210)49.2 (43.8, 17.6–185)0.242
N (%):    
Clinical stage*:   0.003
cT1143 (33.9)52 (46.0)91 (29.4) 
cT2155 (36.7)38 (33.6)117 (37.9) 
cT3124 (29.4)23 (20.4)101 (32.7) 
Biopsy Gleason score°:   <0.001
≤6109 (24.2)43 (36.1)66 (19.9) 
7170 (37.8)45 (37.8)125 (37.7) 
≥8172 (38.1)31 (26.1)141 (42.4) 
Pathological Gleason score:   0.006
8238 (41.0)78 (52.0)160 (37.2) 
9330 (56.9)70 (46.7)260 (60.5) 
1012 (2.1)2 (1.3)10 (2.3) 
Pathological stage:   <0.001
pT2119 (20.5)108 (72.0)11 (2.6) 
pT3a124 (21.4)42 (28.0)82 (19.1) 
pT3b281 (48.4)281 (65.3) 
pT456 (9.7)56 (13.0) 
Specimen-confined disease:   
yes150 (25.9) 
no430 (74.1) 
LN invasion:   <0.001
yes275 (47.4)0275 (64.0) 
no305 (52.6)150 (100)155 (36.0) 
Mean (median, range) follow-up, months53.3 (47.0, 8–226)59.9 (55.5, 10–202)51.0 (43.7, 8–226)0.038
Adjuvant therapy, n (%)   <0.001
No adjuvant therapy111 (19.1)62 (41.3)49 (11.4) 
Radiation therapy (RT) only117 (20.2)27 (18.0)90 (20.9) 
Hormonal therapy (HT) only56 (9.7)5 (3.3)51 (11.9) 
RT + HT176 (30.3)16 (10.7)160 (37.2) 
Missing120 (20.7)40 (26.7)80 (18.6) 

The mean (median, range) follow-up was 53 (47, 10–226) months. BCR-free survival, CSS and OS rates at 5 and 10 years after RP were 76.7% and 49.6%, 87.3% and 69.5%, 84.6% and 64.9%, respectively (Fig. 1). Patients with specimen-confined disease (P < 0.001) and patients with negative LNs (P = 0.012) had significantly better CSS rates than patients with less favourable pathological characteristics (Fig. 2A,B). For example, 5- and 10-year CSS rates were 97.8% and 89.6% in patients with specimen-confined disease and 92.3% and 74.7% in patients with negative LNs. Interestingly, there were no statistically significant differences in CSS rates between patients receiving adjuvant therapy and those who did not receive any adjuvant treatment, both in patients with (P = 0.131) and without specimen-confined disease (P = 0.421) (Fig. 3A,B). When focusing on patients with specimen-confined disease, the presence of extracapsular extension (ECE) appears to be associated with lower CSS rates (data not shown). However, the difference in survival rates between patients with and without ECE did not reach a statistical significance (P = 0.076), probably due to the few patients with ECE (n = 42) within the specimen-confined group of patients.

Figure 1.

KaplanMeier survival curves exploring respectively BCR-free survival (A), CSS (B) and OS (C).

Figure 2.

KaplanMeier survival curves showing CSS rates in patients with or without specimen-confined disease (A) and with or without LN invasion (B).

Figure 3.

KaplanMeier survival curves showing CSS after stratification according to adjuvant therapy administration in patients with specimen-confined disease (A) vs those without specimen-confined disease (B).

In multivariable Cox regression models based on preoperative variables, only clinical stage achieved independent predictor status, with cT3 patients having a 4.6-fold higher risk of dying from prostate cancer than those with cT1 disease (Table 2).

Table 2. Preoperative variables-based univariable and multivariable Cox regression analyses predicting CSS
PREDICTORSUnivariable analysisMultivariable analysis
Hazard ratio (95% CI); PHazard ratio (95% CI); P
Age1.007 (0.973–1.042); 0.6940.986 (0.933–1.043); 0.628
Total PSA concentration1.002 (1.000–1.004); 0.1351.001 (0.997–1.005); 0.680
Prostate volume0.999 (0.989–1.010); 0.8510.989 (0.970–1.009); 0.282
Clinical stage:  
cT2 vs cT1c1.580 (0.635–3.833); 0.3250.959 (0.276–3.330); 0.947
cT3 vs cT1c2.494 (1.032–6.026); 0.0424.624 (1.597–13.39); 0.005
Biopsy Gleason score:  
7 vs 61.003 (0.387–2.600); 0.9960.321 (0.097–1.067); 0.064
8 vs 62.018 (0.848–4.803); 0.4751.429 (0.537–3.809); 0.475

Similarly, in multivariable Cox regression models based on pathological variables, the presence of specimen-confined disease was the only independent predictor of CSS (P = 0.005). Specifically, patients without specimen-confined disease had a 5.2-fold higher risk of dying from prostate cancer than those with specimen-confined disease (P = 0.001; Table 3). Finally, when performing the same analyses in patients with available information on adjuvant therapy (n = 460), the administration of radiotherapy and/or hormonal therapy did not significantly affect the CSS of these patients even after adjustment for pathological stage and Gleason score (all P > 0.05; Table 4).

Table 3. Pathological variables-based univariable and multivariable Cox regression analyses predicting CSS
PREDICTORSUnivariable analysisMultivariable analysis
Hazard ratio (95% CI); PHazard ratio (95% CI); P
Specimen-confined disease  
No vs yes5.491 (2.208–13.660); <0.0015.186 (1.983–13.564); 0.001
pN stage  
pN1 vs pN01.838 (1.136–2.974); 0.0131.061 (0.638–1.764); 0.820
Gleason score  
9–10 vs 81.094 (0.607–1.970); 0.7661.216 (0.746–1.982); 0.433
Table 4. Pathological variables-based univariable and multivariable Cox regression analyses predicting CSS in patients with available adjuvant therapy (n = 460)
PredictorsUnivariable analysisMultivariable analysis
Hazard ratio (95% CI); PHazard ratio (95% CI);
Specimen-confined disease:  
No vs yes4.804 (1.489–15.502); 0.0095.054 (1.456–17.538); 0.011
pN stage:  
pN1 vs pN01.571 (0.868–2.842); 0.1350.959 (0.466–1.970); 0.908
Gleason score:  
9–10 vs 81.320 (0.805–2.164); 0.2710.980 (0.539–1.782); 0.948
Type of adjuvant therapy:  
Radiotherapy (RT) vs none1.187 (0.468–3.010); 0.7170.927 (0.362–2.374); 0.874
Hormonal therapy (HT) vs none0.863 (0.282–2.640); 0.7960.557 (0.172–1.805); 0.329
HT + RT vs none1.706 (0.759–3.835); 0.1961.129 (0.457–2.790); 0.792

Discussion

RP represents the mainstay treatment for patients with low- and intermediate-risk prostate cancer, showing excellent cancer control outcomes [13, 14]. Unfortunately, despite a favourable stage migration of prostate cancer in recent decades, a significant proportion of patients still present with unfavourable pathological characteristics [3, 15]. Among these, pathological Gleason score is considered as one of the strongest predictors of cancer-control outcomes in postoperative prediction models [1, 2]. Generally, poor oncological outcomes are expected in most patients with high-grade prostate cancer despite active treatment, because of the aggressive biological potential of the disease and likelihood of advanced disease at initial presentation. This observation, along with the paucity of long-term data on oncological outcomes, makes the role of RP in patients with pathological Gleason score ≥ 8 controversial.

In the present study, we showed that, at least in a selected group of patients, RP with bilateral PLND resulted in cancer control outcomes comparable with those of patients with low- and intermediate-risk prostate cancer (Fig. 1). Specifically, patients with specimen-confined disease at final pathology, although representing 25.9% of the entire population, showed a 10-year CSS rate of 91.7% (Fig. 2), which is comparable to the benchmark of 90% for patients with low- or intermediate-risk prostate cancer described inprevious studies [16, 17]. Conversely, patients without specimen-confined disease showed substantially worse outcomes, with a 63.1% CSS rate 10 years after RP. Additionally, patients with specimen-confined disease showed a 10-year BCR-free rate of 61.5%, which was significantly higher than the 10-year BCR-free survival of those who did not have specimen-confined disease (35.0%; P < 0.001).

These data were confirmed in multivariable analyses, where the absence of a specimen-confined disease at RP conferred a 5.2-fold higher risk of dying from prostate cancer. Interestingly, the present study showed that, in patients with high pathological Gleason score prostate cancer, commonly used predictors of CSS, e.g. preoperative PSA concentrations and biopsy Gleason score, were not statistically significantly associated with cancer-control outcomes.

These results confirmed the findings of previously published studies, which showed the importance of pathological disease stage in determining the outcomes of patients with a pathological Gleason score ≥ 8 [5-9]. Partin et al. [5] were the first to explore the cancer-control outcomes of 72 patients with high-grade prostate cancer treated with RP. The authors showed acceptable progression-free survival rates in patients with specimen-confined disease and in patients without LN invasion. Similar results were reported by Oefelein et al. [6] in 116 patients treated with RP for high-grade prostate cancer. Tefilli et al. [7] explored the predictors of BCR-free survival in 84 patients treated with RP for pathological Gleason score 8–10 prostate cancer. The authors showed that preoperative PSA concentrations and surgical margin status were independent predictors of BCR-free survival in this patient population. However, these studies were limited by the few patients and by the limited follow-up time, as well as by the use of BCR-free survival as a surrogate endpoint for evaluating treatment effectiveness. Lau et al. [8] also evaluated the long-term outcome of 407 patients treated with RP for pathological Gleason score ≥ 8 prostate cancer. In their study, the authors showed that pathological stage, pathological grade, preoperative PSA concentration and adjuvant therapy were independent predictors of progression-free survival. However, they did not report whether these variables were also predictors of CSS in multivariate analysis. More recently, Pierorazio et al. [9] confirmed the prognostic impact of organ-confined disease in 1061 patients with high-grade prostate cancer. In their analyses, the authors showed that pathological Gleason score, seminal vesicle invasion and LN invasion were the only independent predictors of CSS in multivariate analyses. Conversely, the effect of adjuvant therapy was not explored in multivariable analyses. As in the present study, the authors did not find a correlation between preoperative PSA concentrations and survival. Finally, Bahler et al. [18] also reported their experience in 119 patients with pathologically confirmed high Gleason score prostate cancer treated with RP as initial monotherapy. The authors showed acceptable 10-year BCR-free survival rates in this patient population. Interestingly, no variables were significantly related to BCR-free survival in multivariable analyses.

The present results provide a European validation of the findings from the previous studies, supporting the role of RP and PLND as an effective treatment option in patients with organ-confined pathological Gleason ≥ 8 prostate cancer. In the present cohort the only preoperative independent predictor of CSS was clinical stage, with patients with cT3 tumours having a 4.6-fold higher risk of dying from their disease than those with impalpable disease. Conversely, preoperative PSA concentration and biopsy Gleason score were not capable of preoperatively predicting the prognosis of patients with high-grade prostate cancer. Among pathological variables, only the presence of specimen-confined disease was capable of predicting the risk of CSS in multivariable analyses. These results highlight two important aspects. In this particular subset of patients, a complete, radical excision of the tumour is the most important factor for long-term survival after RP. The importance of local excision exceeds the potential advantages of a more conservative approach. It may be postulated that, especially in patients at high risk of harbouring a pathological Gleason score 8–10, a wide excision of the prostate, without nerve-sparing, may increase the probability of obtaining a specimen-confined disease at final pathology. As a consequence, the results of the present study underline an urgent need for novel markers and novel prediction tools aimed at correctly identifying patients with adverse pathological features. Commonly available preoperative predictors fail to efficiently identify those men who may benefit from multimodality neoadjuvant and adjuvant treatment, with wide RP with PLND as a first-line treatment option.

It is noteworthy that, according to the results of the present study, adjuvant therapies did not emerge as independent predictors of CSS. We think that this finding may be due to the fact that the administration of adjuvant therapies was performed in most patients without specimen-confined disease (86.0%), while adjuvant therapies were less frequently administered to patients with specimen-confined disease (44.5%). The lack of effect of adjuvant therapies on high Gleason prostate cancer in both patients with and without specimen-confined disease further enhances the importance of local surgical control of the disease. This finding was also reported in previous studies, where the authors reported high biochemical failure rates in patients with high Gleason score subjected to adjuvant radiotherapy [19, 20].

The present study is not devoid of limitations. Firstly, the retrospective nature of the present study may limit its results due to a selection bias, as patients who are surgical candidates may have better outcomes than patients who are not suitable for surgery. Secondly, the present data report the results of a single-institutional series from a tertiary care high-volume centre. While representing a potential advantage, as the patients’ characteristics and follow-up information was collected in our institutional database, our results may not be representative of a patient population treated outside of a tertiary care setting. Third, due to the retrospective nature of the present study, we did not have detailed information on adjuvant therapies, e.g. the total amount of radiation delivered or the duration of hormonal therapy. Moreover, the time span of the study involves >20 years, which implies several modifications in the treatment regimens for adjuvant therapies that cannot be accounted for. As accurate patient selection represents a fundamental step for evaluating the efficacy adjuvant therapies administration, the present results should be interpreted with caution and need to be validated in different settings. Ideally, prospective studies are needed to determine the impact of adjuvant therapies on cancer-control outcomes in patients with high pathological Gleason score. Finally, lack of some potentially prognostic clinical variables, e.g. the percentage of positive cores, represents an additional limitation that may limit the significance of the preoperative variables based Cox regression analyses.

In conclusion, the presence of pathological Gleason score 8–10 represents a poor prognostic factor in the outcome of men with prostate cancer. However, in patients with specimen-confined disease, RP and bilateral PLND provided cancer-control outcomes similar to those of patients with more favourable disease characteristics. To date, no preoperative factors are capable of accurately defining those patients at high risk of harbouring Gleason score 8–10 at final pathology. Therefore, novel markers and novel prediction tools are needed to accurately identify patients with specimen-confined prostate cancer, who may benefit the most from RP as the first step in a multimodal approach. Adjuvant therapies seem to have a negligible impact on CSS in patients with high pathological Gleason score prostate cancer, underscoring the need for local surgical control of the disease.

Conflict of Interest

None declared.

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