Five-year oncological outcomes of endoscopic extraperitoneal radical prostatectomy (EERPE) for prostate cancer: results from a medium-volume UK centre

Authors


Abstract

Objective

  • To determine the 5-year oncological outcomes of endoscopic extraperitoneal radical prostatectomy (EERPE) from a medium-volume centre, thereby providing much needed data on outcomes from the UK.

Patients and Methods

  • From January 2006 to January 2012, 575 patients underwent EERPE for localized prostate cancer, performed by a single surgeon who had completed a modular training programme.
  • Follow-up was as per local hospital policy and data were collected in our prospective database.
  • A retrospective review of patient demographics, prostate-specific antigen (PSA) levels, pathological T stages, Gleason scores, surgical margin status and biochemical recurrence (BCR) data was performed. BCR was defined as PSA >0.2 μg/L.

Results

  • The mean (range) patient age was 62 (40.3–76.5) years and the mean (range) follow-up was 30 (12–72) months. The median (interquartile range [IQR]) operating time was 135 (120–170) min and the median (IQR) blood loss was 200 (100–250) mL.
  • Of the 575 patients, 135 (23.5%) had positive surgical margins (PSMs). The PSM rate for pT2 disease was 66/406 patients (16.3%) and for pT3 disease it was 68/168 patients (40.5%). Overall BCR-free survival at 5-years was 81.5%.
  • Multivariate Cox analysis showed that PSMs, Gleason score, D'Amico risk category and pT stage were independent predictors of BCR-free survival.

Conclusions

  • This assessment of the oncological results of EERPE, which included the surgical learning curve, shows that the adoption of EERPE after mentored fellowship training translates into mid-term oncological outcomes in line with those of retropubic/transperitoneal laparoscopic approaches and with large-volume centres worldwide which have pioneered laparoscopic radical prostatectomy.
  • The study shows that EERPE in a medium-volume second generation laparoscopic centre (that introduced EERPE after adequate training in pioneering centres) produces results with good 5-year oncological outcomes, similar to those of other major series, for patients in the UK.
Abbreviations
EERPE

endoscopic extraperitoneal radical prostatectomy

BCR

biochemical recurrence

IQR

interquartile range

PSM

positive surgical margin

LRP

laparoscopic radical prostatectomy

ORP

open radical retropubic prostatectomy

ns

nerve-sparing

PLND

pelvic lymph node dissection

Introduction

Radical prostatectomy is a recognized method of curative treatment for localized prostate cancer. The advantages of laparoscopic radical prostatectomy (LRP) over open radical retropubic prostatectomy (ORP) are less blood loss and blood transfusion, improved cosmesis, a shorter hospital stay and a shorter time to resumption of normal activities [1, 2]. Endoscopic extraperitoneal radical prostatectomy (EERPE), an alternative technique to transperitoneal LRP, is now a well established laparoscopic technique for the treatment of prostate cancer [3].

Recent data from large European centres have reported medium-term data for EERPE [4] and long-term outcome data for transperitoneal LRP [5], which have shown that the laparoscopic approach is both safe and effective oncologically. These large European centres have pioneered LRP and acquired expertise since the late 1990s. The barriers to diffusion of the technique into mid- to low-volume centres, such as those in the UK and Ireland, have been the technically challenging nature of the procedure and the lack of local expertise. It has been shown, however, that the use of a mentored fellowship programme results in good peri-operative and short-term outcomes for EERPE [6, 7]. There is a paucity of data on the oncological outcomes from LRP from UK centres.

The aim of the present study was to evaluate the 5-year oncological outcomes of patients undergoing EERPE in a second generation LRP centre in the UK.

Materials and Methods

Patients undergoing EERPE between February 2006 and January 2012 were included. EERPE was performed by a single surgeon (SAMcN) who had undergone modular training in EERPE [8]. The initial cohort of patients underwent EERPE, whilst later in the series nerve-sparing (ns)EERPE was offered where appropriate (Table 1).

Table 1. Criteria for PLND, standard (non-ns)EERPE and nsEERPE
ProcedurePSA level, μg/LGleason score
PLND≥10≥7
EERPE>10>6
nsEERPE<106

The technique used in our centre is that of the University of Leipzig, Germany, and has been described previously [3, 9]. Patients with localized prostate cancer on clinical and radiological staging (MRI and bone scan for patients with Gleason score ≥ 7 and/or PSA ≥ 10 μg/L) who decided to have surgical treatment were offered LRP after discussion at a regional multidisciplinary meeting. Patients also underwent careful counselling, both with regard to the alternative treatment options and the procedure itself, and were provided with a written information booklet about the procedure. The criteria for pelvic lymph node dissection (PLND), standard (non-ns) EERPE and nsEERPE are shown in Table 1.

We used data from our prospectively maintained database which included: patient demographics; preoperative investigations; intra-operative data; and pathological and postoperative details including complications, classified according to the Clavien–Dindo system [10]. We performed a preoperative risk analysis using the D'Amico risk score [11]. Patients underwent standard 10-core TRUS-guided prostate biopsies. All pathological specimens were reviewed by a specialist uropathologist at our institution. Positive surgical margins (PSMs) were defined as the presence of tumour at the inked surface of the specimen, excluding those where a surgical incision was deemed responsible. Operating time was calculated from first incision to application of dressings in theatre.

Follow-up included 3-monthly outpatient visits in the first year, 6-monthly visits in the second year and annual visits thereafter. A PSA test was performed and recorded at each visit. Biochemical recurrence (BCR) was defined as PSA > 0.2 μg/L or PSA never reaching the nadir of <0.1 μg/L. All patients' postoperative pathology was reviewed at a multidisciplinary meeting to determine if adjuvant radiotherapy was necessary. Patients were reviewed in a specialized prostate cancer clinic at 3 months and according to local protocol (above) to determine if there was failure for PSA to reach nadir or BCR, at which time the opinion of a radiation-oncologist would be sought on salvage radiotherapy.

For functional outcomes, the number of pads used per 24-h was used to assess urinary continence at 12 months' follow-up. ‘Dry’ was defined as 0 or 1 [confidence] pad per 24 h. Potency was defined as erections satisfactory or unsatisfactory for intercourse and was assessed at the 12-month clinic review. All patients were routinely started on an oral phosphodiesterase-5 inhibitors at 6 weeks after surgery. Unfortunately, at the start of our series we did not use validated questionnaires such as the ICS short-form and the short-form International Index of Erectile Function-5 questionnaires and this we concede is a shortcoming of our study.

All statistical analyses were performed using PASW Statistics 18.0 (Chicago, IL, USA). A P value ≤ 0.05 was considered to indicate statistical significance. BCR-free survival was estimated using the Kaplan–Meier method. Survival curves were stratified by D'Amico risk classification, Gleason grade, surgical margin status and pathological stage. The multivariate Cox proportional hazard regression model was used to determine factors influencing BCR-free survival.

Results

A total of 575 patients underwent LRP from February 2006 to January 2012. The patients' pre- and peri-operative characteristics are shown in Table 2. Preoperative D'Amico risk groups show that the majority were in the intermediate-risk group (49.2%). Postoperative details are shown in Table 3. The overall complication rate was 8.9% (51/575 patients [Table 4]).

Table 2. Pre- and peri-operative data
Total no. of patients575
Mean (range) age, years62 (40.3–76.5)
Mean PSA level, μg/L7.5
Mean (range) prostate weight, g52.0 (17–251)
Biopsy Gleason score, n (%) 
<7182 (31.6)
7370 (64.3)
>723 (4)
D'Amico risk group, n (%) 
Low229 (39.8)
Intermediate283 (49.2)
High63 (11)
Intra-operative details 
Median (IQR) operating time, min135 (120–170)
Open conversion rate, n/N (%)0/575 (0)
Median (IQR) blood loss200 (100–250)
Blood transfusion rate, n/N (%)2/575 (0.35)
Median (IQR) length of hospital stay, days3 (2–3)
No PLND, n/N (%)273/575 (47.5)
PLND, n/N (%)302/575 (52.5)
No. of positive PLNDs, n/N (%)6/302 (2)
EERPE, n/N (%)225/575 (39.1)
nsEERPE, n/N (%)350/575 (60.9)
Table 3. Postoperative pathological data
 n/N (%)
pT2406/575 (70.6)
pT3168/575 (29.2)
pT41/575 (0.2)
N+6/575 (1)
Gleason <7285/575 (49.6)
Gleason = 7248/575 (43.1)
Gleason >742/575 (7.3)
No. of specimens upstaged on Gleason score148/575 (25.7)
Table 4. A breakdown of complications by Clavien–Dindo classification
ComplicationClavien–Dindo gradeNo. of patientsManagement
Acute urinary retentionI6Catheterization
PyrexiaI4Conservative
Pelvic haematomaI1Conservative
Wound infectionI1Conservative
Lower Respiratory Tract InfectionII5i.v. antibiotics
Deep vein thrombosisII2Warfarin
UTIII7Antibiotics
IleusII2Conservative
LymphoceleII1Conservative
Low haemoglobinII2Blood transfusion
Acute tubular necrosisII1i.v. fluids
Epididimo-orchitis (simulatenous hydrocele repair)II1Antibiotics
LymphoceleIIIa4Percutaneous drainage
Pelvic haematomaIIIa1Percutaneous drainage
Rectal injuryIIIb2Intra-operative two-layer suture
Pelvic haematomaIIIb2Open evacuation
StrictureIIIb2Dilatation and urethrotomy
LymphoceleIIIb1Open drainage
Clot retentionIIIb1Cystoscopy and washout
IleusIIIb1Laparotomy
Retained stentIIIb2General Anaesthetic removal
Port site herniaIIIb1Hernia repair
Pulmonary embolismIV1Intensive care unit
Overall complication rate (%)51/575 (8.9)  

The postoperative pathological data, including pathological T stage, are shown in Table 3. The PSM rate was 135/575 (23.5%) overall, and 66/406 (16.3%) for pT2 and 68/168 (40.5%) for pT3 tumours (Table 5).

Table 5. A breakdown of PSM rate by pathological stage of disease
Pathological T stagePSM rate, n/N (%)Pathological T stage (summary)PSM rate, n/N (%)
pT2a2/67 (3.0)  
pT2b2/16 (12.5)pT2 (overall)66/406 (16.3)
pT2c62/323 (19.2)  
pT3a53/137 (38.7)  
pT3b15/31 (48.4)pT3 (overall)68/168 (40.5)
pT41/1 (100)  
Overall PSM rate135/575 (23.5)  

The median (interquartile range [IQR]) follow-up was 30 (16.3–44.0) months. BCR occurred in 54 patients, with a median (IQR) time to BCR of 23.5 (14–35.8) months. A total of 13 patients died during the study; 12 deaths were not prostate cancer-related and one was from prostate cancer. This one patient had high-risk disease (Gleason score 9, pT3b). The overall 1-, 3- and 5-year BCR-free survival rates, as calculated from Kaplan–Meier curves, were 98, 90.5 and 81.5%, respectively.

A total of 29 patients (5%) received postoperative radiotherapy. Of these, 14 patients had failed to reach a PSA nadir of <0.1 ng/mL and 14 patients received salvage radiotherapy for BCR. One patient received adjuvant radiotherapy (without failure to reach PSA nadir or BCR) and was not excluded from analysis. A total of 36 patients (6%) were lost to follow-up and were excluded from the analysis; none of these had failed to reach PSA nadir nor had they experienced BCR at the time of last follow-up.

The BCR-free survival rates stratified by preoperative D'Amico risk group are shown in Fig. 1. The 1-, 3- and 5-year BCR-free survival rates for the low-risk group were 98.7, 96.8 and 90.6%, respectively, for the intermediate-risk group they were 98.5, 88.1 and 79.3, respectively, and for the high-risk group they were 93.3, 65.0 and 54.2%, respectively.

Figure 1.

Kaplan–Meier curves showing BCR-free survival by preoperative D'Amico risk groups (low, intermediate and high).

Stratification by postoperative pathological details was also performed, by Gleason score (Fig. 2A,B), by pathological T stage (Fig. 3) and by surgical margin status (Fig. 4). The 5-year BCR-free survival rate for Gleason score <7 was 92.2%, for Gleason score 7 it was 70.2% (84.3% for Gleason 3 + 4 and 46.8% for Gleason 4 + 3), and for Gleason score >7 it was 44.2%. The 5-year BCR-free survival for pT2 disease was 88% and for pT3 disease it was 69%. The 5-year BCR-free survival rate associated with a negative surgical margin was 89.2% and for a PSM it was 68.1%.

Figure 2.

(A) Kaplan–Meier curves of BCR-free survival stratified by postoperative Gleason score. (B) Graph showing subanalysis of Gleason 7 into Gleason 3 + 4 and Gleason 4 + 3 for BCR-free survival.

Figure 3.

Kaplan–Meier curves of BCR-free survival stratified by pathological stage.

Figure 4.

Kaplan–Meier curves of BCR-free survival stratified by surgical margin status.

The multivariate Cox proportional hazard model showed that preoperative D'Amico risk status, margin status, pathological T stage and Gleason score were significant, independent predictors of BCR-free survival (Table 6).

Table 6. Multivariate Cox proportional hazard model for different variables for the prediction of BCR-free survival
VariableRisk ratio95% CIP
Negative margin status1
PSM status2.2341.249–3.9980.007
PSA < 10μg/L1
PSA 10–20μg/L1.8150.955–3.4500.069
PSA > 20μg/L2.5430.869–7.4400.089
Gleason score <71
Gleason score = 72.1611.123–4.1580.021
Gleason score >75.522.415–12.616<0.001
pT21
pT32.6201.412–4.8620.002
Nodes negative1
Nodes positive1.5340.344–6.8490.575
High D'Amico risk9.7844.301–22.259<0.001
Intermediate D'Amico risk3.0831.489–6.3820.002
Low D'Amico risk1

With regard to functional outcomes, the follow-up rate for urinary continence was 525/575 (91%) and for potency it was 495/575 (86%). At 12 months' follow-up, 88% of patients (460/525) were ‘dry’. Of 230 patients undergoing bilateral nsEERPE, 213 (93%) were dry, whilst 81/72 (89%) patients undergoing a unilateral nsEERPE and 175/214 (82%) undergoing a non-ns EERPE were dry. In total, 15 patients required a continence procedure (artificial urinary sphincter or urethral sling).

At 12 months' follow-up, the overall rate of erections satisfactory for intercourse was 39%, for bilateral nsEERPE it was 52% (122/234 patients), and for unilateral nsEERPE it was 43% (26/61 patients).

Discussion

The acquisition of a new surgical technique is a complex process and LRP has faced criticism because of its long learning curve; this has resulted in low diffusion of the technique [6]. Whilst the large-volume specialist European and US centres have published mid-term transperitoneal outcome data and, more recently, are starting to publish long-term (10-year) oncological data, there are few published data on the mid-term results from lower volume, second generation LRP centres such as ours [4, 5, 12, 13]. The mentored modulated fellowship is a programme recommended for the acquisition and implementation of LRP in centres not currently performing the technique [6, 8]. There have been studies published to support this method of training for implementing a new service in urology units, with good peri-operative and short-term outcomes [6, 7]; however, there are no data on the 5-year oncological outcomes of this method of EERPE training in surgeons who have set-up their (second generation LRP) units in smaller-volume centres than those large centres where this training occurs [3]. Our centre started to offer EERPE in 2006 after one surgeon (A.S.M.) completed a mentored fellowship training programme. The unit currently performs ∼ 150 EERPEs per year.

In 2010, Paul et al. [4]published their mid-term results of extraperitoneal LRP which gave the first confirmation that this treatment method offered mid-term oncological outcomes similar to those of transperitoneal LRP. They reported PSM rates of 26% overall, and 16.1% for pT2 and 34.6% for pT3 disease, and BCR-free survival rates at 3 and 5 years of 84 and 83%, respectively [4]. The results of the present study, an overall PSM rate of 23.5%, and rates of 16.3 and 40.5% for pT2 and pT3 disease, respectively, were similar for pT2 but higher for pT3 disease. These results included early learning curve results for which there were higher PSM rates than in the later years when more experience had been gained [6]. It should also be noted that, in our centre, frozen sections are not taken at the apical margins. Positive apical margins accounted for 53% of the overall PSM rate; this rate may have been improved if frozen sections were taken. Our 3- and 5-year BCR-free survival rates of 90.5 and 81.5% also compare favourably with those of the study by Paul et al. [4], and are similar to transperitoneal LRP results in the literature: Guillonneau et al. [14] reported BCR-free survival rates of 92% for pT2 and 77% for pT3 disease at 3 years and 83% for pT2 and 69% for pT3 disease at 5 years [5], Rassweiler et al. [15] reported BCR-free survival rates of 89.5% for pT2 and 68.2% for pT3 disease at 5 years. Our results were similar, with BCR-free survival rates at 3 and 5 years for pT2 disease of 95% and 88%, respectively, and for pT3 disease of 73 and 69%, respectively. In addition, our results compare well with large ORP studies: Roehl et al. [16] reported a 5-year BCR-free survival rate of 80% in a cohort of 3478 patients (St. Louis, MO, USA), Chun et al. [17] reported a rate of 70% in 4277 patients (Hamburg, Germany) and Bianco et al. [18] reported a rate of 82% in their cohort of patients from the Memorial Sloan-Kettering Cancer Centre (New York, NY, USA).

The functional outcomes of the present study were similar to those in the literature [19, 20] with regard to urinary continence (93% of patients undergoing bilateral nsEERPE were dry) and potency rates (52% of patients undergoing bilateral nsEERPE were potent) and these results are further confirmation of the efficacy of nsEERPE. Potency rates are still improving after nsEERPE, suggesting that there is a longer learning curve for LRP in terms of achieving potency [21].

Our PSM rates were initially higher during the learning curve in the series (27% for pT2 disease) and have continued to fall with increasing experience, as previously reported [6]. Excluding the first 100 cases of the series, the PSM rate for pT2 disease was 10.9%. The learning curve was overcome quicker than that stated in the literature, which estimates that the ‘oncological’ learning curve takes ∼200–250 cases [22]; this was probably helped by the completion of a dedicated laparoscopic mentored fellowship [23].

Paul et al. [4] provide a rigorous analysis of the postoperative outcomes of extraperitoneal LRP that affect BCR-free survival, but do not offer patients any further insight into the outcomes of LRP based on preoperative risk stratification. The D'Amico classification is the preoperative risk stratification that patients and their surgeons use when deciding/advising on treatment method. The present study shows that BCR-free survival rates using the D'Amico preoperative risk score at 5 years for patients in the low-, intermediate- and high-risk groups were 90.6, 79.3 and 54.2%, respectively (Fig. 1). This is important information for patients undergoing EERPE. Toujer et al. [5] reported 5-year BCR-free survival rates based on a preoperative risk score for transperitoneal LRP for low-, intermediate- and high-risk groups of 91, 77 and 53%, respectively, which were consistent with the results from the present study.

The paucity of outcome data from LRP in the UK and Ireland is very apparent. There are published outcome studies for ORP [24-26] but UK oncological outcome data are limited to short-term follow-up [27]. One UK centre has published a number of papers since 2002 on outcomes in their series over the last 9 years [21, 28-30], but these papers did not provide a rigorous analysis of oncological outcomes and did not provide important preoperative risk outcome data. More recently, US and European centres have reported 5-year outcomes from robot-assisted radical prostatectomy [31-34]. UK and Irish centres performing robot-assisted radical prostatectomy have begun to publish their early oncological and functional outcome data [35, 36], but there are no other published medium-term oncological outcome data available from the UK to date. Our data shows that units can successfully implement EERPE using a mentored fellowship training programme and, in turn, offer patients 5-year oncological outcomes similar to large-volume specialist centres in Europe and USA. Our study also provides vital data from the UK on LRP outcomes, data that are lacking in the literature to the extent that the current National Institute for Health and Care Excellence guidelines do not contain outcome data from any UK studies. This study provides patients access to outcome data stratified by both preoperative risk status and postoperative histopathological results. It also provides clinicians undertaking LRP and robot-assisted prostatectomy a measure against which to compare their outcome data.

Acknowledgements

The authors would like to acknowledge the assistance of the many colleagues who participated in undertaking the surgical procedures and in gathering the relevant data, in particular Mr Prasad Bollina, Mr Ghulam Nabi, Mr Ismail El Mokadem, Ms Justine Royle, Mr Simon Phipps and Ms Liza McLornan.

Conflict of Interest

None declared.

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