Positive Surgical Margin Trends in Patients with Pathologic T 3 Prostate Cancer Treated with Robot-Assisted Radical Prostatectomy

Abstract

Introduction:

We analyzed the trends of positive surgical margin (PSM) location in patients who had pT₃ disease at robot-assisted radical prostatectomy (RARP). We aimed to describe our changing incidence of PSMs in the largest series to date of patients with pT₃ disease who were treated by RARP.

Methods:

A single-institution, single-surgeon review was performed of all patients who underwent RARP from 2005 to 2011. Perioperative data were collected for all patients with pT₃ prostate cancer from a prospectively maintained RARP database. The PSM incidence and rates were stratified by location. The PSM rates per location were trended over time.

Results:

In total, 2478 consecutive patients underwent RARP between July 2005 and December 2011. Of these patients, 555 were found to have pT₃ disease. The PSM rate for patients with pT₃ disease was 47%. The PSM rate for patients with pT_3a and pT_3B disease was 42.8% and 60.6%, respectively. Over the duration of this study, the PSM rate in patients with pT₃ disease decreased significantly from 70.6% in 2005 to 32.3% in 2011 (p=0.002). The apical PSM rate showed the greatest decrease during this period going from 52.9% in 2005 to 5.2% in 2011 (p=0.018).

Conclusion:

We present the largest series to date involving the treatment of locally advanced prostate cancer initially managed with RARP. Our findings suggest that patients with locally advanced prostate cancer can be treated with RARP with acceptable positive margin rates. Overall PSM rates improved nearly 40% over the 6.5-year period of this study.

Introduction

Prostate cancer was the diagnosis in nearly 240,000 men in 2012 and was the second leading cause of cancer-related deaths in the United States.¹ Radical prostatectomy (RP) continues to be the treatment of choice for clinically localized prostate cancer (clinical stage T_1c-T_2c [cT_1c-cT_2c]) in patients with a life expectancy>10 years.² Robot-assisted radical prostatectomy (RARP) was first introduced in 2001 by Binder and Kramer³ and later popularized by Menon and associates⁴ (2002). As of 2008, RARP accounted for roughly 75% of all RP performed in the United States.⁵ The increased use of RARP in the treatment of patients with prostate cancer is thought to be because of enhanced vision (magnification and three-dimensional), as well as intuitive and wristed instrumentation, thus possibly leading to a relatively shorter learning curve compared with standard laparoscopic approaches.

Continued improvement in RARP technique and increased physician adaptation have allowed robotic surgeons to aggressively approach prostate cancer and pursue the treatment of patients with high-risk⁶ and locally advanced disease.^7,8 Unfortunately, to date no long-term data exist in regard to biochemical recurrence (BCR) after RARP. Three recent studies have provided data on the risk of biochemical recurrence after RARP at 5 years and the results appear promising.^9
–11 Because of the relative paucity of data on BCR, positive surgical margin (PSM) status has been used as a surrogate marker in the evaluation of oncologic safety of the relatively new RARP procedure. PSM status has been shown to be a useful oncologic marker in prostate cancer, because it has been shown to be associated with higher rates of biochemical, local, and metastatic recurrence.^12

–15

Recent evidence has suggested that with increased volume of RARP procedures, surgeons can achieve PSM outcomes similar to, if not better than, that achieved by open radical prostatectomy (ORP) in the management of locally advanced disease.^7,16,17 We sought to evaluate our experience in the treatment of patients with locally advanced prostate cancer (pathologic stage T_3a and T_3a [pT_3a and pT_3a]), specifically looking at PSM status. We evaluated the rate of PSM in pT₃ disease by location and surgeon experience.

Methods

Subjects and data collection

On Institutional Review Board approval, we reviewed all patients who underwent RARP from July 2005 through December 2011. From this cohort, we identified all patients with pT_3a or pT_3b disease. Perioperative data were evaluated from a prospectively maintained RARP database. All patients included in the database were operated on at a single institution and by a single surgeon (DIL).

Descriptive characteristics of each patient were analyzed and included age, body mass index (BMI), preoperative prostate-specific antigen (PSA) level, pathologic Gleason score from final specimen, and pathologic stage from final specimen. PSM incidence and rates were stratified by location. PSM location categories were: Posterior, anterior, lateral, base, apex, bladder neck, and seminal vesicles. The PSM rates per location were trended by year.

Pathology

Prostatectomy specimens were processed with serial sectioning at 3-mm intervals. Tumor involving the inked margin of the cut surface was considered a PSM. The American Joint Committee on Cancer Cancer Staging Manual (6th edition) was used to determine the pathologic stage. Stage pT_3a involved extraprostatic extension and pT_3b involved seminal vesicle invasion. Pathologic staging was performed by uropathologists at our institution. Protocols of specimen analysis, including staining and evaluation of margins, remained consistent throughout the study period.

Statistical analyses

Statistical analysis was conducted after stratifying patients according to the year RARP was performed. Two-tailed chi-square tests were used to determine statistical significance; p<0.05 was considered to be statistically significant. All calculations were performed with Minitab 16 (Minitab Inc., State College, PA.).

Results

In total, 2478 consecutive patients underwent RARP between July 2005 and December 2011. Of these patients, 555 were found to have pT₃ disease. Characteristics of patients with pT₃ disease were identified in Table 1.

Table 1.

Patient Characteristics

Age (mean)	58.9
BMI (mean)	27.9
PSA (mean)	7.69
Pathologic grade
6	32
7	412
8	66
9	42
10	3
Pathologic stage
T_3a	423
T_3b	132

BMI=body mass index; PSA=prostate-specific antigen.

PSM rates according to year of RARP are shown in Table 2. The PSM rate for all patients, those with pT₂ disease, and those with pT₃ disease was 19.2%, 11.2%, and 47%, respectively. Of the 555 patients with pT₃ disease, 423 had pT_3a and 132 had pT_3b. The PSM rate for patients with pT_3a and pT_3b disease was 42.8% and 60.6%, respectively. There was a statistically significant difference in the PSM rate per year in pT₃ patients (p=0.002), with the PSM rate trending downward from 70.6% in 2005 to 32.3% in 2011. Similarly, there was a statistically significant difference in the PSM rate of all patients (p=0.016), with the PSM rate trending downward from 32.8% in 2005 to 15.8% in 2011.

Table 2.

Positive Surgical Margin Rate Per Year

	2005	2006	2007	2008	2009	2010	2011	p value
Total # of T₃ patients with PSM	12	36	57	42	44	39	31	-
Total pT₃ patients	17	81	94	97	84	86	96	-
Overall pT₃ PSM rate	70.6%	44.4%	60.6%	43.3%	52.4%	45.4%	32.3%	0.002
Total # PSM in all patients	20	63	84	70	84	85	71	-
Total patients	61	306	412	438	407	405	449	-
Overal PSM rate in all patients	32.8%	20.6%	20.4%	16.0%	20.6%	21.0%	15.8%	0.016

PSM=positive surgical margin.

Table 3 displays the rate of PSM in patients with pT₃ disease per location of the prostate trended over time. There was a statistically significant difference in the PSM rate at the apex over the 6.5-year study period (p=0.018), with the apical PSM rate trending downward from 52.9% in 2005 to 5.2% in 2011. There were no statistically significant differences in the PSM rate at any other location.

Table 3.

Positive Surgical Margin in Patients with pT₃ Disease Trended Per Location

	2005	2006	2007	2008	2009	2010	2011	p value
Posterior, n (%)	5 (29.4%)	15 (18.5%)	22 (23.4%)	21 (21.7%)	22 (26.2%)	24 (27.9%)	27 (28.1%)	0.164
Anterior, n (%)	4 (23.5%)	6 (7.4%)	6 (6.4%)	5 (5.2%)	2 (2.4%)	7 (8.1%)	4 (4.2%)	0.558
Lateral, n (%)	1 (5.9%)	3 (3.7%)	4 (4.3%)	1 (1.0%)	1 (1.2%)	2 (2.3%)	3 (3.1%)	0.845
Base, n (%)	0 (0%)	2 (2.5%)	4 (4.3%)	4 (4.1%)	1 (1.2%)	0 (0%)	1 (1.0%)	0.184
Apex, n (%)	9 (52.9%)	15 (18.5%)	15 (16.0%)	8 (8.3%)	10 (11.9%)	10 (11.6%)	5 (5.2%)	0.018
Seminal vesicles, n (%)	0 (0%)	3 (3.7%)	4 (4.3%)	2 (2.1%)	4 (4.8%)	6 (7.0%)	0 (0%)	0.323
Bladder neck, n (%)	0 (0%)	2 (2.5%)	4 (4.3%)	3 (3.1%)	7 (8.3%)	10 (11.6%)	8 (8.3%)	0.087

% is based on PSM/total number of patients with T₃.

Patients may have more than one positive surgical margin.

Discussion

The role for RP in patients with locally advanced disease remains in debate. Historically, the preferred treatment for patients with locally advanced disease has been radiation therapy with or without androgen deprivation therapy. Recent literature, however, has challenged this notion. In 2005, two retrospective studies reviewed the treatment of patients with cT₃ disease with ORP.^18

–21 Ward and colleagues¹⁹ (2005) is the largest study to date that describes the treatment of patients with cT₃ prostate cancer with ORP. In total, 842 patients were treated and had a 5-year disease-specific survival of 95%. Similar results have been reproduced by multiple other studies with a 5-year disease-specific survival ranging from 94% to 98.7%. The PSM rate in these studies ranged from 22% to 56% of patients with cT₃ disease. Downstaging occurred in 9% to 27% with review of the final pathologic specimen.^18

–21

Of the patients treated for pT₃ disease at our institution, 47% had PSM. This number decreased significantly during our study from 70.6% in 2005 to 32.3% in 2011. Our results compare appropriately with these studies, especially when taking into account the large number of patients whose pathologic stage was downstaged when compared with the clinical stage in each study after ORP.

Vora and coworkers¹⁷ (2013) recently reported the first large retrospective review of pathology proven locally advanced disease managed initially with RARP. This article describes the authors' experience with pT₃ and pT₄ prostate cancer managed with either RARP or ORP. This multicenter retrospective review found the PSM rate of 47.1% in the RARP group and 58.9% for the ORP. Our study, involving 555 patients, is the largest study to date looking at RARP in the treatment of patients with locally advanced prostate cancer. Our PSM rate of 47% was nearly identical to what Vora and associates¹⁷ reported with RARP.

Over time and with increased experience, our PSM rates for patients with pT₃ prostate cancer saw a significant decrease from 70.6% in 2005 to 32.3% in 2011 with an overall rate of 47%. A recent meta-analyses by Novara and associates⁷ (2012) reviewed all published RARP series involving more than 100 cases between 2008 and 2011. The average PSM for pT₃ disease was 37% with a range from 29% to 50%. The continued improvement demonstrated in our study has been replicated many times in other studies.^14,22

–25 All of these studies demonstrated that with increased surgeon experience, PSM rates decrease.

The overall importance of PSM cannot be overstated. Multiple studies have shown that PSMs are associated with increased risk of BCR as well as local and metastatic recurrence.^12

–15 There remains debate on whether PSMs are associated with prostate cancer-specific mortality. Using SEER data, Wright and coworkers²⁶ (2010) reviewed 65,633 patients undergoing treatment for prostate cancer with radical prostatectomy. This study was able to demonstrate that PSM was an independent predictor of prostate cancer-specific mortality. In a recent study by Stephenson and colleagues²⁷ (2014), however, 11,521 patients undergoing RP between 1987 and 2005 were evaluated, and PSM was not associated with prostate cancer-specific mortality.

There is no clear consensus on the importance of the location of PSM in regard to risk of recurrence. The apex appears to be consistently the most common site of PSM accounting for up to 58% of PSM; however, the importance of this remains controversial.^{14,28

–32} In the initial year of experience, our study demonstrated a 52.9% PSM rate at the apex. The following year, this dropped to 18.5%, and in the final year, the rate dropped down to 5.2%. This area alone showed a significant change in PSM rates. These findings are consistent with those described by Atug and associates¹⁴ (2006) who noted the greatest improvement in PSM status at the apex over the first 100 cases in their study.

Like many other high-volume centers, our center is a major referral center. Because of this, many of the patients who undergo RARP travel from long distances and therefore prefer to follow their PSA levels with their local urologist closer to home. This unfortunately leads to insufficient long-term follow-up for many patients, and subsequent inadequate PSA data. Regardless, PSM is still a very good marker for recurrence of disease and a useful tool for measuring the short-term oncologic utility of RARP. Our data in regard to PSM rates suggest that RARP is a reasonable option for the initial treatment of patients with locally advanced prostate cancer.

During the 6.5-year period of this study, the PSM rate for patients with pT₃ disease decreased significantly from 70.6% to 32.3%. During this period, we saw a significant decrease in the PSM rate at the apex. We believe that the single biggest factor contributing to the significant decrease in apical PSM is secondary to the use of the stapler to gain control of the dorsal venous complex (DVC) (Fig. 1). Stapling of the DVC allows for minimal blood loss with subsequent increased visualization for dissection. We think that this aspect is critically important because dissection through the apex can be challenging; sparing as much of the striated sphincter as possible while avoiding a capsular incision in the apex necessitates as clean a field as possible. Stapling also allows for increased mobility of the entire prostate during the posterior dissection of the prostate and apex after removal of the vascular pedicles.

FIG. 1.

Appearance of dorsal venous complex after (A) stapler placement, (B) stapling of the dorsal venous complex (DVC), (C) left lateral tension during dissection of the right pedicles.

Another factor, which may in turn play a role in decreasing the rate of PSM, is the use of magnetic resonance imaging (MRI) to better guide the surgical procedure. In our current practice, we routinely order multiparametric endorectal (eMRI) of the prostate for men with intermediate and high-risk disease to assess for visible tumor adjacent to or encroaching on the capsule of the prostate (Fig. 2). This practice began in selected patients at our institution in 2007. The incidence of eMRI use increased from 17.6% in 2007 to 64.6% in 2011 in those patients found to have pT₃ disease (unpublished data). A negative association between eMRI positivity rate and PSM rate in the pT3 population was statistically significant with a Pearson correlation coefficient of −0.888 (p=0.044). The eMRI utilization rate is also negatively associated with the PSM rate with a Pearson correlation coefficient of−0.908 (p=0.033).

FIG. 2.

Axial T2-weighted image of high-grade prostate cancer in right midprostate measuring 1.7×1.5×2.8 cm. Further images from the same magnetic resonance image revealed extensive extracapsular extension.

In summary, both eMRI use and eMRI positivity rate have a statistically significant negative correlation with PSM rate in the pT₃ population. Such correlations have implications for eMRI use during preoperative planning for patients of higher risk disease. The significant associations suggest a potential positive effect of eMRI on surgical margin outcomes in the pT₃ population. One explanation for this relationship is the improved intraoperative awareness of the tumor derived from preoperative eMRI results.

Another key factor in the overall decrease of PSM includes experience and the ability to better identify nerve-sparing planes. With the outstanding visualization and fine dexterity provided by the robotic platform, tailoring of the nerve-sparing plane in similar manner as is performed according to Tewari and coworkers³³ (2011) becomes an excellent method to both maintain low margins rates while still performing partial nerve sparing. As with any new operation or technique, experience plays a key role in success. This certainly is emphasized by the apparent learning curve still needed for a fellowship-trained robotic surgeon in regard to PSM status. Future directions of study may involve evaluating surgeon experience with regard to simulation training, robotic experience in residency, and fellowship training with regard to PSM status.

To date, the use of the stapler to control the DVC, multiparametric MRI, and surgeon experience remain hypothetical and further evaluation is necessary; however, in our experience, we think they have proven quite useful in assisting with the dramatic decrease of PSM in all patients and, in particular, those with pT₃ prostate cancer.

Conclusion

We present the largest series to date involving the treatment of patients with locally advanced prostate cancer that was initially managed with RARP. Our findings suggest that locally advanced prostate cancer can be managed with RARP with acceptable positive margin rates. Overall PSM rates improved nearly 40% over the 6.5-year period of this study, echoing the results of previous studies that suggested PSM improves with experience.

Footnotes

Disclosure Statement

Dr. David I. Lee has an industrial relationship with Myriad (lecturer). For the remaining authors, no competing financial interests exist.

Abbreviations Used

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