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Robotic Extended Pelvic Lymphadenectomy for Intermediate- and High-Risk Prostate Cancer
EUROPEAN UROLOGY 61 (2012) 1004–1010
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Surgery in Motion
Robotic Extended Pelvic Lymphadenectomy for Intermediate- and High-Risk Prostate Cancer Bertram E. Yuh *, Nora H. Ruel, Rosa Mejia, Chelsea M. Wilson, Timothy G. Wilson Urologic Oncology, City of Hope National Cancer Center, Duarte, CA, USA
Article info
Abstract
Article history: Accepted January 27, 2012 Published online ahead of print on February 22, 2012
Background: Accurate staging of prostate cancer is enhanced by a thorough evaluation of the pelvic lymph nodes. Limited data are available regarding robotic extended pelvic lymphadenectomy (PLA) in this setting. Objective: Analyze our experience performing robotic extended PLA. Design, setting, and participants: A total of 143 consecutive men with intermediate- or high-risk clinically localized adenocarcinoma of the prostate underwent robotic extended PLA and radical prostatectomy between September 2010 and November 2011 by a single surgeon. Surgical procedure: Lymph node packets were sent separately from bilateral common, external, and internal iliacs, obturators, node of Cloquet, and anterior prostatic fat. Measurements: Descriptive statistics were used to summarize lymph node yields and positive nodes. Clinical variables were examined in logistic regression models to predict lymph node positivity. Results and limitations: Median lymph node yield was 20 (range: 9–65, interquartile range: 15–25). Eighteen patients (13%) were found to have metastatic prostate cancer in the lymph nodes. The mean number of positive nodes found was 2.9 (range: 1–11). In 14 of 18 node-positive patients (78%), the extent of nodal invasion was outside the boundaries of a limited PLA. For four patients with positive nodes (22%), prostate biopsy predicted unilateral disease but PLA revealed contralateral positive lymph nodes. A total of 82% of patients experienced no complications, and most Clavien grade 1–2 complications consisted of anastomotic leakage, urinary retention, ileus, and lymphocele. Only 4% of patients experienced a grade 3 complication. Under multivariate regression analysis, prostatespecific antigen (PSA), clinical stage, and maximum biopsy core tumor volume were identified as significant predictors of finding positive pelvic lymph nodes (area under the curve: 91%). The main limitations include short follow-up and lack of randomization. Conclusions: Robotic extended bilateral PLA for prostate cancer up to the common iliac bifurcation increases nodal yield and positive nodal rate and can be performed safely. PSA, clinical stage, and maximum biopsy core volume are predictors for lymph node invasion. Long-term follow-up is needed to evaluate for therapeutic benefit. # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords: Pelvic lymphadenectomy Robotics Positive lymph nodes Prostate Cancer Please visit www.europeanurology.com and www.urosource.com to view the accompanying video.
* Corresponding author. City of Hope National Cancer Center, 1500 E Duarte Rd., Duarte, CA 90017, USA. Tel. +1 626 256 4673; Fax: +1 626 301 8285. E-mail address: [email protected] (B.E. Yuh).
1.
Introduction
The pelvic lymph node spread of prostate cancer often signifies aggressive or advanced disease. Although staging radiography with computed tomography (CT) or magnetic
resonance imaging (MRI) has improved resolution, pelvic lymphadenectomy (PLA) at the time of radical prostatectomy remains the most robust means of determining the presence of cancer in the lymph nodes [1]. For patient counseling and prognosis determination, staging through
0302-2838/$ – see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2012.01.048
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lymph node sampling at surgery is unique compared with other primary treatment options for prostate cancer. Accurate staging may affect risk stratification and decision making with regard to adjuvant therapy after surgery. Although staging PLA has been performed for decades, the extent and indications for dissection remain a topic of debate [2]. It is increasingly acknowledged that a limited PLA encompassing the obturator fossa does not generally improve survival. In low-risk patients, even the staging benefit of PLA is limited because malignant involvement is uncommon. For patients with more aggressive cancer, a pelvic PLA should be performed and in extended fashion. Minimally invasive PLA can produce similar lymph node yields compared with open PLA. Truesdale et al. found no significant difference in lymph node yields for intermediate- and high-risk men with PLA performed open compared with robotically [3], although overall nodal yields were low in both groups. Extended PLA has been performed by both laparoscopic [4–6] and robotic means [7,8] with increased nodal yields and detection of lymph node invasion compared with limited or standard PLA. With robotic technology, fine dissection and threedimensional magnification can assist with an anatomic PLA. A thorough understanding of the anatomic pelvic lymph node drainage basins and preferential dissection of these areas allows for efficient extended PLA with minimal morbidity. We describe our dissection technique and the experience of consecutive patients undergoing robotassisted extended pelvic lymphadenectomy at the time of robotic radical prostatectomy. 2.
Patients and methods
Between September 2010 and November 2011, 143 consecutive patients with intermediate- or high-risk clinically localized adenocarcinoma of the prostate underwent robot-assisted extended PLA in conjunction with radical prostatectomy by a single surgeon. Patients gave their consent to be entered into the City of Hope prostate cancer database and were prospectively enrolled in our study that was approved by the institutional review board. Patients were selected based on D’Amico risk criteria, specifically those with a prostate-specific antigen (PSA) >10, Gleason score 7, or clinical stage T2b. Patients with neoadjuvant hormonal therapy were excluded. Patients had staging bone scans as well as CT scans or T3 MRI of the abdomen and pelvis documenting no evidence of metastatic spread. Database records were reviewed for demographic data, biopsy data, pathology, and operative data. Complications were recorded for the entire length of follow-up and classified using a modified Clavien system.
2.1.
Surgical technique
Extended PLA was performed through a six-port transperitoneal approach using the four-arm da Vinci (Sunnyvale, CA, USA) robotic surgical system. For all patients, PLA was carried out prior to division of the bladder neck or urethra. Robotic port placements were not altered and were fanned out at a 21-cm distance from the pubic symphysis. A right iliac assistant port was typically a 15-mm port to assist with lymph node retrieval. An initial peritoneal opening was carefully carried out over the perceived area of the common iliac bifurcation, and the fourth arm was used for retraction.
The ureters were identified bilaterally and guided the identification of the common iliac bifurcation. The nodal tissue around the bifurcation was dissected free. When possible, the proximal extents of dissection were controlled with Weck clips and divided. The external iliac artery was skeletonized from its origin down to the circumflex iliac vessels with dissection limited to the lateral edge of the artery. The obliterated umbilical artery was reflected away from the iliac vessels, and the lymphatic tissue medially was sent with the internal iliac specimen. Lymphofatty tissue surrounding the internal iliacs and branches was similarly removed. Nodal tissue around the internal iliac often coalesced with the obturator packet. The node of Cloquet distally and surrounding tissue was dissected and sent separately; the obturator packet was removed last. After developing the space of Retzius, we would also send the anterior prostate lymphofatty tissue as previously described [9]. The limits of dissection were thus the common iliac bifurcation proximally, the node of Cloquet distally, the lateral edge of the external iliac artery laterally, and the lateral border of the obliterated umbilical artery medially. Separate packets were sent from the bilateral common iliacs, external iliacs, internal iliacs, node of Cloquet, and from the anterior prostatic fat pad for a total of 11 packets per patient. Specimens were individually retrieved and removed through an assistant port and sent for pathologic analysis in individual containers. EndoCatch bags were not routinely used for lymph node extraction because the 15-mm assistant port would typically permit packet passage. All prostatectomy specimens and corresponding pelvic lymph nodes were submitted routinely for processing and examination in the pathology department after surgery. All possible nodal tissue was processed fresh, fixed in formalin, and embedded into paraffin tissue blocks and then
Table 1 – Patient demographics Age, yr Mean (median) IQR Body mass index Mean (median) IQR Preoperative PSA Mean (median) IQR Biopsy Gleason sum, n (%) 6 7 8 9 Clinical stage, n (%) T1 T2 T3 Operative time, h Mean (median) IQR Estimated blood loss, ml Mean (median) IQR Pathologic stage, n (%) pT2a/pT2b pT2c pT3 Pathologic Gleason sum, n (%) 6 7 8 9 Hospital length of stay, d Mean (median) IQR IQR = interquartile range; PSA = prostate-specific antigen.
63.7 (64) 59–69 28.3 (27) 25.1–30.6 7.8 (5.6) 4.2–8.3 6 115 18 4
(4.2) (80.4) (12.6) (2.8)
101 (70.6) 41 (28.7) 1 (0.7) 3.1 (3) 2.9–3.2 220 (200) 150–250 21 (14.7) 83 (58.0) 39 (27.3) 7 120 6 7
(4.9) (83.9) (4.2) (4.9)
1.8 (1) 1–2
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subject to standard pathologic assessment for lymph nodes. No clearing of adipose tissue or special detection methods were used. A postoperative Jackson-Pratt drain was left in the pelvis and removed when output was <100 ml/24 h. The last 50 patients did not undergo drain placement if bladder neck reconstruction was not performed and anastomosis was watertight (41 with no drain). Data analysis was performed using a standard statistical package (SAS). Data were summarized using descriptive statistics. Univariate and multivariate logistic regression analysis was used to test the association of clinical parameters (eg, PSA, stage, Gleason score, biopsy cores positive, percentage biopsy core involved) with pelvic lymph node invasion status. The natural log of the PSA was used because of a skewed distribution. Predictive accuracy was tested using the area under the receiver operating characteristics curve.
3.
Results
Table 1 lists patient demographics. Median preoperative PSA was 5.6 ng/ml (range: 0.1–48.1). A total of 114 were classified as intermediate-risk patients (80%); 29 were highrisk patients (20%). The median number of biopsy cores taken at prostate biopsy was 12 (range: 6–23). The percentage of positive cores was recorded as the number of positive cores divided by the total number of cores taken. Median percentage of positive cores was 26% (range: 5–100%). Median maximum cancer involvement of a single core was 32% (range: 1–100%). The median lymph node yield was 20 (range: 9–65; [(Fig._1)TD$IG]interquartile range: 15–25). Eighteen patients (13%) were
found to have metastatic prostate cancer involving the lymph nodes. Figure 1 shows the distribution of lymph node yields, and Figure 2 shows the nodal yield and incidence of positive nodes by anatomic site. Nodal yield increased over time chronologically from the first 47 cases to the second and third, with 17, 21, and 24 nodes removed, respectively. Operative time for bilateral extended PLA was between 30 and 45 min. Median blood loss was 200 ml (range: 5–800 ml), and no patients were transfused. Average length of follow-up was 7 mo. Final pathologic stages were pT2 in 105 patients (73%), pT3a in 23 patients (16%), and pT3b in 15 patients (10%). A total of 27 patients were found to have a positive surgical margin (19%). Positive margins for pT2 carcinomas were found in 17 of 105 patients (16%) and 10 of 38 patients (26%) with pT3 carcinomas. A total of 52 positive lymph nodes were found with 24 positive in the obturator lymph nodes (46%). When positive, between 1 and 11 positive nodes were found (mean: 2.9). For patients with positive lymph nodes, 4 (22%) were pT2 patients and 14 (78%) were pT3 patients. Eight patients (7%) were in the D’Amico intermediate-risk group, and 10 patients (33%) were in the high-risk group. Several patients had positive lymph nodes in more proximal nodes without obturator involvement. Four patients had positive lymph nodes only in the obturator fossa, six were both inside and outside the obturator fossa, and eight were exclusively outside the obturator fossa. Thus in 14 of 18 patients (78%), some positive nodes were outside the
Fig. 1 – Distribution of lymph node yields.
[(Fig._2)TD$IG]
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EUROPEAN UROLOGY 61 (2012) 1004–1010
Fig. 2 – Lymph node yield and incidence of positive nodes by anatomic site.
confines of the obturator fossa and would have been underestimated had only a limited PLA been performed. Four patients with positive nodes (22%) had a unilateral preoperative prostate biopsy and contralateral nodes positive for cancer. In these four patients, preoperative T3 MRI showed only unilateral prostate involvement without lymphadenopathy. One patient had a previous negative prostate biopsy; the others had no prior biopsies. On final pathology, all four had bilateral pT3 disease. In regard to morbidity, 117 patients (82%) had no postoperative complications. Thirty-one total complications were recorded for the patient population with 24 (77%) Clavien grade 1 or 2 (Table 2). Only six patients (4%) had a grade 3 complication including deep vein thrombosis (DVT), pulmonary embolus, ileus, lymphocele, and ureteral injury. The most common complications were prolonged urinary anastomotic leak (4%), urinary retention (3%), ileus (3%), and lymphocele (3%). Routine pelvic imaging postoperatively was not performed, and therefore the incidence of asymptomatic lymphocele was likely higher. In univariate logistic regression analysis, PSA, primary Gleason score, clinical stage T2, and maximum percentage of a single biopsy core >40% were significant in predicting
the incidence of men with positive lymph nodes (all p < 0.05) (Table 3). In multivariate analysis, PSA, cT2, and maximal cancer biopsy volume remained independently predictive for malignancy with an area under the curve of 91% (Fig. 3). The percentage of positive biopsy cores,
Table 2 – List of all complications seen Clavien grade
Anastomotic leakage Urinary retention Ileus Lymphocele Incisional bruising Scrotal swelling Pulmonary embolus Deep vein thrombosis Ureteral injury Bladder spasms Fever Groin numbness Total
1 or 2
3
6 5 2 2 3 3 0 0 0 1 1 1 24
0 0 2 2 0 0 1 1 1 0 0 0 7
Total (%) 6 5 4 4 3 3 1 1 1 1 1 1 31
(4) (3) (3) (3) (2) (2) (<1) (<1) (<1) (<1) (<1) (<1)
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Table 3 – Logistic regression models predicting lymph node positivity Parameter
Univariate model Point estimate
PSA Primary Gleason Secondary Gleason Highest biopsy 40% Percentage of positive cores Clinical stage T2 (vs T1) Area under the curve
6.589 5.137 0.564 13.735 1.338 3.633 –
Confidence interval 2.768 1.717 0.202 3.022 0.399 1.32 –
15.688 15.372 1.575 62.427 4.482 10.002 –
Multivariate model p value
Point estimate
<0.0001 0.0034 0.2742 0.0007 0.6368 0.0125 –
6.129 – – 8.257 – 5.243 91%
Confidence interval 2.232 – – 1.59 – 1.446 –
16.105 – – 42.88 – 19.01 –
p value 0.0002 – – 0.0120 – 0.0117 –
PSA = prostate-specific antigen.
[(Fig._3)TD$IG]
Fig. 3 – Logistic regression model predicting lymph node positivity. Bx = biopsy; PSA = prostate-specific antigen; ROC = receiver operating characteristic.
primary and secondary Gleason, and Gleason sum did not achieve significance with a multivariate analysis. 4.
Discussion
Pathologic assessments such as Gleason score, pathologic stage, margin status, and percentage of prostate involved by tumor confer survival information and are readily obtainable through surgical pathologic reporting. Similarly, cancer involvement of the pelvic lymph nodes also negatively affects survival. To define this accurately, however, a systematic and thorough evaluation is required. Detection of lymph node positivity depends on tumor characteristics [10] as well as the extent of dissection. Traditional nomograms for predicting pelvic lymph node involvement at radical prostatectomy have been generated in the setting of limited PLA that for staging appears
suboptimal. To date, an ideal anatomic PLA template has not been widely validated. PLA is regrettably being performed less commonly in minimally invasive radical prostatectomy, and the extent of dissection when performed is likely inadequate [11]. The oncologic potential for extended PLA is prognostic and possibly even a therapeutic benefit [2]. In an updated nomogram, Briganti et al. found that the percentage of positive cores, clinical stage, and primary Gleason grade were independent predictors of lymph node invasion [12]. Because their patient population consisted of prostate cancer patients from all risk groups, the nodepositive rate was only 8.3%. In the present study, we examined a higher risk group because we believed patients with positive nodes would most benefit from an extended PLA. Our analysis did not show that the percentage of positive cores predicted lymph node invasion. Notably in comparison, the overall average of percentage of positive cores was much lower (26% vs 44%), which may be a result of sampling differences. Drainage basins in prostate cancer can be notoriously variable and even involve the retroperitoneum [13]. A limited PLA involving only the obturator fossa risks significant underevaluation of possible lymph node drainage sites. Some studies have shown internal iliac lymph nodes to be involved 58% of the time [14]. Functional studies with technetium-labeled indocyanine green and fluorescence studies may offer adjunctive means to improve lymph node removal in the future [15]. Although the staging significance of PLA is widely acknowledged, a possible therapeutic benefit may exist as well. Allaf et al. found that extended PLA increased nodal positive detection rate and provided a benefit in biochemical recurrence-free survival [16]. Schiavina et al. noted that patients with >10 lymph nodes removed had a significantly lower biochemical recurrence [17]. Finally, Joslyn and Konety noted similarly that an increased number of nodes removed lowered the risk of cancerspecific death [18]. Lymph node yield and lymph node positive rates increase with more extensive dissection. Briganti et al. found that node positivity rate increased with the number of nodes removed [19]. The mean number of nodes removed was 15 with a 10.3% positive rate. Klevecka et al. found a lymph node positive rate of 6.3% for limited
EUROPEAN UROLOGY 61 (2012) 1004–1010
PLA and 14.7% for extended PLA [20]. Although dissection targeting anatomic drainage basins is likely more important than a strict number of removed nodes, previous literature has suggested 20 lymph nodes as a guideline for a sufficient PLA [21]. The thoroughness depends not only on the extent of dissection but on surgical performance and experience as well. Higher volume surgeons have been shown to have higher node-positive rates when controlling for disease characteristics [22]. In our series, increased nodal yield over time may be reflective of the learning curve either in surgical or lymph node analysis technique. Nine patients with positive nodes were noted in the first 72 patients and 9 in the final 71 patients, demonstrating no significant difference with experience. The mean number of nodes removed among nodenegative and node-positive patients was 21.2 and 21.1, respectively. Several authors have reported similar results performing laparoscopic extended PLA. Wyler et al. examined 123 men with high-risk prostate cancer with a mean lymph node count of 21 and a 17% node positivity rate [4]. Lattouf et al. found an even higher lymph node positive rate (31%), although the average PSA was 20 in their series [5]. A total of 15% of patients had metastases exclusively outside the obturator fossa, comparable with our findings. Two smaller studies looked at the performance of robotic extended PLA with nodal counts averaging 18–19 with node-positive rates of 12–16% [7,8]. Our nodal yield of 21 and nodepositive rates of 13% are comparable with a larger number of patients. Under multivariate analysis, PSA, palpable disease, and maximum single-core percentage were independent predictors of node positivity. Using only these three covariates, we were able to obtain an AUC of 91%. Notably, primary or secondary Gleason grade as well as Gleason sum was not predictive at multivariate analysis. Possibly by selecting only intermediate- and high-risk patients, we increased the homogeneity of Gleason scores. In addition, Gleason grading at biopsy is often over- or undergraded with undergrading sometimes >40% [23]. In regard to patient safety, the benefits of improved staging and possibly in survival need to be balanced against the technical complications associated with performing an extended PLA. Although some comparison studies have shown no increased complication rate [22], Briganti et al. found a complication rate of 20% with extended PLA compared with 8% in a more limited dissection because of a higher postoperative lymphocele rate [24]. Lindberg et al. noted higher rates of lymphocele, pulmonary embolus, and DVT in an extended PLA group [25]. Clark et al. also noted a trend toward increased complication rates, although this was not statistically significant [26]. In our series, complication rates and severity according to a standardized system were comparable. Only 4% of patients experienced a Clavien grade 3 complication. Conceivably, ileus, lymphocele, scrotal swelling, DVT, and groin numbness could be related to extended PLA. The most common complications of urinary retention and anastomotic leakage were not believed to be related to the extent of dissection.
1009
Limitations of this study include relatively small population size, short follow-up, and lack of randomization. Longitudinally, we sought to reduce bias by studying only a single-surgeon experience of consecutive patients. This represents the largest series of patients closely followed after robotic extended PLA that we are aware of. As we continue to perform extended PLA for those patients at higher risk, more will be learned about the natural course of removal of these nodes both in node-positive and nodenegative patients. Long-term follow-up is needed to be able to determine a survival advantage. 5.
Conclusions
Robotic extended PLA at the time of radical prostatectomy can be performed safely with nodal yields >20. The positive lymph node rate exceeds 13% for intermediateand high-risk patients and should be considered a useful staging mechanism. PSA, clinical stage, and maximum biopsy core volume are significant predictors for lymph node invasion.
Author contributions: Bertram E. Yuh 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: Yuh, T. Wilson. Acquisition of data: Yuh, T. Wilson, C. Wilson, Ruel, Mejia. Analysis and interpretation of data: Yuh, T. Wilson, Ruel. Drafting of the manuscript: Yuh, T. Wilson. Critical revision of the manuscript for important intellectual content: Yuh, T. Wilson, Ruel. Statistical analysis: Yuh, T. Wilson, Ruel. Obtaining funding: None. Administrative, technical, or material support: Yuh, T. Wilson, C. Wilson, Ruel, Mejia. Supervision: Yuh, T. Wilson, C. Wilson, Ruel, Mejia. Other (specify): None. Financial disclosures: I certify 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: Timothy Wilson is on speaker panels for Covidien. Funding/Support and role of the sponsor: None.
Appendix A. Supplementary data The Surgery in Motion video accompanying this article can be found in the online version at doi:10.1016/ j.eururo.2012.01.048 and via www.europeanurology.com.
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available at www.sciencedirect.com journal homepage: www.europeanurology.com
Surgery in Motion
Robotic Extended Pelvic Lymphadenectomy for Intermediate- and High-Risk Prostate Cancer Bertram E. Yuh *, Nora H. Ruel, Rosa Mejia, Chelsea M. Wilson, Timothy G. Wilson Urologic Oncology, City of Hope National Cancer Center, Duarte, CA, USA
Article info
Abstract
Article history: Accepted January 27, 2012 Published online ahead of print on February 22, 2012
Background: Accurate staging of prostate cancer is enhanced by a thorough evaluation of the pelvic lymph nodes. Limited data are available regarding robotic extended pelvic lymphadenectomy (PLA) in this setting. Objective: Analyze our experience performing robotic extended PLA. Design, setting, and participants: A total of 143 consecutive men with intermediate- or high-risk clinically localized adenocarcinoma of the prostate underwent robotic extended PLA and radical prostatectomy between September 2010 and November 2011 by a single surgeon. Surgical procedure: Lymph node packets were sent separately from bilateral common, external, and internal iliacs, obturators, node of Cloquet, and anterior prostatic fat. Measurements: Descriptive statistics were used to summarize lymph node yields and positive nodes. Clinical variables were examined in logistic regression models to predict lymph node positivity. Results and limitations: Median lymph node yield was 20 (range: 9–65, interquartile range: 15–25). Eighteen patients (13%) were found to have metastatic prostate cancer in the lymph nodes. The mean number of positive nodes found was 2.9 (range: 1–11). In 14 of 18 node-positive patients (78%), the extent of nodal invasion was outside the boundaries of a limited PLA. For four patients with positive nodes (22%), prostate biopsy predicted unilateral disease but PLA revealed contralateral positive lymph nodes. A total of 82% of patients experienced no complications, and most Clavien grade 1–2 complications consisted of anastomotic leakage, urinary retention, ileus, and lymphocele. Only 4% of patients experienced a grade 3 complication. Under multivariate regression analysis, prostatespecific antigen (PSA), clinical stage, and maximum biopsy core tumor volume were identified as significant predictors of finding positive pelvic lymph nodes (area under the curve: 91%). The main limitations include short follow-up and lack of randomization. Conclusions: Robotic extended bilateral PLA for prostate cancer up to the common iliac bifurcation increases nodal yield and positive nodal rate and can be performed safely. PSA, clinical stage, and maximum biopsy core volume are predictors for lymph node invasion. Long-term follow-up is needed to evaluate for therapeutic benefit. # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords: Pelvic lymphadenectomy Robotics Positive lymph nodes Prostate Cancer Please visit www.europeanurology.com and www.urosource.com to view the accompanying video.
* Corresponding author. City of Hope National Cancer Center, 1500 E Duarte Rd., Duarte, CA 90017, USA. Tel. +1 626 256 4673; Fax: +1 626 301 8285. E-mail address: [email protected] (B.E. Yuh).
1.
Introduction
The pelvic lymph node spread of prostate cancer often signifies aggressive or advanced disease. Although staging radiography with computed tomography (CT) or magnetic
resonance imaging (MRI) has improved resolution, pelvic lymphadenectomy (PLA) at the time of radical prostatectomy remains the most robust means of determining the presence of cancer in the lymph nodes [1]. For patient counseling and prognosis determination, staging through
0302-2838/$ – see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2012.01.048
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lymph node sampling at surgery is unique compared with other primary treatment options for prostate cancer. Accurate staging may affect risk stratification and decision making with regard to adjuvant therapy after surgery. Although staging PLA has been performed for decades, the extent and indications for dissection remain a topic of debate [2]. It is increasingly acknowledged that a limited PLA encompassing the obturator fossa does not generally improve survival. In low-risk patients, even the staging benefit of PLA is limited because malignant involvement is uncommon. For patients with more aggressive cancer, a pelvic PLA should be performed and in extended fashion. Minimally invasive PLA can produce similar lymph node yields compared with open PLA. Truesdale et al. found no significant difference in lymph node yields for intermediate- and high-risk men with PLA performed open compared with robotically [3], although overall nodal yields were low in both groups. Extended PLA has been performed by both laparoscopic [4–6] and robotic means [7,8] with increased nodal yields and detection of lymph node invasion compared with limited or standard PLA. With robotic technology, fine dissection and threedimensional magnification can assist with an anatomic PLA. A thorough understanding of the anatomic pelvic lymph node drainage basins and preferential dissection of these areas allows for efficient extended PLA with minimal morbidity. We describe our dissection technique and the experience of consecutive patients undergoing robotassisted extended pelvic lymphadenectomy at the time of robotic radical prostatectomy. 2.
Patients and methods
Between September 2010 and November 2011, 143 consecutive patients with intermediate- or high-risk clinically localized adenocarcinoma of the prostate underwent robot-assisted extended PLA in conjunction with radical prostatectomy by a single surgeon. Patients gave their consent to be entered into the City of Hope prostate cancer database and were prospectively enrolled in our study that was approved by the institutional review board. Patients were selected based on D’Amico risk criteria, specifically those with a prostate-specific antigen (PSA) >10, Gleason score 7, or clinical stage T2b. Patients with neoadjuvant hormonal therapy were excluded. Patients had staging bone scans as well as CT scans or T3 MRI of the abdomen and pelvis documenting no evidence of metastatic spread. Database records were reviewed for demographic data, biopsy data, pathology, and operative data. Complications were recorded for the entire length of follow-up and classified using a modified Clavien system.
2.1.
Surgical technique
Extended PLA was performed through a six-port transperitoneal approach using the four-arm da Vinci (Sunnyvale, CA, USA) robotic surgical system. For all patients, PLA was carried out prior to division of the bladder neck or urethra. Robotic port placements were not altered and were fanned out at a 21-cm distance from the pubic symphysis. A right iliac assistant port was typically a 15-mm port to assist with lymph node retrieval. An initial peritoneal opening was carefully carried out over the perceived area of the common iliac bifurcation, and the fourth arm was used for retraction.
The ureters were identified bilaterally and guided the identification of the common iliac bifurcation. The nodal tissue around the bifurcation was dissected free. When possible, the proximal extents of dissection were controlled with Weck clips and divided. The external iliac artery was skeletonized from its origin down to the circumflex iliac vessels with dissection limited to the lateral edge of the artery. The obliterated umbilical artery was reflected away from the iliac vessels, and the lymphatic tissue medially was sent with the internal iliac specimen. Lymphofatty tissue surrounding the internal iliacs and branches was similarly removed. Nodal tissue around the internal iliac often coalesced with the obturator packet. The node of Cloquet distally and surrounding tissue was dissected and sent separately; the obturator packet was removed last. After developing the space of Retzius, we would also send the anterior prostate lymphofatty tissue as previously described [9]. The limits of dissection were thus the common iliac bifurcation proximally, the node of Cloquet distally, the lateral edge of the external iliac artery laterally, and the lateral border of the obliterated umbilical artery medially. Separate packets were sent from the bilateral common iliacs, external iliacs, internal iliacs, node of Cloquet, and from the anterior prostatic fat pad for a total of 11 packets per patient. Specimens were individually retrieved and removed through an assistant port and sent for pathologic analysis in individual containers. EndoCatch bags were not routinely used for lymph node extraction because the 15-mm assistant port would typically permit packet passage. All prostatectomy specimens and corresponding pelvic lymph nodes were submitted routinely for processing and examination in the pathology department after surgery. All possible nodal tissue was processed fresh, fixed in formalin, and embedded into paraffin tissue blocks and then
Table 1 – Patient demographics Age, yr Mean (median) IQR Body mass index Mean (median) IQR Preoperative PSA Mean (median) IQR Biopsy Gleason sum, n (%) 6 7 8 9 Clinical stage, n (%) T1 T2 T3 Operative time, h Mean (median) IQR Estimated blood loss, ml Mean (median) IQR Pathologic stage, n (%) pT2a/pT2b pT2c pT3 Pathologic Gleason sum, n (%) 6 7 8 9 Hospital length of stay, d Mean (median) IQR IQR = interquartile range; PSA = prostate-specific antigen.
63.7 (64) 59–69 28.3 (27) 25.1–30.6 7.8 (5.6) 4.2–8.3 6 115 18 4
(4.2) (80.4) (12.6) (2.8)
101 (70.6) 41 (28.7) 1 (0.7) 3.1 (3) 2.9–3.2 220 (200) 150–250 21 (14.7) 83 (58.0) 39 (27.3) 7 120 6 7
(4.9) (83.9) (4.2) (4.9)
1.8 (1) 1–2
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subject to standard pathologic assessment for lymph nodes. No clearing of adipose tissue or special detection methods were used. A postoperative Jackson-Pratt drain was left in the pelvis and removed when output was <100 ml/24 h. The last 50 patients did not undergo drain placement if bladder neck reconstruction was not performed and anastomosis was watertight (41 with no drain). Data analysis was performed using a standard statistical package (SAS). Data were summarized using descriptive statistics. Univariate and multivariate logistic regression analysis was used to test the association of clinical parameters (eg, PSA, stage, Gleason score, biopsy cores positive, percentage biopsy core involved) with pelvic lymph node invasion status. The natural log of the PSA was used because of a skewed distribution. Predictive accuracy was tested using the area under the receiver operating characteristics curve.
3.
Results
Table 1 lists patient demographics. Median preoperative PSA was 5.6 ng/ml (range: 0.1–48.1). A total of 114 were classified as intermediate-risk patients (80%); 29 were highrisk patients (20%). The median number of biopsy cores taken at prostate biopsy was 12 (range: 6–23). The percentage of positive cores was recorded as the number of positive cores divided by the total number of cores taken. Median percentage of positive cores was 26% (range: 5–100%). Median maximum cancer involvement of a single core was 32% (range: 1–100%). The median lymph node yield was 20 (range: 9–65; [(Fig._1)TD$IG]interquartile range: 15–25). Eighteen patients (13%) were
found to have metastatic prostate cancer involving the lymph nodes. Figure 1 shows the distribution of lymph node yields, and Figure 2 shows the nodal yield and incidence of positive nodes by anatomic site. Nodal yield increased over time chronologically from the first 47 cases to the second and third, with 17, 21, and 24 nodes removed, respectively. Operative time for bilateral extended PLA was between 30 and 45 min. Median blood loss was 200 ml (range: 5–800 ml), and no patients were transfused. Average length of follow-up was 7 mo. Final pathologic stages were pT2 in 105 patients (73%), pT3a in 23 patients (16%), and pT3b in 15 patients (10%). A total of 27 patients were found to have a positive surgical margin (19%). Positive margins for pT2 carcinomas were found in 17 of 105 patients (16%) and 10 of 38 patients (26%) with pT3 carcinomas. A total of 52 positive lymph nodes were found with 24 positive in the obturator lymph nodes (46%). When positive, between 1 and 11 positive nodes were found (mean: 2.9). For patients with positive lymph nodes, 4 (22%) were pT2 patients and 14 (78%) were pT3 patients. Eight patients (7%) were in the D’Amico intermediate-risk group, and 10 patients (33%) were in the high-risk group. Several patients had positive lymph nodes in more proximal nodes without obturator involvement. Four patients had positive lymph nodes only in the obturator fossa, six were both inside and outside the obturator fossa, and eight were exclusively outside the obturator fossa. Thus in 14 of 18 patients (78%), some positive nodes were outside the
Fig. 1 – Distribution of lymph node yields.
[(Fig._2)TD$IG]
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Fig. 2 – Lymph node yield and incidence of positive nodes by anatomic site.
confines of the obturator fossa and would have been underestimated had only a limited PLA been performed. Four patients with positive nodes (22%) had a unilateral preoperative prostate biopsy and contralateral nodes positive for cancer. In these four patients, preoperative T3 MRI showed only unilateral prostate involvement without lymphadenopathy. One patient had a previous negative prostate biopsy; the others had no prior biopsies. On final pathology, all four had bilateral pT3 disease. In regard to morbidity, 117 patients (82%) had no postoperative complications. Thirty-one total complications were recorded for the patient population with 24 (77%) Clavien grade 1 or 2 (Table 2). Only six patients (4%) had a grade 3 complication including deep vein thrombosis (DVT), pulmonary embolus, ileus, lymphocele, and ureteral injury. The most common complications were prolonged urinary anastomotic leak (4%), urinary retention (3%), ileus (3%), and lymphocele (3%). Routine pelvic imaging postoperatively was not performed, and therefore the incidence of asymptomatic lymphocele was likely higher. In univariate logistic regression analysis, PSA, primary Gleason score, clinical stage T2, and maximum percentage of a single biopsy core >40% were significant in predicting
the incidence of men with positive lymph nodes (all p < 0.05) (Table 3). In multivariate analysis, PSA, cT2, and maximal cancer biopsy volume remained independently predictive for malignancy with an area under the curve of 91% (Fig. 3). The percentage of positive biopsy cores,
Table 2 – List of all complications seen Clavien grade
Anastomotic leakage Urinary retention Ileus Lymphocele Incisional bruising Scrotal swelling Pulmonary embolus Deep vein thrombosis Ureteral injury Bladder spasms Fever Groin numbness Total
1 or 2
3
6 5 2 2 3 3 0 0 0 1 1 1 24
0 0 2 2 0 0 1 1 1 0 0 0 7
Total (%) 6 5 4 4 3 3 1 1 1 1 1 1 31
(4) (3) (3) (3) (2) (2) (<1) (<1) (<1) (<1) (<1) (<1)
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Table 3 – Logistic regression models predicting lymph node positivity Parameter
Univariate model Point estimate
PSA Primary Gleason Secondary Gleason Highest biopsy 40% Percentage of positive cores Clinical stage T2 (vs T1) Area under the curve
6.589 5.137 0.564 13.735 1.338 3.633 –
Confidence interval 2.768 1.717 0.202 3.022 0.399 1.32 –
15.688 15.372 1.575 62.427 4.482 10.002 –
Multivariate model p value
Point estimate
<0.0001 0.0034 0.2742 0.0007 0.6368 0.0125 –
6.129 – – 8.257 – 5.243 91%
Confidence interval 2.232 – – 1.59 – 1.446 –
16.105 – – 42.88 – 19.01 –
p value 0.0002 – – 0.0120 – 0.0117 –
PSA = prostate-specific antigen.
[(Fig._3)TD$IG]
Fig. 3 – Logistic regression model predicting lymph node positivity. Bx = biopsy; PSA = prostate-specific antigen; ROC = receiver operating characteristic.
primary and secondary Gleason, and Gleason sum did not achieve significance with a multivariate analysis. 4.
Discussion
Pathologic assessments such as Gleason score, pathologic stage, margin status, and percentage of prostate involved by tumor confer survival information and are readily obtainable through surgical pathologic reporting. Similarly, cancer involvement of the pelvic lymph nodes also negatively affects survival. To define this accurately, however, a systematic and thorough evaluation is required. Detection of lymph node positivity depends on tumor characteristics [10] as well as the extent of dissection. Traditional nomograms for predicting pelvic lymph node involvement at radical prostatectomy have been generated in the setting of limited PLA that for staging appears
suboptimal. To date, an ideal anatomic PLA template has not been widely validated. PLA is regrettably being performed less commonly in minimally invasive radical prostatectomy, and the extent of dissection when performed is likely inadequate [11]. The oncologic potential for extended PLA is prognostic and possibly even a therapeutic benefit [2]. In an updated nomogram, Briganti et al. found that the percentage of positive cores, clinical stage, and primary Gleason grade were independent predictors of lymph node invasion [12]. Because their patient population consisted of prostate cancer patients from all risk groups, the nodepositive rate was only 8.3%. In the present study, we examined a higher risk group because we believed patients with positive nodes would most benefit from an extended PLA. Our analysis did not show that the percentage of positive cores predicted lymph node invasion. Notably in comparison, the overall average of percentage of positive cores was much lower (26% vs 44%), which may be a result of sampling differences. Drainage basins in prostate cancer can be notoriously variable and even involve the retroperitoneum [13]. A limited PLA involving only the obturator fossa risks significant underevaluation of possible lymph node drainage sites. Some studies have shown internal iliac lymph nodes to be involved 58% of the time [14]. Functional studies with technetium-labeled indocyanine green and fluorescence studies may offer adjunctive means to improve lymph node removal in the future [15]. Although the staging significance of PLA is widely acknowledged, a possible therapeutic benefit may exist as well. Allaf et al. found that extended PLA increased nodal positive detection rate and provided a benefit in biochemical recurrence-free survival [16]. Schiavina et al. noted that patients with >10 lymph nodes removed had a significantly lower biochemical recurrence [17]. Finally, Joslyn and Konety noted similarly that an increased number of nodes removed lowered the risk of cancerspecific death [18]. Lymph node yield and lymph node positive rates increase with more extensive dissection. Briganti et al. found that node positivity rate increased with the number of nodes removed [19]. The mean number of nodes removed was 15 with a 10.3% positive rate. Klevecka et al. found a lymph node positive rate of 6.3% for limited
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PLA and 14.7% for extended PLA [20]. Although dissection targeting anatomic drainage basins is likely more important than a strict number of removed nodes, previous literature has suggested 20 lymph nodes as a guideline for a sufficient PLA [21]. The thoroughness depends not only on the extent of dissection but on surgical performance and experience as well. Higher volume surgeons have been shown to have higher node-positive rates when controlling for disease characteristics [22]. In our series, increased nodal yield over time may be reflective of the learning curve either in surgical or lymph node analysis technique. Nine patients with positive nodes were noted in the first 72 patients and 9 in the final 71 patients, demonstrating no significant difference with experience. The mean number of nodes removed among nodenegative and node-positive patients was 21.2 and 21.1, respectively. Several authors have reported similar results performing laparoscopic extended PLA. Wyler et al. examined 123 men with high-risk prostate cancer with a mean lymph node count of 21 and a 17% node positivity rate [4]. Lattouf et al. found an even higher lymph node positive rate (31%), although the average PSA was 20 in their series [5]. A total of 15% of patients had metastases exclusively outside the obturator fossa, comparable with our findings. Two smaller studies looked at the performance of robotic extended PLA with nodal counts averaging 18–19 with node-positive rates of 12–16% [7,8]. Our nodal yield of 21 and nodepositive rates of 13% are comparable with a larger number of patients. Under multivariate analysis, PSA, palpable disease, and maximum single-core percentage were independent predictors of node positivity. Using only these three covariates, we were able to obtain an AUC of 91%. Notably, primary or secondary Gleason grade as well as Gleason sum was not predictive at multivariate analysis. Possibly by selecting only intermediate- and high-risk patients, we increased the homogeneity of Gleason scores. In addition, Gleason grading at biopsy is often over- or undergraded with undergrading sometimes >40% [23]. In regard to patient safety, the benefits of improved staging and possibly in survival need to be balanced against the technical complications associated with performing an extended PLA. Although some comparison studies have shown no increased complication rate [22], Briganti et al. found a complication rate of 20% with extended PLA compared with 8% in a more limited dissection because of a higher postoperative lymphocele rate [24]. Lindberg et al. noted higher rates of lymphocele, pulmonary embolus, and DVT in an extended PLA group [25]. Clark et al. also noted a trend toward increased complication rates, although this was not statistically significant [26]. In our series, complication rates and severity according to a standardized system were comparable. Only 4% of patients experienced a Clavien grade 3 complication. Conceivably, ileus, lymphocele, scrotal swelling, DVT, and groin numbness could be related to extended PLA. The most common complications of urinary retention and anastomotic leakage were not believed to be related to the extent of dissection.
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Limitations of this study include relatively small population size, short follow-up, and lack of randomization. Longitudinally, we sought to reduce bias by studying only a single-surgeon experience of consecutive patients. This represents the largest series of patients closely followed after robotic extended PLA that we are aware of. As we continue to perform extended PLA for those patients at higher risk, more will be learned about the natural course of removal of these nodes both in node-positive and nodenegative patients. Long-term follow-up is needed to be able to determine a survival advantage. 5.
Conclusions
Robotic extended PLA at the time of radical prostatectomy can be performed safely with nodal yields >20. The positive lymph node rate exceeds 13% for intermediateand high-risk patients and should be considered a useful staging mechanism. PSA, clinical stage, and maximum biopsy core volume are significant predictors for lymph node invasion.
Author contributions: Bertram E. Yuh 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: Yuh, T. Wilson. Acquisition of data: Yuh, T. Wilson, C. Wilson, Ruel, Mejia. Analysis and interpretation of data: Yuh, T. Wilson, Ruel. Drafting of the manuscript: Yuh, T. Wilson. Critical revision of the manuscript for important intellectual content: Yuh, T. Wilson, Ruel. Statistical analysis: Yuh, T. Wilson, Ruel. Obtaining funding: None. Administrative, technical, or material support: Yuh, T. Wilson, C. Wilson, Ruel, Mejia. Supervision: Yuh, T. Wilson, C. Wilson, Ruel, Mejia. Other (specify): None. Financial disclosures: I certify 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: Timothy Wilson is on speaker panels for Covidien. Funding/Support and role of the sponsor: None.
Appendix A. Supplementary data The Surgery in Motion video accompanying this article can be found in the online version at doi:10.1016/ j.eururo.2012.01.048 and via www.europeanurology.com.
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