Super Extended Versus Extended Pelvic Lymph Node Dissection in ...

Super Extended Versus Extended Pelvic Lymph Node Dissection in Patients Undergoing Radical Cystectomy for Bladder Cancer: A Comparative Study Pascal Zehnder,* Urs E. Studer, Eila C. Skinner, Ryan P. Dorin, Jie Cai, Beat Roth, Gus Miranda, Frédéric Birkhäuser, John Stein,† Fiona C. Burkhard, Sia Daneshmand,‡ George N. Thalmann, Inderbir S. Gill and Donald G. Skinner From the University of Southern California Institute of Urology, Catherine and Joseph Aresty Department of Urology, Keck School of Medicine, University of Southern California (PZ, ECS, RPD, JC, GM, JS, SD, ISG, DGS), Los Angeles, California, and Department of Urology, University of Bern (PZ, UES, BR, FB, FCB, GNT), Bern, Switzerland

Purpose: There is evidence from retrospective studies that radical cystectomy with extended pelvic lymph node dissection provides better staging and outcomes than limited lymph node dissection. However, the optimal limits of extended lymph node dissection remain unclear. We compared oncological outcomes at 2 cystectomy centers where 2 different extended lymph node dissection templates are practiced to determine whether removing lymphatic tissue up to the inferior mesenteric artery confers an additional survival advantage. Materials and Methods: Patients undergoing radical cystectomy and extended lymph node dissection with curative intent from 1985 to 2005 were included in analysis if they met certain criteria, including clinically organ confined urothelial bladder carcinoma (cN0M0), pathological stage pT2-pT3, negative surgical margins and no neoadjuvant therapy. Survival and recurrence data were analyzed. Results: Demographic data and pathological subgroup distribution (pT2 and pT3) were similar in the 554 University of Southern California and 405 University of Bern patients. University of Southern California patients had higher median number of lymph nodes removed than University of Bern patients (38 vs 22, p ⬍0.0001) and a higher incidence of lymph node metastasis (35% vs 28%, p ⫽ 0.02). However, the University of Southern California and University of Bern groups had similar 5-year recurrence-free survival for pT2pN0-2 (57% vs 67%) and pT3pN0-2 (32% vs 34%) disease (p ⫽ 0.55 and 0.44, respectively). The overall recurrence rate was equal at the 2 institutions (38%). Conclusions: Meticulous extended lymph node dissection up to the mid-upper third of the common iliac vessels appears to provide survival and recurrence outcomes similar to those of a super extended template up to the inferior mesenteric artery. Complete skeletonization in the extended lymph node dissection template is more important than nodal yield. This does not exclude the possibility that certain patient subgroups with suspicious nodes or after neoadjuvant chemotherapy may benefit from more extensive lymph node dissection.

Abbreviations and Acronyms IMA ⫽ inferior mesenteric artery LN ⫽ lymph node LND ⫽ LN dissection OS ⫽ overall survival RC ⫽ radical cystectomy RFS ⫽ recurrence-free survival UB ⫽ University of Bern USC ⫽ University of Southern California Submitted for publication February 17, 2011. Study received institutional review board approval. Supplementary material for this article can be obtained at http://www.insel.ch/fileadmin/urologie/ urologie_users/Supplementary_tables_1_2_03_ 29_2011.pdf. * Correspondence: Department of Urology, University Hospital of Bern, Inselspital, 3010 Bern, Switzerland (telephone: ⫹41 31 632 3641; FAX: ⫹41 31 632 2180; e-mail: pascal.zehnder@ insel.ch). † Deceased April 11, 2008. ‡ Financial interest and/or other relationship with Endo Pharmaceutical.

For another article on a related topic see page 1481.

Key Words: urinary bladder; urinary bladder neoplasms; cystectomy; lymph node excision; mesenteric artery, inferior RADICAL cystectomy with LND is the treatment cornerstone for invasive bladder cancer. In 1982 the value of

meticulous LND was first addressed1 and there is evidence from retrospective studies that extensive LND al-

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Vol. 186, 1261-1268, October 2011 Printed in U.S.A. DOI:10.1016/j.juro.2011.06.004

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SUPER EXTENDED VERSUS EXTENDED PELVIC LYMPH NODE DISSECTION

lows more accurate staging and better outcomes.2–5 However, the proximal boundaries of the LND template remain undefined.6 Our analysis focused on patients with pT2-3 cN0M0 bladder cancer, who are most likely to have nodal involvement or harbor undetected nodal micrometastasis. The aim was to better define LND extent by comparing outcomes at 2 high volume institutions where meticulous extended LND is consistently performed but each with a different proximal boundary.

PATIENTS AND METHODS Patient Selection This study consists of data collected from the participating sites, which provided the necessary institutional data agreements on data use. USC and UB maintain independent, institutionally approved bladder cancer databases that have prospectively accrued data on more than 4,100 patients who underwent cystectomy. All patients who underwent RC and LND with curative intent for pT2-3 cN0M0 urothelial carcinoma of the bladder were eligible for study inclusion. Patients who received neoadjuvant chemotherapy/radiation and those with positive soft tissue margins were excluded from analysis. The observation period comprised 1985 to 2005. A total of 554 USC and 405 UB patients met these inclusion criteria. Patients with pT1 disease were omitted from analysis due to an inhomogeneous treatment strategy and the low incidence of LN metastasis. Patients with pT4 tumors were excluded since survival differences at such advanced disease stages are rather unlikely to be related to LND extent.

LND Templates The pure intrapelvic template is almost identical at the 2 institutions. The boundaries of dissection were the genitofemoral nerve and the pelvic side wall laterally, the circumflex iliac vein and Cloquet’s node distally, the obturator fossa with full exposure of the intrapelvic course of the obturator nerve (Marcille’s triangle) and the internal

iliac vessels posteriorly, and the tissue medial to these vessels. At USC the template also included removal of lymphatic tissue along the common iliac vessels, the distal vena cava/aorta to the IMA takeoff and complete dissection of the presacral space from the bifurcation of the aorta into the sacral fossa (fig. 1, A). At UB the template ended proximally at the mid-upper third of the common iliac vessels. It included the presacral region medial to the internal iliac vessels but left tissue containing the hypogastric nerves located medial to the retracted ureters and inferior to the aortic bifurcation (fig. 1, B).

Pathological Analysis LNs were sent in 13 (USC) or 6 (UB) anatomically defined packages. Pathologists identified LNs visually and by palpation without clearing techniques/special stains at USC. At UB tissue has been degreased with acetone since 1990. Pathological staging was done according to the 1997 American Joint Committee on Cancer TNM classification.

Followup and Clinical Outcomes At USC patients were seen at 4-month intervals in year 1, 6-month intervals in year 2 and annually thereafter. At UB patients were examined at 3, 6 and 12 months in year 1, every 6 months for 5 years and annually thereafter. Primary outcomes were RFS and OS. Pelvic soft tissue density 2 cm or greater inferior to the aortic bifurcation was defined as local recurrence and all other sites were captured as systemic recurrence.

Statistical Analysis Statistical analyses were performed with SAS®, version 9.2. Pearson’s chi-square or Fisher’s exact test was used to examine the association between categorical demographic and clinical variables. The Wilcoxon rank sum test was used to assess differences in not normally distributed continuous variables and Kaplan-Meier plots were used to estimate survival probabilities. The log rank test was used to compare differences in survival or recurrence in subgroups. The Cox proportional hazard model was applied to evaluate independent prognostic factors. All p values are 2-sided with p ⬍0.05 considered statistically significant.

Figure 1. LND templates. A, USC. B. UB LND is done up to level between mid and upper third of common iliac vessels (yellow arrow).


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Table 1. Patient characteristics and pathological findings USC No. gender (%): M F Age: Median (range) No. less than 65 (%) No. 65 or greater (%) No. pathological subgroup (%): pT2 pT3 No. high grade G3 disease (%) No. LN pos (%): pT2 pT3 Median No. lymph nodes removed (range): Totals Pos No. adjuvant chemotherapy (%): Neg LN Pos LN No. urinary diversions (%): Orthotopic continent, continent cutaneous Incontinent ileal conduit Median followup (range) Median OS (range) RFS*

UB

p Value 0.58

421 133

(76) (24)

314 91

(78) (22)

67 227 327

(31–91) (41) (59)

67 159 246

(36–89) (39) (61)

253 301 534 195 57 138

(46) (54) (96) (35) (23) (46)

169 236 390 114 26 88

(42) (58) (96) (28) (15) (37)

38 0 195 74 121

(10–179) (0–97) (35) (21) (62)

22 0 46 0 46

(10–60) (0–16) (11)

0.59

0.22

0.94 0.02 0.07 0.05 ⬍0.0001 0.02 ⬍0.001

(40) 0.004

406 (73) 148 (27) 10.9 Yrs (0 day–24.1 yrs) 5 Yrs (0 days–24.1 yrs) 0 Day–24.1 Yrs

206 (65) 143 (35) 9.9 Yrs (0 day–22.3 yrs) 5.8 Yrs (0 days–22.3 yrs) 0 Day–22.3 yrs

0.06 0.45 0.75

* Median could not be calculated since 50% or more of patients had no recurrence.

RESULTS Patient Characteristics In each cohort median patient age at surgery was 67 years. A higher proportion of USC patients received adjuvant chemotherapy (p ⬍0.001). USC patients had a rather longer median followup (p ⫽ 0.06, table 1). Pathological Findings The 2 groups had similar pathological stage and grade distribution (p ⫽ 0.22 and 0.94, respectively). The median number of total and positive LNs removed per patient was higher at USC (p ⬍0.0001

and 0.02, respectively). Overall (pT2-3) 35% of USC and 28% of UB patients unexpectedly had LN metastasis (p ⫽ 0.02). When evaluated separately, this difference persisted in patients with pT3 but not pT2 disease (p ⫽ 0.05 and 0.07, respectively, table 1). RFS and OS Data RFS and OS in the 2 groups were notably similar (p ⫽ 0.75 and 0.45, respectively, fig. 2). Stratification by pathological tumor stage regardless of nodal status did not result in any interinstitutional differences (fig. 3). When stratified by LN status, the similarities persisted with a 5-year RFS and OS in

Figure 2. RFS and OS for pT2-3 pN0-2 disease

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Figure 3. RFS according to pT stage 2 or 3 disease

LN negative cases of 71% and 59% at USC vs 69% and 60% at UB, respectively. Similarly in LN positive cases 5-year RFS and OS were 40% and 34% at USC, and 42% and 38% at UB, respectively (figs. 4 to 6). Multivariate analysis was performed, including institution (UB vs USC), age (greater than 65 vs 65 years or less), pathological subgroup (pT3 vs pT2), LN status (positive vs negative), number of positive LNs (8 or greater vs fewer than 8) and adjuvant chemotherapy (with vs without). Pathological subgroup, LN status and number of positive LNs were independent risk factors for RFS and OS while institution, age and adjuvant chemotherapy predicted only OS. Recurrence Rates The overall recurrence rate was 38% at USC and UB (210 of 554 and 154 of 405 patients, respectively). At

USC 5 of 253 patients (2%) with pT2 and 20 of 301 (7%) with pT3 had local recurrence vs 2 of 169 (1%) with pT2 and 16 of 236 (7%) with pT3 at UB. Distant recurrence was diagnosed in 59 of 253 patients (23%) with pT2 and 126 of 301 (42%) with pT3 at USC vs 40 of 169 (24%) and 96 of 236 (41%) at UB, respectively. Stratification by pathological subgroup alone or combined with LN status did not reveal any difference in recurrence number or pattern (table 2).

DISCUSSION Retrospective studies indicate that RC with extended LND at least up to the mid-upper third of the common iliac vessels achieves a better survival rate than RC with limited LND predominantly in the obturator fossa.3–5,7 One of the more illustrative investigations of the benefits of extending LND boundaries was the interinstitutional comparison by Dhar

Figure 4. RFS by LN status


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Figure 5. RFS in patients with organ confined pT2 disease by LN status

et al.3 There was a 2-fold increase in the rate of LN positive disease in the extended LND group, suggesting significant under staging in patients undergoing limited LND. Regardless of LN status patients with pT3 pN0-2 disease had a better 5-year RFS rate after extended than after limited LND (49% vs 19%, p ⬍0.0001). Improved identification of LN positive cases by extended LND was noted in another large series.8 More extensive LND has also improved survival and recurrence rates in patients with pathologically negative LNs.5,7,9,10 This may result from removing occult microscopic metastasis that is undetected on conventional histological analysis, which may miss 20% to 30% of positive LNs detected on reverse transcriptase-polymerase chain reaction assays.11 Applying an extended LND template increases the number of LNs removed,7 and improves staging accuracy and survival. LND also consecutively facilitates RC by fewer positive margins and better vascular control.8,12 However, the optimal LND boundaries are unknown, especially in regard to the cephalad extent. Similar to the limited vs extended LND comparison, we examined whether an addi-

tional survival advantage could be achieved by expanding the template to the IMA takeoff. The rationale for this super extended template is based on mapping studies showing that, although most of the primary echelon of lymphatic drainage involves areas caudal to the common iliac bifurcation,13 up to approximately 25% of patients with LN metastasis have positive LNs surrounding the common iliac vessels and overlying the sacral promontory14 while up to 28% with positive LNs have metastasis in the paracaval/para-aortic regions.15 The problem in these mapping studies was that the area to which a retrieved node was assigned depended on surgeon discretion. Furthermore, it was known where LNs were found but not where they were missed. More reliable information on the localization and distribution of the primary lymphatic landing sites of the bladder was prospectively obtained using technetium isotopes.13 According to that study 8% to 10% of the primary lymphatic landing sites of the bladder are cephalad to the mid-upper third of the common iliac vessels. The other difference in the USC and UB templates concerns presacral dissection. At USC all tis-

Figure 6. RFS in patients with extravesical pT3 disease by LN status

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Table 2. Local and distant RFS % ⫾ SE USC 5 Yrs

% ⫾ SE UB

10 Yrs

5 Yrs

10 Yrs

p Value

Local pT2: pN0 pN0-2 pT3: pN0 pN0-2 pT2-3: pN0 pN0-2 pT2: pN0 pN0-2 pT3: pN0 pN0-2 pT2-3: pN0 pN0-2

96 ⫾ 2 96 ⫾ 1

95 ⫾ 2 95 ⫾ 2

97 ⫾ 2 97 ⫾ 2

97 ⫾ 2 97 ⫾ 2

0.53 0.57

89 ⫾ 3 88 ⫾ 2

89 ⫾ 3 88 ⫾ 2

92 ⫾ 3 90 ⫾ 2

92 ⫾ 3 90 ⫾ 2

0.49 0.99

93 ⫾ 2 92 ⫾ 1

92 ⫾ 2 92 ⫾ 1

95 ⫾ 2 93 ⫾ 1 Distant

95 ⫾ 2 93 ⫾ 1

0.41 0.83

83 ⫾ 3 78 ⫾ 3

82 ⫾ 3 76 ⫾ 3

80 ⫾ 4 79 ⫾ 3

77 ⫾ 4 78 ⫾ 2

0.32 0.91

66 ⫾ 4 53 ⫾ 3

65 ⫾ 4 52 ⫾ 2

66 ⫾ 4 56 ⫾ 4

65 ⫾ 4 53 ⫾ 4

0.56 0.81

76 ⫾ 3 65 ⫾ 2

74 ⫾ 3 63 ⫾ 2

73 ⫾ 3 66 ⫾ 3

71 ⫾ 3 63 ⫾ 3

0.19 0.66

sue overlying the common iliac vessels, sacral promontory and sacral fossa is removed. At UB presacral dissection does not include the region directly overlying the sacral promontory but it requires removing lymphatic tissue lateral to the promontory and medial to the internal iliac vessels (fig. 1). The rationale for this modification is the preservation of autonomic nerves that may have a role in sexual and pelvic floor function postoperatively.16 Our study showed no improvement in the recurrence or survival rate in patients in whom LND was extended cephalad to the mid-upper third of the common iliac vessels. This result was consistent regardless of pathological tumor stage, nodal status or the receipt of adjuvant chemotherapy. The reason may be related to the low incidence of metastasis at these regions in patients with few positive LNs, who are most likely to benefit from surgery alone.17 Alternatively the added benefit of super extended LND in patients with metastasis at these regions may be too small compared with the effect of adjuvant chemotherapy.18 Several other patho-anatomical mapping studies showed that skip lesions or nodes above the common iliac artery are rare events19 –21 and may be the result of missed positive LNs in the true pelvis or specimen mislabeling.22 Thus, extended dissection to the mid-upper third of the common iliac vessels should correctly stage almost all cases. Furthermore, a recent report from USC demonstrated that all patients with positive nodes above the external/internal iliac bifurcation and no adjuvant chemotherapy died despite super extended LND, raising concern whether the extra operative time and operative risk, and possible damage to

autonomic nerves are justified in all patients who undergo RC.18 As noted by Skinner et al,23 strict application of a meticulous dissection technique with complete skeletonization of pelvic structures within the template is likely to result in the most effective removal of metastatic LNs. Of particular importance is dissection around the internal iliac vessels. This was corroborated by the technetium based LN mapping study by Roth et al, which showed that 26% of the primary lymphatic landing sites of the bladder were in the internal iliac region, of which 42% were medial to the artery.13 Despite equivalent oncological outcomes there were some significant interinstitutional differences. At USC the median number of LNs removed per patient was higher than at UB (38 vs 22, p ⬍0.0001). This was likely a result of not only the expanded template at USC but also different LN packaging and pathological processing.24,25 Since 1991, LNs have been submitted in 6 anatomical packets at UB and since 2002, LNs have been submitted in 13 anatomical packets at USC. While this practice resulted in an increase in the median number of total LNs removed from 31 to 65 per patient at USC, the nodal yield at UB remained constant during the entire study period.26 This discrepancy serves to highlight the limitations of LN count as a surrogate for LND quality since complete removal of all fibroadipose tissue within the dissection boundaries is more important than attaining a particular minimum cutoff for the number of LNs removed. Furthermore, there are interindividual differences within the same template.26 There was a significant institutional difference in the number of patients who underwent adjuvant chemotherapy, which was done in 62% with positive LNs at USC and in 40% at UB. Also, 21% of LN negative cases at USC were treated but none at UB, reflecting significant variability in selection criteria. This could be expected to result in better survival rates in the USC cohort. Because this was apparently not the case, it may rather reflect the limited efficacy of systemic chemotherapy in patients with LN metastasis. This observation underscores the importance of thorough LND relative to chemotherapy in patients with rather few positive LNs. Adjuvant chemotherapy cannot compensate for less than meticulous pelvic LND. Followup multivariate analysis of patients in the Southwest Oncology Group 8710 trial27 showed a similar result, finding that the number of LNs removed was in fact a more important predictor of survival than neoadjuvant chemotherapy.28 There may be patients in whom extending LND up to the IMA takeoff may result in an improved oncological outcome, especially those who received neoadjuvant chemotherapy for suspicious LNs on


preoperative imaging, locally advanced tumors or clinically enlarged LNs at surgery. Significant longterm survival rates were reported in patients with grossly positive LNs29 or metastasis above the iliac bifurcation who were treated with surgery only,30 demonstrating that diligent surgical excision has a role in treatment for extensive metastatic disease. The current study did not include these patients. Although we report a relatively large comparative analysis, it is limited by the inherent shortcomings of any retrospective study. Surgery performed by multiple surgeons, differences in patient selection and referral patterns between institutions are but a few factors that may confound our results. A prospective, randomized trial, such as that proposed by Southwest Oncology Group, would enable this to be overcome. The awaited results of a German trial are likely to show better results with super extended than with conventional LND (obturator fossa, external and some internal iliac nodes but not Marcille’s triangle and common iliac nodes). However, it will not show what we found in this study, namely that

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extended LND up to the mid-upper third of the common iliac vessels is sufficient in most patients since it provides results comparable to those of super extended LND. We believe that the long followup, the large, consecutive patient series, and the consistency of surgical philosophy and technique at the 2 institutions make this study uniquely suited to address the question of the ideal LND template for bladder cancer.

CONCLUSIONS In patients with pT2-3 cN0M0 disease undergoing RC extended LND up to the mid-upper third of the common iliac vessels seems to provide local and systemic oncological control similar to that of a template extending to the IMA takeoff. It should be considered standard treatment in all patients undergoing RC. The number of LNs retrieved or the incidence of positive LNs may vary among institutions for the same template but provided that this is cleaned meticulously outcomes seem to be similar.

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metastases from urothelial carcinoma of the bladder is an independent prognostic factor. J Clin Oncol 2005; 23: 2358. 27. Grossman HB, Natale RB, Tangen CM et al: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003; 349: 859. 28. Herr HW, Faulkner JR, Grossman HB et al: Surgical factors influence bladder cancer outcomes: a cooperative group report. J Clin Oncol 2004; 22: 2781.

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