Systematic pelvic and aortic lymphadenectomy in intermediate and high-risk endometrial cancer: Lymph-node mapping and identification of predictive factors for lymph-node status

European Journal of Obstetrics & Gynecology and Reproductive Biology 149 (2010) 199–203

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Systematic pelvic and aortic lymphadenectomy in intermediate and high-risk endometrial cancer: Lymph-node mapping and identification of predictive factors for lymph-node status Christina Fotopoulou a,*, Konstantinos Savvatis b, Robert Kraetschell a, Joerg C. Schefold c, Werner Lichtenegger a, Jalid Sehouli a a

Department of Gynecology and Obstetrics, Charite´, Campus Virchow Clinic, University Hospital, Augustenburger Platz 1, 13353 Berlin, Germany Department of Cardiology and Pneumology, Charite´, Campus Benjamin Franklin, University Hospital, Berlin, Germany c Department of Nephrology and Intensive Care, Campus Virchow Clinic, Charite´ Medical University of Berlin, Germany b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 16 June 2009 Received in revised form 14 November 2009 Accepted 21 December 2009

Objective: To systematically assess the metastatic pattern of intermediate- and high-risk endometrial cancer in pelvic and para-aortic lymph-nodes and to evaluate risk factors for lymph-node metastases. Study Design: Between 01/2005 and 01/2009 62 consecutive patients with intermediate- and high-risk endometrial cancer who underwent a systematic surgical staging including pelvic and para-aortic lymphadenectomy were enrolled into this study. Patients’ characteristics, histological findings, lymphnode localization and involvement, surgical morbidity and relapse data were analyzed. Univariate analysis was performed to define risk factors for lymph-node metastasis. Results: Of the 13 patients (21%) with positive lymph-nodes (N1), 8 (61.5%) had both pelvic and paraaortic lymph-nodes affected, 2 (15.4%) only para-aortic and 3 (23%) only pelvic lymph-node metastases. Overall, 54% of the N1-patients had positive lymph-nodes above the inferior mesenteric artery (IMA) to the level of the renal veins. Univariate analysis revealed lymph vascular space invasion (p-value: <0.001), vascular-space-invasion (p-value: <0.001) and incomplete tumor resection (p-value: 0.008) as significant risk factors for N1-status. Overall and progression-free survival was not significantly different between N1- and N0-patients. Conclusions: Since the proportion of N1-endometrial cancer patients with positive para-aortic lymphnodes is, at 76%, considerably high, and more than half of them have affected lymph-nodes above the IMA-level, lymphadenectomy for endometrial cancer should be extended up to the renal veins, when indicated. The therapeutic impact of systematic lymphadenectomy on overall and progression-free survival has still to be evaluated in future prospective randomized studies. ß 2009 Elsevier Ireland Ltd. All rights reserved.

Keywords: Endometrial cancer Pelvic lymphadenectomy Para-aortic lymphadenectomy Inferior mesenteric artery Survival

1. Introduction Despite the unquestionable role of lymph-node metastasis in endometrial cancer (EC) there is a controversy and debate about the therapeutic relevance of systematic pelvic and para-aortic lymphadenectomy (PAL) [1]. The current recommendation of the American College of Obstetricians & Gynecologists [2] and the National Comprehensive Cancer Network [3] is to perform systematic lymphadenectomy rather than merely nodal sampling. However, in clinical practice a systematic PAL are not considered to be standard surgical procedures in most countries.

* Corresponding author. E-mail address: [email protected] (C. Fotopoulou). 0301-2115/$ – see front matter ß 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2009.12.021

Earlier protocols defined that a lymph-node sampling in the para-aortic region should be performed at least up to the insertion of the inferior mesenteric artery (IMA). However, recent sporadic reports revealed high rates of lymphatic metastasis above the IMA, indicating the need for systematic lymphadenectomy up to the renal vessels, equivalent to the dissection performed for epithelial ovarian cancer [4,5]. Still, optimal treatment for the management of EC, especially regarding the impact and extent of lymphadenectomy, remains controversial, particularly in patients with early- and intermediate-risk profile [6,7]. The objective of the present study was to systematically evaluate the pelvic and par-aortic lymphatic dissemination pattern of intermediate and high-risk EC, in terms of a lymph-node mapping. Furthermore we aimed to identify the predisposing factors for lymph-node metastases in patients who underwent PAL up to the level of the renal veins.

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2. Materials and methods

2.1. Statistical analysis

We analyzed the data of 62 consecutive patients who were operated in our clinic between 01/2005 and 01/2009 due to intermediate- or high-risk EC. Only patients who underwent a PAL up to the renal veins were included into the present analysis. All operations were performed by gynecologic oncologists. Standard procedures included midline laparotomy, peritoneal cytology, hysterectomy, bilateral adnectomy and systematic PAL up to the renal veins. The depth of tumor invasion, cervical extension and the tumor diameter were intraoperatively assessed via fresh frozen section of the removed uterus. The complete excision of the gonadal veins was left to the discretion of the treating surgeons. In cases of serous-papillary histology an infragastric omentectomy was additionally performed according to the International Federation of Gynecology & Obstetrics (FIGO) recommendations [8]. The criteria for performing lymphadenectomy were as follows: high tumor grade, deep myometrial invasion (>50%), cervical extension, primary tumor diameter >2 cm, non-endometrioid histologic type and FIGO-stage Ic. With documented macroscopic extrauterine disease, systematic lymphadenectomy was routinely performed when optimal cytoreduction was anticipated. Bilateral pelvic lymphadenectomy included complete skeletonization of the common, external and internal iliac vessels and the harvesting of all lymphatic tissue in the upper and lower parts of obturator fossa after visualization of the obturator nerve and lumbosacral trunk. The superior surgical margin of dissection for the pelvic nodes was where the ureters cross the common iliac arteries. The anterior distal surgical margin of the pelvic lymphadenectomy was the circumflex iliac vein. The para-aortic lymphadenectomy was performed by mobilizing the paracolic peritoneum along the lateral border of the ascending and descending colon, permitting identification of the proximal ureters and high division of the ovarian vessels. This allowed visualization of the whole retroperitoneum up to the superior borders of the renal veins. All lymphatic tissue was then harvested from the lateral, anterior, and medial aspects of the vena cava and aorta up to the renal veins. The submission of the para-aortic node-bearing tissue occurred separately according to the level of the IMA and the side of origin; tissue removed between the renal vein and the IMA (infrarenal) was identified separately from that removed between the IMA and the aortic bifurcation (inframesenterial). The lymphatic tissue of the aortic bifurcation was also harvested separately. The lymph-node-bearing tissue was submitted, according to the level of origin, into the following spaces:

All results are presented in raw numbers, rates, median and range or mean and standard deviation according to the underlying distribution. The analyses of time-to-event data in the case of recurrence and overall survival were calculated according the Kaplan–Meier method. For the calculation of recurrence-free and overall survival, the interval between day of surgery and date of tumor progression, death or last contact was analyzed. Univariate analysis was performed using the logistic regression procedure for dichotomous dependent variables. Prognostic factors were assessed for significance using Cox regression analysis. Binomial-exact 95% confidence intervals (CI) are also reported. All statistical analyses were performed by SPSS-15 (SPSS Inc. Chicago, IL). All reported significance was twotailed at a level of 0.05.

Pelvic lymph-nodes: left/right common iliac arteries, left/right external iliac arteries, left/right obturator fossa, left/right lateral pelvic wall, aortic bifurcation. Para-aortic lymph-nodes: inframesenterial, infrarenal/supramesenterial, interaortocaval and paracaval. With all surgeries performed and all pathologic findings interpreted in a single institution, the number of nodes removed from the pelvis and para-aortic basins was the surrogate for quality assessment of the extent and thoroughness of the lymphadenectomy. All relevant patients’ data including history, surgery data and histological report were abstracted from the patients’ records. Follow-up data were updated to the present time by a new contact with the patients or their physicians. Staging was defined in accordance with FIGO criteria for EC based on clinical data and the results of the histopathological report [8].

3. Results 3.1. Patient characteristics Overall 62 women with EC were analyzed. Mean patients’ age was 65.02  10.5 years (range: 39–86). The number of all patients with primary EC treated surgically in the same time period was 93, meaning that the patients who underwent PAL constituted 66.6% of all patients. Histology data, tumor stage, resection margins and lymph-node status are presented in detail in Table 1. Since in only a minority of the cases the tumor size was described in the operative protocol and the pathology report, we did not include the tumor size in the present evaluation. Patients with early FIGO stages received a vaginal cuff brachytherapy or merely close surveillance depending on their compliance, since there is no evidence that vaginal cuff brachytherapy has an impact on overall survival. Those patients with lymph-node metastases were treated with adjuvant combination chemotherapy with doxorubicin and cisplatin or paclitaxel and carboplatin or with abdominal percutaneous radiation. 3.2. Surgical outcome, morbidity and survival The mean operative time was 145  32.90 min (range: 95–330); the mean hospital stay was 10.08  6.66 days (range: 6–23). The morbidity was as follows: 15 (24%) retroperitoneal lymph cysts, 5 (8%) subileus/ileus, 1 (1.6%) peripheral neurologic impairment and 1 (1.6%) fatal thromboembolic event. Five patients (8%) underwent relaparotomy due to persistent lymph cyst or fistula and/or ileus within 3 months after surgery. Survival and follow-up data were estimated by the Kaplan– Meier survival curves. Since from the 62 patients only 8 died during the follow-up period of maximal 49 months, estimation by Kaplan–Meier survival curves is limited to the longest survival time of the censored patients. The median follow-up period was 14 months (range: 0.6–49 months). The median progression-free survival time (PFS) was 46 months (95% CI: 32.08–43.23 months). The median overall survival (OS) was 49 months (95% CI: 37.23–47.21 months). Nine patients (14.5%) experienced an EC-relapse. Eight out of nine relapses occurred within the 19 months after the time of primary diagnosis. The mean time to progression for these 9 patients was 13 months (range: 4–31 months), with a median of 11 months (95% CI: 6.9–19.0 months). The sites of metastases were as follows: 3 vaginal cuff and 5 distant metastases (2 pulmonary and ossary, 1 cutaneous and peritoneal and 2 hepatic).

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Table 1 Descriptive statistics of the 62 patients with primary high- or intermediate-risk endometrial cancer. All patients underwent complete surgical staging with pelvic and paraaortic lymphadenectomy (LVSI: lymph vascular space invasion. VSI: vascular space invasion). Patients [%] (total = 62)

Patients [%] (total = 62)

pT-stage 1a 1b 1c 2a 2b 3a 3b 4

6 14 15 7 11 5 1 3

Lymph-node-status N0 N1

49 [79] 13 [21]

R-status R0 R1

Grading 1 2 3

10 [16] 33 [53] 19 [30.6]

Lymph-node areas affected Only para-aortic Only pelvic Both

LVSI L0 L1

46 [74] 16 [26]

VSI V0 V1

Experience a relapse during follow-up

[9.7] [22.6] [24] [11.3] [17.7] [8] [1.6] [5]

Histology Serous-papillary Endometroid Non-differentiated/mixed

8 [13] 50 [80.6]

4 [6.5]

55 [89] 7 [11.3]

(% of 13 N1-patients) 2 [15.4] 3 [23] 8 [61.5]

51 [82] 11 [17.7]

9 [14.5]

3.3. Lymph-node mapping and prognostic factors predictive of lymphnode metastases The mean number of extirpated pelvic lymph-nodes was 24.15  14.2 (range: 1–65), with 0.9  0.3 pelvic lymph-nodes on average being affected by tumor (range: 0–12). The mean number of extirpated para-aortic lymph-nodes was 16.1  1.4 (range: 1–49), whereas the mean number of malignant transformed aortic lymphnodes was 0.7  0.3 (range: 0–18). Thirteen patients (21%) had a positive lymph-node status (N1). Of them, 8 patients (61.5%) had positive lymph-nodes both pelvic and para-aortic; 2 patients (15.4%) presented with only para-aortic positive lymph-nodes and 3 patients (23%) had only pelvic positive lymph-nodes. In 7 (54%) patients the para-aortic lymph-nodes affected were located above the IMA up to the level of the renal veins. The distribution of the N1-patients with positive para-aortic lymph-nodes according to their localization was as follows: 3 patients (23%) had positive inframesenterial lymph-nodes, 3 patients (23%) had positive interaortocaval lymph-nodes, 2 patients (15.4%) had positive lymph-nodes at the bifurcation and 1 patient (7.7%) had positive paracaval lymph-nodes. The distribution of the N1-patients with positive pelvic lymphnodes according to their localization was as follows: 6 patients (46%) along the external iliac artery (left and/or right), 4 patients (31%) along the common iliac artery (left and/or right), 2 patients (15.4%) in the obturator fossa and 3 patients (23%) along the pelvic sidewall (left and/or right). A detailed distribution is presented in Table 2 and Fig. 1. 25% of all extirpated positive lymph-nodes were located above the inferior mesenteric artery on the level of the left renal vein; 7.4% inframesenterial, 10.5% along both common iliac arteries, 17% in both lateral pelvic walls and obturator fossa, 21% along both external iliac arteries; 14% interaortocaval and 4% on the aortic bifurcation. Univariate analysis revealed following parameters as risk factors for a positive lymph-node status in patients with primary EC: lymphovascular space involvement (LVSI) (p < 0.001), vascular space involvement (VSI) (p < 0.001), incomplete tumor resection (p = 0.008) and histology (serous-papillary vs. endometrioid

(p = 0.026). Grade of differentiation was of borderline significance (p = 0.05), whereas age was not significant. When evaluating the risk factors for positive para-aortic lymphnode status (vs. N0 or only pelvic lymph-nodes positive) only LVSI Table 2 Detailed description of the extirpated and affected pelvic and para-aortic lymphnodes divided by area in the 62 patients with primary high- or intermediate-risk endometrial cancer. Lymph-node areas

N-status

Mean

Median  SD

Range

N0 N1

3.64 .18

3.00  3.09 .00  .69

0–16 0–3

Left external iliac artery

N0 N1

3.15 .15

3.00  2.47 .00  .65

0–9 0–3

Right common iliac artery

N0 N1

2.34 .10

2.00  2.30 .00  .66

0–9 0–5

Left common iliac artery

N0 N1

3.07 .07

1.00  4.49 .00  .40

0–26 0–3

Right obturator fossa

N0 N1

4.07 .03

4.00  3.56 .00  .25

0–15 0–2

Left obturator fossa

N0 N1

3.34 .10

3.00  3.14 .00  .57

0–14 0–4

Right lateral pelvic wall

N0 N1

1.78 .07

1.00  2.38 .00  .52

0–11 0–4

Bifurcation

N0 N1

1.65 .07

.50  2.72 .00  .36

0–18 0–2

Left lateral pelvic wall

N0 N1

2.04 .07

1.00  3.12 .00  .32

0–17 0–2

N0 N1

5.70 .39

5.00  5.30 .00  1.54

0–23 0–10

Inframesenterial

N0 N1

3.52 .11

2.50  4.12 .00  .57

0–20 0–4

Interaortocaval

N0 N1

3.05 .22

2.50  3.42 .00  1.10

0–18 0–8

Paracaval

N0 N1

3.75 .02

4.00  3.55 .00  .13

0–16 0–1

Pelvic nodes Right external iliac artery

Para-aortic nodes Infrarenal/supramesenterial

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Fig. 1. Patients with positive pelvic and para-aortic lymph-nodes classified according to their localization. The percentages refer to the total number of N1patients (n = 13).

(p = 0.004), and incomplete tumor resection (p = 0.01) were identified as such. Grade of differentiation (G3 vs. G1/G2) (p = 0.3), histology (serous-papillary vs. endometrioid; p = 0.13), VSI (p = 0.07) and advanced age (>65 years vs. <65 years) did not appear to be significant in this regard. The likelihood ratio of positive para-aortic lymph-nodes when positive pelvic lymphnodes were present was 26.3 (p < 0.001). Due to the small number of patients with positive lymph-nodes (13 patients), no multivariate analysis was performed, since no valid data for statistical significances could be extracted. Data are presented in Table 3. 4. Discussion Lymphadenectomy is currently one of the most controversial discussed topics in the management of EC [22,27,28]. Since FIGO introduced surgical staging of EC in 1988, essential questions have remained unanswered, including the extent of an optimal lymphadenectomy and which subgroup of patients would benefit [9–12]. In many cases the decision to perform systematic pelvic and/or para-aortic lymphadenectomy reflects individual surgeons’ preferences based on their personal experience, as well as potential technical difficulties derived from the high body mass index and the advanced age of the affected women; factors which often apply unfavourably to the typical patients with EC [13]. These factors often lead to an incomplete lymphadenectomy limited to the Table 3 Risk factors for positive lymph-node status (N1): univariate analysis (logistic regression) in patients who underwent systematic pelvic and para-aortic lymphadenectomy due to primary high- and intermediate-risk endometrial cancer. Variable

Hazard ratio

95% confidence interval

p-Value

Lymph vascular space invasion (V1) (vs. L0) Vascular space invasion (V1) (vs. V0) Serous-papillary histology (vs. endometriod or mixed) Microscopically clear tumor marginsa (R0) (vs. R1) Low differentiation grade (G3)a (vs. G1 or G2)

48.4

8.261–283.56

<0.001

4.87–123.51

<0.001

24.53 6.14

1.24–30.41

0.026

12.86

1.97–83.83

0.008

3.93

1.0–15.38

All the bold values have statistical significant. a Protective.

0.05

pelvis or to the area below the IMA [14], since the dissection of the para-aortic lymph-nodes, especially in the infrarenal area, requires higher operative skills and a steeper learning curve necessary to obtain proficiency. In a recent prospective randomized trial on over 500 EC patients with stage I disease randomized to undergo pelvic systematic lymphadenectomy or no lymphadenectomy, Benedetti Panici et al. showed that although systematic pelvic lymphadenectomy significantly improved surgical staging, it did not improve PFS or OS [15]. Also in this study design though, the lymphadenectomy was not extended up to the renal veins but was limited to the pelvic region, thus potentially missing para-aortic lymph-node metastases. Bakkum-Gamez et al., reviewing the treatment strategies for EC, comment that there is no evidence that inadequate lymphadenectomy should be superior to complete omission of lymphadenectomy [12]. This hypothesis potentially explains not only the findings of Benedetti Panici but also these of the ASTEC-study group [16], which shows in a prospective randomized design no evidence of benefit in terms of OS or PFS for pelvic lymphadenectomy alone in women with early EC. A comparison of the GOG99 (lymphadenectomy performed) [17] and the PORTEC-trials (no lymphadenectomy performed) [18] would also seem to suggest that lymphadenectomy does not affect disease-related and recurrence-free survival in patients with intermediate-risk tumors confined to the uterus [19]. It is important to underline that in both studies para-aortic lymphadenectomy was limited to the area below the IMA, while the number of lymph-nodes harvested was not reported and so the quality of the extent and thoroughness of the lymphadenectomy cannot be adequately evaluated. In the present analysis we found a considerable high rate of affected para-aortic lymph-nodes in the N1-patients; more than 50% of them presented positive para-aortic nodes located above the IMA up to the level of the renal veins. Mariani et al. found in a prospective assessment of over 400 EC patients, that 77% of the patients with para-aortic lymphatic spread had positive lymphnodes in the area above the IMA [4]. In a more limited series, Hirahatake similarly observed that 7 (64%) of 11 patients had positive nodes above the IMA [20]. These findings are reflected into the statement of Mariani et al., who, commenting recently on the developing changes in the staging criteria for uterine cancer, acknowledge that if appropriate surgical staging is performed, the majority of patients with positive lymph-nodes will have tumor in the para-aortic area [21]. Since the number of our patients and the follow-up period were limited, only restricted conclusions can be derived from our data regarding the prognostic impact of lymph-node metastases. In a recent retrospective study of Amato et al., aiming to evaluate if the surgical approach in high-risk EC without pelvic lymphadenectomy but with adjuvant radiotherapy can be substituted in early stage by only surgery with pelvic lymphadenectomy (with or without para-aortic lymphadenectomy), the authors conclude that in the high-risk patient group the cancer-related OS and the PFS were better with standard surgery with lymphadenectomy than with standard surgery without lymphadenectomy and adjuvant radiotherapy [23]. If only bulky nodes are removed in an attempt to identify lymph-node metastases intraoperatively on the basis of their size, some of the affected nodes might go undiagnosed, since the diameters of metastatic nodes may be as small as 1 mm [24–26]. In conclusion, we suggest that in the case of well defined risk factors where a lymphadenectomy is indicated according to current FIGO guidelines, the procedure should be extended up to the level of the insertion of the renal veins. Otherwise potentially affected lymph-nodes of the high para-aortic area will remain undiagnosed and so not only may residual disease be left, but also the type and extent of adjuvant therapy may be

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inappropriate. Nevertheless, the impact of systemic pelvic and para-aortic lymphadenectomy on overall survival remains to be evaluated in future randomized prospective settings. Further prospective trials are warranted to define the risk-benefit ratio of systematic lymph-node dissection in EC. 5. Conflict of interest statement

[14] [15]

[16]

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