Views and counter views The role of pelvic and para-aortic lymph node dissection in the surgical treatment of endometrial cancer: a view from the USA

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1 The Obstetrician & Gynaecologist /toag ;11: Views and counter views Views and counter views The role of pelvic and para-aortic lymph node dissection in the surgical treatment of endometrial cancer: a view from the USA Authors Andrea Mariani / Sean Dowdy / Karl Podratz Key content: Intraoperative tumour diameter measurement in endometrial cancer is useful for identifying women at extremely low risk of lymph node invasion. Surgical staging in endometrial cancer is instrumental for defining the need for and extent of postoperative therapy, thus avoiding over- and undertreatment. Adequate surgical staging in endometrial cancer includes bilateral pelvic and para-aortic lymphadenectomy extending to renal vessels. Learning objectives: To define diagnostic and possible therapeutic roles of systematic surgical staging in endometrial cancer. To define anatomical borders of adequate surgical staging in endometrial cancer. Ethical issues: How can over- and undertreatment of endometrial cancer be avoided? Keywords external beam radiotherapy / inferior mesenteric artery / surgical staging / vaginal brachytherapy Please cite this article as: Mariani A, Dowdy S, PodratzK. The role of pelvic and para-aortic lymph node dissection in the surgical treatment of endometrial cancer: a view from the USA. The Obstetrician & Gynaecologist 2009;11: Author details Andrea Mariani MD Associate Professor of Obstetrics and Gynecology Division of Gynecologic Surgery, Mayo Clinic, Rochester, MN 55905, USA Mariani.Andrea@mayo.edu (corresponding author) Sean C Dowdy MD Associate Professor of Obstetrics and Gynecology Division of Gynecologic Surgery, Mayo Clinic, Minnesota, USA Karl C Podratz MD PhD Professor of Obstetrics and Gynecology Division of Gynecologic Surgery, Mayo Clinic, Minnesota, USA 199

2 Views and counter views 2009;11: The Obstetrician & Gynaecologist Table 1 Metastatic site frequency in women with endometrial cancer with documented para-aortic node involvement relative to the position of the inferior mesenteric artery (IMA). 12 (Copyright 2009, with permission from Elsevier Limited) Table 2 Frequency of observed endometrial cancer metastases to the pelvic and/or para-aortic node-bearing region in women with lymphatic dissemination who had had systematic pelvic and para-aortic lymphadenectomy. 12 (Copyright 2009, with permission from Elsevier Limited) 200 Introduction Endometrial cancer is the most common malignancy of the female genital tract and the fourth most frequently diagnosed cancer in women in the USA. An estimated new cases of cancer and 7400 deaths in the USA during 2007 were attributed to corpus cancer. 1 Surgical treatment of endometrial cancer consists of total hysterectomy and removal of remaining adnexal structures. Systematic surgical staging in women considered at risk of extrauterine disease is a widely accepted management strategy in the USA. However, this approach has been criticised, especially in Europe, and an alternative method of treatment without surgical staging has been proposed. 2 Unfortunately, there are no clear and widely accepted guidelines for selecting women who may potentially benefit from surgical staging. Moreover, the accuracy and the extent of the nodal dissection have not been standardised. This lack of standardisation is reflected in the lack of uniformity of surgical treatment of endometrial cancer worldwide. 3,4 The lymph nodes represent a relatively frequent area of primary metastatic spread in endometrial cancer. 5 Lymphadenectomy is considered the most reliable method to assess lymph node status. It has been demonstrated that both preoperative imaging and intraoperative palpation of the lymph nodes are inaccurate. One investigation 6 showed that fluorodeoxyglucose positron emission tomography had only a limited sensitivity for detecting lymphatic metastases. Girardi et al. 7 showed that 37% of metastatic lymph nodes measured 2 mm in diameter. At our institution we therefore consider lymph node dissection a fundamental aspect of the surgical management of endometrial cancer. Lymphadenectomy is performed with the following aims: Staging: to document the extent of disease spread accurately, thus permitting comparative evaluations. Node site Node status % Para-aortic Above IMA Positive 77 Below IMA and ipsilateral a Negative 60 Common iliac Ipsilateral b Negative 71 a At least one side declared negative below the positive ipsilateral nodes above the IMA b At least one side declared negative below the positive ipsilateral para-aortic nodes Node site positive for metastasis Positive (n [%]) Pelvic region only 19 (33) Pelvic plus para-aortic regions 29 (51) Para-aortic region only 9 (16) Therapeutics: to treat in accordance with retrospective investigations that have suggested a therapeutic role for pelvic 8 and para-aortic 8,9 lymphadenectomy. Diagnostics: to determine the need for and extent of postoperative treatment. Numerous retrospective studies 10 suggest that women with stage I cancer who have negative lymph nodes after systematic surgical staging can be safely treated with vaginal brachytherapy alone; historically, these women have been treated with adjuvant pelvic radiotherapy. Patterns of lymphatic spread in endometrial cancer The presence of positive lymph nodes is a sign of disease that has escaped the uterine cavity and which may warrant treatment in addition to hysterectomy. Analysis of the routes of lymphatic spread in endometrial cancer is of particular interest for directing surgical therapy.moreover,an understanding of the routes of spread to the pelvic and para-aortic lymph nodes assists in determining the need for surgical and radiation treatment of those areas. A study from Mayo Clinic 5 showed that the external iliac basins are the regional lymph nodes most commonly involved in endometrial cancer. Endometrial cancers that invade the cervix have a propensity to spread more readily to the common iliac lymph nodes than tumours limited to the uterine corpus. In the presence of pelvic node involvement, the rate of para-aortic lymph node invasion is between 47 60%. 11,12 We recently demonstrated that, in cases with para-aortic lymphatic spread, the area above the inferior mesenteric artery (IMA) was involved in 77% of cases (20 of 26) (Table 1). There was a lack of ipsilateral involvement of the nodes below the IMA in 60% of cases and an absence of metastases in the ipsilateral common iliac nodes in 71% of cases with positive lymph nodes above the IMA. Furthermore, 16% of women with lymphatic dissemination presented with isolated para-aortic nodal involvement (Table 2). In addition, carcinoma was detected in the tissues submitted with the gonadal vessels in 28% of women with paraaortic nodal involvement. 12 All of these findings seem to suggest a direct route of spread to the para-aortic nodes, without passage through the pelvic nodes. These observations are instrumental to a better understanding of the need for complete and systematic surgical staging in endometrial cancer. Identification of women at risk of lymph node invasion The selection of risk factors for lymph node dissemination allows the identification of women

3 The Obstetrician & Gynaecologist 2009;11: Views and counter views Tumour diameter (cm) Women (n) Pelvic lymphadenectomy (n [%]) Positive nodes (n [%]) (48) 0 (0) (63) 8 (7) a Characteristics of endometrial cancer in these women were: myometrial invasion 50%, grade 1 or 2, endometrioid histologic subtype and no macroscopic tumour outside the uterine corpus. Table 3 Stratification of pelvic lymph node metastases according to tumour diameter in women at low risk of lymph node invasion. a (Copyright Mayo Foundation for Medical Education and Research) 29 Recurrences Sites of recurrence (n of women who died of disease) Tumour diameter, cm Women (n) n % Locoregional Distant Local distant (0) b 0 (0) 0 (0) (1) 6 (6) 5 (4) a Characteristics of endometrial cancer in these women were: myometrial invasion 50%, grade 1 or 2, endometrioid histologic subtype and no macroscopic tumour outside the uterine corpus. b All vaginal recurrences Table 4 Stratification of endometrial cancer according to tumour diameter and recurrences in women at low risk of lymph node metastasis. a (Copyright Mayo Foundation for Medical Education and Research) 29 who may potentially benefit from surgical staging, while it spares other women from the morbidity of lymphadenectomy. At Mayo Clinic, we demonstrated that the primary tumour diameter measured at surgery together with the histologic subtype, grade and depth of myometrial invasion allows the selection of low-risk women whose treatment can be safely managed with hysterectomy alone, avoiding the morbidity of lymphadenectomy. 13 Among women who presented with endometrioid histologic subtype, histologic grade 1 or 2, myometrial invasion of 50%, tumour diameter 2 cm and no evidence of macroscopic tumour beyond the uterine corpus, neither positive lymph nodes nor lymph node recurrences were identified (Table 3 and Table 4). None of the 123 women with these characteristics died of disease at 5 years, independent of the type of surgical treatment or the administration of postoperative radiotherapy (Table 5). Only 3 recurrences (2%) were detected; all 3 were localised on the vaginal vault and were cured with radiotherapy (Table 4). These findings support the importance of primary tumour diameter in predicting lymph node invasion in this defined low-risk group. Women with these characteristics, who do not require full surgical staging, represent 27% of the women with endometrial cancer who underwent operations at our institution. 12 Guidelines for the surgical treatment of endometrial cancer at Mayo Clinic are shown in Box 1. The diagnostic role of surgical staging The role of pelvic external beam radiotherapy in the management of endometrial cancer confined to the uterus has been intensively debated in the medical literature during the last decade. In fact, many retrospective series describe very favourable outcomes in women with disease confined to the uterus after systematic surgical staging and who were not treated with postoperative radiotherapy except vaginal brachytherapy. 10 The suggestion that postoperative pelvic external radiotherapy can be safely omitted in women with low-risk or Treatment Women (n) 5-year survival, % Hysterectomy only Hysterectomy LND and/or RT b Total LND lymphadenectomy; RT radiotherapy a Characteristics of endometrial cancer in these women were: myometrial invasion 50%, grade 1 or 2, endometrioid histologic subtype and no macroscopic tumour outside the uterine corpus. b Ten women received radiotherapy, 7 of whom received it for positive peritoneal cytology. intermediate-risk endometrial cancer confined to the uterus has been further confirmed by three prospective, randomised clinical trials These studies show that external pelvic radiotherapy improves locoregional control, but without any significant benefit on survival, in endometrial cancer confined to the uterus in women whose treatment is managed both with 15,16 and without 14 surgical staging. 2 In addition, cost benefit analyses show that the use of complete lymphadenectomy can decrease the use of adjuvant radiotherapy in early stage endometrial cancer. 17 In a previous retrospective study from Mayo Clinic, 11 we observed that 47% of women with positive pelvic lymph nodes either had positive para-aortic lymph nodes or subsequently experienced a paraaortic recurrence. Moreover, it has also been reported that approximately 55 67% of women with positive lymph nodes have tumour in the para-aortic area. 5,12,18 These observations should guide recommendations for and the extent of adjuvant radiotherapy in women who have either Hysterectomy Bilateral salpingo-oophorectomy Peritoneal cytology Bilateral pelvic and para-aortic lymphadenectomy Para-aortic dissection up to renal vessels Excision of gonadal vessels at insertions (optional) No lymphadenectomy if no disease beyond corpus and if 1) endometrioid cancer grade 1 or 2, MI 50% and PTD 2 cm or 2) endometrioid cancer and no MI (independent of grade and PTD) Omentectomy, staging biopsies or cytoreduction for non-endometrioid or advanced cancer MI myometrial invasion; PTD primary tumour diameter Table 5 Survival of 123 low-risk women with endometrial cancer a (primary tumour diameter 2 cm) according to definitive method of treatment. (Copyright Mayo Foundation for Medical Education and Research) 29 Box 1 Guidelines for surgical management of endometrial cancer, Mayo Clinic, Rochester, Minnesota, (Copyright 2009, with permission from Elsevier Limited) 201

4 Views and counter views 2009;11: The Obstetrician & Gynaecologist Figure 1 Management of 100 women with a 20% risk of lymph node (LN) invasion, using external pelvic radiotherapy (RT) without surgical staging Figure 2 Management of 100 women, who carry a 20% risk of lymph node (LN) invasion, with use of systematic surgical staging followed by disease-based postoperative therapy. LND lymphadenectomy (pelvic and para-aortic); RT radiotherapy definitively staged or inadequately staged cancer. If external beam radiotherapy is selected as adjuvant therapy to decrease pelvic sidewall recurrence in non-staged endometrial cancer, these observations suggest that the para-aortic area should routinely be included in the field of treatment. For further clarification of this concept, let us consider an imaginary series of 100 women with unstaged cancer and apparent stage I disease. We assume that, on the basis of traditional risk factors observed in the uterus (i.e. histologic grade and depth of myometrial invasion), the estimated risk of lymph node invasion in these women is 20% (Figure 1). If we treat all the women with pelvic radiotherapy in an attempt to prevent pelvic sidewall recurrences, overtreatment will occur in 80 women, for whom vaginal brachytherapy (or having no radiotherapy) is potentially adequate therapy. Moreover, because up to 67% of women with positive lymph nodes have disease in the paraaortic area, women (i.e. 67% of the 20 women with positive lymph nodes) will continue to be undertreated in the para-aortic area. Therefore, potentially adequate treatment will be given to only 7 women with disease limited to the pelvis (Figure 1). In summary, with this strategy, 80% of women will be overtreated with pelvic radiotherapy and 13% will be undertreated by virtue of unirradiated paraaortic lymphatic metastases. In contrast, let us consider a similar example (Figure 2) of 100 women whose treatment is managed with surgical staging followed by disease-based postoperative therapy. 19 Staging permits the collection of additional factors that facilitate decision making regarding the need for and extent of postoperative therapy. With this approach, 80 women will be potentially overtreated by unnecessary lymphadenectomy (without taking into account the benefit given by the procedure s diagnostic value), because they have negative lymph nodes. However, all of the other 20 women,on the basis of the information given by surgical staging, will receive disease-based therapy that targets the documented or predicted sites of recurrence. 19 Prospective data showing that this approach improves prognosis are not yet available. However, a prospective study is ongoing at Mayo Clinic. 12 Using this surgical staging approach, 80% of women will be overtreated with lymphadenectomy, and, theoretically, no woman will be undertreated because assessment of disease spread will be accurate. Do high-risk women with stage I endometrial cancer benefit from pelvic radiotherapy irrespective of surgical staging? In 1980, in a landmark prospective study, Aalders et al. 20 randomly assigned women with clinical stage I endometrial cancer, after hysterectomy (without systematic surgical staging), to external pelvic radiotherapy plus vaginal brachytherapy versus vaginal brachytherapy only. The investigators found that administration of external pelvic irradiation improved survival and local control in women with poorly differentiated and deeply invasive tumours. Similarly, in a more recent prospective trial, 15 the Gynecologic Oncology Group (GOG) 99 evaluated external pelvic radiotherapy compared with no additional treatment. This trial included surgically staged endometrial cancers confined to the uterus. In the analysis of the high-risk subgroup (which had a combination of the characteristics of old age, histologic grade 2 or 3, presence of lymphovascular invasion and deep myometrial invasion), 15 a significant improvement in local control was observed in the radiotherapy arm, regardless of the presence of negative lymph nodes. On the basis of these data, it has been inferred that women with histologic grade 3 and deep myometrial invasion may potentially benefit from external pelvic radiotherapy, irrespective of lymph node status. 15 However, doubts have been raised about the adequacy of the surgical staging performed in the GOG 99 trial. 21 Moreover, most of the local recurrences in the GOG 99 trial were in the vagina. 15 Vaginal recurrences can potentially be prevented by vaginal brachytherapy, 22 thus avoiding the morbidity of external pelvic radiotherapy. In addition, poorly differentiated, deeply invasive tumours have an approximately 30% risk of positive lymph nodes. 23 It is, therefore, intuitive that the survival advantage and the improved locoregional control observed by Aalders et al. 20 in women who received irradiation are mainly related to the presence of occult lymphatic metastases. This statement is supported by the fact that the 202

5 The Obstetrician & Gynaecologist 2009;11: Views and counter views investigators observed a 20% rate of locoregional recurrences in women without radiotherapy and a 14 16% rate of distant recurrences in both subgroups of women with and without external radiotherapy. Similarly, Creutzberg et al. 24 analysed 99 women who had unstaged endometrial cancer with poorly differentiated and deeply infiltrative tumours and observed a 31% rate of distant recurrences at 5 years after the administration of external pelvic radiotherapy. As we have demonstrated, 12 at least part of these extrapelvic failures are probably due to disease in the paraaortic area or to other distant disease that was not treated by locoregional radiotherapy. Therefore, we suggest that, even in women with poorly differentiated and deeply invasive tumours, surgical staging may be useful in selecting candidates for external radiotherapy and in directing the treatment appropriately to the predicted areas of spread. Adequacy of surgical staging The lack of clearly defined guidelines for the appropriate extent of lymphadenectomy in endometrial cancer has led to variability in staging and treatment algorithms. As previously mentioned, this lack of standardisation is reflected in the wide variability of surgical treatment of endometrial cancer worldwide. 3,4,14 The assessment of lymph nodes varies from complete omission, to sampling, to systematic pelvic and para-aortic lymphadenectomy for all women ,25 Furthermore, in women subjected to para-aortic node dissection, the anatomical extent of the procedure remains ill defined. 17 The GOG surgical manual 26 suggests the origin of the IMA as the recommended upper boundary of the para-aortic lymphadenectomy. As previously discussed, we recently demonstrated that the area above the IMA was involved in 77% of cases with para-aortic lymphatic spread (Table 1). Moreover, ipsilateral nodes below the IMA were not involved in 60% of cases. A consequence of these findings is that when we perform para-aortic lymphadenectomy it needs to extend to the renal vessels to achieve its diagnostic, and possibly therapeutic, value. In fact, routinely performing lymphadenectomies only up to the IMA will potentially miss 38 46% of women with positive para-aortic lymph nodes. 12 The potential therapeutic role of surgical staging Various retrospective studies in the medical literature have suggested a potential therapeutic role of pelvic and para-aortic lymphadenectomy in endometrial cancer. In particular, in a paper from Mayo Clinic 9 that analysed a subgroup of women with documented positive lymph nodes, we observed that both diseaserelated and recurrence-free survivals were improved in women who had extended para-aortic lymph node dissection compared with those who had no or only limited surgical procedure in the para-aortic area. Moreover, in a subsequent paper we demonstrated that pelvic and para-aortic lymphadenectomy are instrumental in improving the efficacy of postoperative radiotherapy in both treatment of nodal disease and prevention of lymph node recurrence. 8 However, all these studies are retrospective. Prospective data demonstrating a therapeutic role for lymphadenectomy are not available. Nevertheless, caution must be used when interpreting the results of prospective trials that test the therapeutic role of lymphadenectomy but confine the dissection to the pelvic area and which include low-risk women. 27,28 In fact, it is intuitive that women who may potentially receive increased benefit from lymph node dissection are those at high risk for or with documented lymphatic metastases. However, two recently published prospective studies 27,28 included a large proportion of low-risk women, thus decreasing the probability of finding a therapeutic effect of lymph node dissection. Moreover, as we previously demonstrated, 12 67% of women with positive lymph nodes have tumour in the para-aortic area. A surgical treatment confined to the pelvis will miss lymphatic metastases in these women, in whom lymphadenectomy is more likely to be beneficial. This suboptimal surgical treatment is unlikely to provide a noteworthy survival benefit. Therefore, it is still unknown whether careful identification of women at high risk of lymph node invasion would improve outcomes (i.e. prognosis, cost and morbidity) by triggering complete surgical removal of pelvic and para-aortic nodal disease and by guiding decisions on postoperative treatment. Conclusions Surgical staging in apparent early stage endometrial cancer is instrumental in avoiding over- and undertreatment with postoperative radiotherapy. The information provided by surgical staging has a profound influence on the decision on and extent of postoperative therapy. It allows postoperative therapy to be directed at the documented or predicted sites of disease dissemination. Lymphadenectomy can be safely omitted in women with small, well-differentiated endometrioid tumours and superficial myometrial invasion. We suggest performing both pelvic and para-aortic lymphadenectomy in all other women. Para-aortic lymphadenectomy must be extended to the renal vessels to be adequate from a diagnostic, and possibly therapeutic, point of view. A prospective validation study of our proposed surgical and postoperative approaches in endometrial cancer is currently ongoing at Mayo Clinic. 203

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