The role of lymph node dissection in endometrial cancer therapy is controversial.10,11 A Study in the Treatment of Endometrial Cancer trial showed no survival benefit of staging with pelvic lymphadenectomy in patients with apparent stage I disease.12 To avoid morbidity related to systemic lymphadenectomy, the concept of sentinel lymph node dissection recently was introduced for endometrial cancer staging.13 In contrast, reports demonstrated that the removal of an increasing absolute number of metastatic lymph nodes improved prognosis of patients with endometrial cancer. It was shown that a high number of metastatic nodes is associated with adverse outcome.11,14 Recently, the prognostic concept of lymph node ratio emerged, which incorporates the metastatic lymph node count in relation to the removed lymph node count.6,8
Patients with a high count of involved lymph nodes or with a low count of removed lymph nodes have a high lymph node ratio. Thus, this parameter reflects not only the burden of nodal disease but also the quality and extent of pelvic lymph node dissection. In our analysis, patients with 10% or less lymph node ratio had considerably favorable prognosis, with a 5-year overall survival rate of 79.0%. It seems that this distinct group of patients has comparable outcome with patients with stage II disease without lymph node metastasis.2 In contrast, patients with more than 10–50% and more than 50% lymph node ratio showed adverse outcome, with 5-year overall survival rates of 69.6% and 35.8%, respectively. In contrast to the number of removed or positive lymph nodes alone, lymph node ratio was associated with progression-free survival and overall survival in both subgroup analyses in patients with or without grossly involved lymph nodes and in patients with at least 10 lymph nodes removed.
Presence of a high number of metastatic lymph nodes was associated with adverse outcome. This is in concordance with previously published reports.6,15 For patients with advanced disease and presence of lymph node metastasis, recent studies reported a survival benefit of resection of lymph node metastasis and extensive lymph node dissection.16–18 In the subset of our patients with grossly suspicious lymph nodes, this effect was only present for progression-free survival but not for overall survival. It is reasonable to accept that the presence of grossly bulky nodal disease reflects a sign of more aggressive tumor burden and advanced disease. Therefore, the number of metastatic lymph nodes alone does not add additional prognostic information. Recommendations for the extent of lymph node dissection in patients with known lymph node metastasis are controversial. The Gynecologic Oncology Group recommends that a positive pelvic or para-aortic node should indicate no further sampling from that area is necessary and that only palpably positive nodes must be sampled for histology.19 Thus, several academic institutions question the necessity of extensive lymph node dissection in patients with stage IIIC disease.10,20 In contrast, an analysis of the Surveillance, Epidemiology, and End Results database showed a prognostic benefit of the resection of more than 20 lymph nodes, even in patients with stage IIIC–IV endometrial cancer.14 It seems biologically plausible that a minimum number of lymph nodes needs to be removed to acquire representative information on lymph node status and to remove metastatic disease. It is unclear if this assumption remains valid at the moment of finding metastatic disease to the lymph nodes. It is important to consider that extensive lymph node dissection is associated with a notable rate of perioperative complications and increases morbidity.21,22 Future studies are needed to identify if patients with lymph node metastasis would benefit from extensive lymph node dissection, especially as sentinel lymph node dissection techniques are becoming an accepted alternative to complete lymph node dissection in selected patients.
Patient age was one of the most important predictors of survival in our analysis. Older patients showed remarkably worse outcome than younger patients independent of other prognostic factors. This is in accordance with previous reports, suggesting that endometrial cancer appears to be intrinsically more aggressive in older patients.23 In contrast, other studies reported that elderly patients with early-stage endometrioid endometrial cancers have similar progression-free survival compared with their younger counterparts and suggested that the lower overall survival in this patient population is likely because of coincident comorbidities rather than death attributable to endometrial cancer.24 According to recent changes to the FIGO staging system, positive peritoneal washings are no longer considered.5 These changes were made because of a lack of prognostic relevance of positive cytology. In our study and other recent studies, positive peritoneal washings were associated with impaired overall survival in multivariable analysis.25 One might argue that this parameter might be a surrogate parameter for adnexal metastasis or extrauterine spread, but adnexal metastasis was not associated with survival in our cohort. We also identified cervical involvement as a prognostic parameter. Previous reports have described similar findings on the prognostic effect of cervical involvement and positive peritoneal washings and suggested the incorporation of these additional parameters into a novel staging system to separate patients into different prognostic subgroups.15
Patients who received adjuvant radiotherapy experienced improved progression-free survival compared with patients treated with chemotherapy or hormone therapy alone. This is in accordance with a previous study reporting similar survival outcomes after adjuvant chemotherapy and radiotherapy for patients with high-risk endometrial cancer; chemotherapy seemed to prevent or delay distant relapses, whereas radiotherapy tended to prevent or delay local relapses.26
Our study is limited by the many inherent limitations of any retrospective review and analysis of data. These data are hypothesis-generating, and this must be kept in mind when assessing these data. The patients seen in the three tertiary centers may not reflect general patient cohorts. Adjuvant therapy was administered individually and was not standardized in our study because over the relatively long study period adjuvant treatment concepts changed. The optimal treatment regimen for node-positive endometrial cancer is still controversial and remains to be determined. The current review cannot compare outcomes between the various treatments used. Additionally, the extent of lymphadenectomy in the presence of grossly metastatic disease was based on individual surgeon intraoperative decisions and did not follow a standard requirement. These shortcomings of our study need to be kept in mind when interpreting our results. Nevertheless, our study investigated a remarkably high number of patients with stage IIIC endometrial cancer in a multicenter setting. We investigated the prognostic value of lymph node ratio and also focused on various clinicopathologic parameters. Therefore, we think that our findings are clinically applicable and add valuable information for patient counseling. If our findings can be validated in a prospective study, then useful information for individualized treatment of patients with endometrial cancer could be gained. Patients with high lymph node ratio showing high risk of recurrence and cancer-related death might be candidates for intense adjuvant therapy and close follow-up.
Patients with stage IIIC endometrial cancer show remarkable differences in outcome.3 In this multicenter study, we evaluated the prognostic significance of lymph node ratio and additional prognostic parameters. Our study provides evidence that lymph node ratio is the strongest independent prognostic parameter and is useful for stratifying patients with stage IIIC endometrial cancer into distinct prognostic groups. We did not observe a positive survival effect of extensive lymph node dissection in the presence of positive lymph nodes, especially not in the presence of grossly positive lymph nodes.
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