The issue
Cancer of the lining of the womb (endometrial cancer) is now the most common gynaecological cancer among women in western Europe and North America. Most of these women (75%) have tumours confined to the body of the womb at the time of diagnosis, and three-quarters of women will survive for 10 years after diagnosis. Lymph node metastases can be found in one in 10 women who appear to have cancer confined to the womb at the time of diagnosis, and removal of all pelvic and para-aortic lymph nodes has been advocated, even for women with presumed early-stage cancer. This recommendation is based on non-randomised studies that suggested improvement in survival following removal of pelvic and para-aortic lymph nodes. However, treatment of pelvic lymph nodes may not be beneficial, and additional treatment to lymph nodes might not necessarily be better treatment, especially as surgical removal of lymph nodes has serious potential short-term and long-term harmful effects.
The aim of the review
To evaluate the safety and efficacy of lymphadenectomy in the management of endometrial cancer.
What are the main findings?
We found only three trials that compared lymphadenectomy with no lymphadenectomy among women with endometrial cancer. One of these trials could not be included in the meta-analysis of this review, as it provided insufficient information about outcomes for women. When we combined findings from the two remaining trials, which included 1945 women, we found no evidence that women who received lymphadenectomy were less likely to die or have a relapse of their cancer. In addition, severe adverse events experienced as a consequence of lymphadenectomy outnumbered those reported when no lymphadenectomy was performed.
Quality of the evidence
The overall quality of the evidence for lymphadenectomy versus standard surgery was moderate for survival outcomes and adverse events (other than evidence for presence or absence of lymphoedema or lymphocyst, which was of high quality). The quality of evidence for quality of life was very low, as this outcome was not reported.
What are the conclusions?
The uncertainty of whether lymphadenectomy or no lymphadenectomy is best in the management of early-stage endometrial cancer probably reflects the fact that evidence shows no reduction in death or in disease relapse when lymphadenectomy is performed, rather than lack of evidence. In addition, women undergoing lymphadenectomy experienced more severe adverse events than those who did not undergo lymphadenectomy.
This review found no evidence that lymphadenectomy decreases risk of death or disease recurrence compared with no lymphadenectomy in women with presumed stage I disease. Evidence on serious adverse events suggests that women who undergo lymphadenectomy are more likely to experience surgery-related systemic morbidity or lymphoedema/lymphocyst formation. Currently, no RCT evidence shows the impact of lymphadenectomy in women with higher-stage disease and in those at high risk of disease recurrence.
This is an update of a previous Cochrane review published in Issue 1, 2010 and updated in Issue 9, 2015. The role of lymphadenectomy in surgical management of endometrial cancer remains controversial. Lymph node metastases can be found in approximately 10% of women who before surgery are thought to have cancer confined to the womb. Removal of all pelvic and para-aortic lymph nodes (lymphadenectomy) at initial surgery has been widely advocated, and pelvic and para-aortic lymphadenectomy remains part of the FIGO (International Federation of Gynaecology and Obstetrics) staging system for endometrial cancer. This recommendation is based on data from studies that suggested improvement in survival following pelvic and para-aortic lymphadenectomy. However, these studies were not randomised controlled trials (RCTs), and treatment of pelvic lymph nodes may not confer a direct therapeutic benefit, other than allocating women to poorer prognosis groups. Furthermore, the Cochrane review and meta-analysis of RCTs of routine adjuvant radiotherapy to treat possible lymph node metastases in women with early-stage endometrial cancer found no survival advantage. Surgical removal of pelvic and para-aortic lymph nodes has serious potential short-term and long-term sequelae. Therefore, it is important to investigate the clinical value of this treatment.
To evaluate the effectiveness and safety of lymphadenectomy for the management of endometrial cancer.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase to June 2009 for the original review, updated the search to June 2015 for the last updated version and further extended the search to March 2017 for this version of the review. We also searched registers of clinical trials, abstracts of scientific meetings, and reference lists of included studies, and we contacted experts in the field.
RCTs and quasi-RCTs that compared lymphadenectomy versus no lymphadenectomy in adult women diagnosed with endometrial cancer.
Two review authors independently extracted data and assessed risk of bias. Hazard ratios (HRs) for overall and progression-free survival and risk ratios (RRs) comparing adverse events in women who received lymphadenectomy versus those with no lymphadenectomy were pooled in random-effects meta-analyses. We assessed the quality of the evidence using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach.
978 unique references were identified via the search strategy. All but 50 were excluded by title and abstract screening. Three RCTs met the inclusion criteria; for one small RCT, data were insufficient for inclusion in the meta-analysis. The two RCTs included in the analysis randomly assigned 1945 women, reported HRs for survival adjusted for prognostic factors and based on 1851 women and had an overall low risk of bias, as they satisfied four of the assessment criteria. The third study had an overall unclear risk of bias, as information provided was not adequate concerning random sequence generation, allocation concealment, blinding, or completeness of outcome reporting.
Results of the meta-analysis remained unchanged from the previous versions of this review and indicated no differences in overall and recurrence-free survival between women who underwent lymphadenectomy and those who did not undergo lymphadenectomy (pooled hazard ratio (HR) 1.07, 95% confidence interval (CI) 0.81 to 1.43; HR 1.23, 95% CI 0.96 to 1.58 for overall and recurrence-free survival, respectively) (1851 participants, two studies; moderate-quality evidence).
We found no difference in risk of direct surgical morbidity between women who underwent lymphadenectomy and those who did not undergo lymphadenectomy. However, women who underwent lymphadenectomy had a significantly higher risk of surgery-related systemic morbidity and lymphoedema/lymphocyst formation than those who did not undergo lymphadenectomy (RR 3.72, 95% CI 1.04 to 13.27; RR 8.39, 95% CI 4.06 to 17.33 for risk of surgery-related systemic morbidity and lymphoedema/lymphocyst formation, respectively) (1922 participants, two studies; high-quality evidence).