1408 women were randomly assigned: 704 to the standard surgery group and 704 to the lymphadenectomy group (). Patient characteristics at randomisation were generally much the same between the two groups ().
summarises the pathology findings of women who were confirmed as having endometrial cancer at surgery. Most women (80%) had endometrioid endometrial cancer (545/681 [80%] standard surgery group, 541/684 [79%] lymphadenectomy group). Slightly more women had worse prognosis tumours with respect to histology (clear cell and papillary serous) and greater depth of invasion (10% more involvement of the outer half of the myometrium) in the lymphadenectomy group than in the standard surgery group ().
Almost all women in both groups had a total abdominal hysterectomy and BSO (). In the lymphadenectomy group, 58 (8%) women had no nodes removed because of anaesthetic concerns (n=22), obvious extra-uterine disease (12), obesity (9), withdrawal at patient request (9), or unknown reasons (6). We obtained the number of lymph nodes removed from the pathology report. In the lymphadenectomy group, 72 (12%) had one to four nodes removed and 396 (65%) women had ten or more removed (median 12 nodes). In the standard surgery group, of the 35 (5%) women who had any nodes removed (as was allowed within the protocol at the surgeon's discretion), the median node count was two, and only four women had ten or more removed. In the standard surgery group, surgeons mainly took biopsy samples of suspect nodes, which accounted for the difference in the proportion of positive nodes in the standard surgery group compared with the lymphadenectomy group.
Women in both groups were managed in a similar way with respect to thromboprophylaxis, use of prophylactic antibiotics, type of anaesthetic, requirement for blood transfusion, and number of days spent in hospital (). The median length of operation was 50% longer when lymphadenectomy was done (). The proportion of women having laparoscopic procedures was similar in both groups (). More women in the standard surgery group had a transverse incision rather than a vertical incision compared with the lymphadenectomy group. The risk of developing short-term major surgical complications was generally low in both groups but more women in the lymphadenectomy group than in the standard surgery group developed specific complications of: ileus (18 [3%] vs eight [1%]), deep-vein thrombosis (six [1%] vs one [0·1%]), lymphocyst (ten [1%] vs two [0·3%]), and major wound dehiscence (ten [1%] vs two [0·3%]).
summarises use of adjuvant radiotherapy for all randomised women. Similar proportions of women in both groups received postoperative radiotherapy. Of those who had radiotherapy, most had a combination of EBRT and brachytherapy (). A few women with low-risk early-stage disease received radiotherapy and a smaller proportion received EBRT with or without brachytherapy (). In the intermediate-risk and high-risk early-stage group, 137 (56%) and 138 (53%) women in the standard surgery and lymphadenectomy groups, respectively, received postoperative radiotherapy; 102 (42%) and 98 (37%), respectively, received EBRT with or without brachytherapy. About half the women in this subgroup received EBRT as part of the ASTEC radiotherapy trial (46/102 standard surgery group and 51/98 lymphadenectomy group). In the advanced disease group, a higher proportion of women in the standard surgery group than the lymphadenectomy group had radiotherapy and EBRT with or without brachytherapy ().
Adjuvant radiotherapy received (within 3 months after surgery)
Adjuvant radiotherapy received (within 3 months after surgery), nodes removed, nodal status, and external-beam radiotherapy (EBRT) received in node-positive patients by risk group defined according to ASTEC radiotherapy eligibility
A small proportion of women in both groups received other anticancer treatment during follow-up before disease recurrence, including chemotherapy (31 standard surgery group; 26 lymphadenectomy group) and progestogens (15 standard surgery group; 17 lymphadenectomy group).
Within the treatment groups, the median number of nodes removed was similar in the three subgroups of low-risk early-stage, intermediate-risk and high-risk early-stage, and advanced disease (). Within these subgroups, the proportion of women with nodes removed who had positive nodes in the lymphadenectomy group was 2·4% (six of 255 women), 9% (21 of 244), and 24% (25 of 103), respectively.
After adjuvant treatment, including postoperative radiotherapy in participants who received it, more women in the lymphadenectomy group than in standard surgery group reported moderate or severe morbidity or treatment-related complications (119/684 [17%] vs 85/686 [12%]). Of the 26 women (two standard surgery group; 24 lymphadenectomy group) who had lymphoedema, eight received EBRT (all in lymphadenectomy group). In the lymphadenectomy group we noted no clear evidence of an association between EBRT and lymphoedema (relative risk 1·57 [95% CI 0·66–3·74]; p=0·28).
By May, 2006, with a median follow up of 37 months (IQR 24–58 months), 191 (14%) women had died (). Overall survival curves showed no evidence of a difference between the two groups ().
Overall survival (A), disease and treatment-related deaths (B), and recurrence-free survival (C) by treatment group
Deaths were classified as treatment related, or disease and treatment related, in four (0·6%) women in the standard surgery group and nine (1·3%) in the lymphadenectomy group (). A third of the deaths were not related to treatment or disease (26/88 deaths in standard surgery group and 28/103 in lymphadenectomy group). 54 deaths were classified as non-disease and non-treatment related (). We therefore undertook a competing risk analysis that takes this factor into account. An analysis of disease or treatment-related deaths again showed an HR in favour of the standard surgery group (), although inevitably the confidence intervals were wider since there were fewer events in this analysis.
173 (12%) women had had disease recurrence (75 standard surgery group, 98 lymphadenectomy group), and 251 (18%) had died or had recurrence of disease (107 standard surgery group, 144 lymphadenectomy group) at the time of analysis. summarises the site of recurrence.
Kaplan-Meier curves for recurrence-free survival showed a conventionally significant benefit for the standard surgery group (). shows the Kaplan-Meier plots for overall survival and recurrence-free survival together with the model curves from fitting the Royston-Parmar parametric model, as well as the absolute difference between the treatment groups over time. The absolute difference in 5-year overall survival estimated from these curves was a 1% (95% CI −4·0 to 6) improvement in favour of standard surgery (). The 5-year overall survival was 81% (95% CI 77–85) in the standard surgery group and 80% (76–84) in the lymphadenectomy group. The absolute difference in 5-year recurrence-free survival was 6% (1–12) in favour of standard surgery (). 5-year recurrence-free survival was 79% (75–83) in the standard surgery group and 73% (69–77) in the lymphadenectomy group. Over time, the absolute difference in overall survival between the two groups remained close to zero, whereas the absolute difference for recurrence-free survival increased over time in favour of standard surgery ().
Kaplan-Meier plots for the two treatment groups for overall and recurrence-free survival together with the model curves from fitting the Royston-Parmar parametric model
Despite randomisation of a large number of women, we recorded some differences in the pretreatment characteristics with respect to histological features that suggested women in the standard surgery group might be at lower risk of recurrence than were those in the lymphadenectomy group. Results of analyses adjusting for these imbalances () gave an HR closer to 1·0 for both overall survival and recurrence-free survival, and did not suggest a benefit with lymphadenectomy for overall survival (adjusted HR 1·04 [95% CI 0·74–1·45]; p=0·83) or for recurrence-free survival (1·25 [0·93–1·66]; p=0·14), with the point estimate for recurrence-free survival still in favour of standard surgery.
Table 8 Unadjusted and adjusted analysis using the Cox model for overall survival and recurrence-free survival (deaths from all causes), and for disease-specific survival and recurrence-free disease-specific survival (disease and treatment specific deaths only) (more ...)
We also undertook analyses of disease-specific survival, adjusting for baseline characteristics with the Cox model (). Results were similar to the unadjusted analysis (). Exploratory interaction analyses did not provide any evidence that the effect of lymphadenectomy on overall survival or recurrence-free survival differed in subgroups defined by age, WHO performance status, and pathological features of endometrial cancer including depth of invasion, histology, or grade of tumour (data not shown). We did a predefined analysis to explore the effect of number of nodes removed for systematic lymph node dissection in an unbiased manner by classifying centres according to the median number of nodes removed in the lymphadenectomy group: less than ten, between ten and 14, and 15 or more nodes (). Our results suggest that, if anything, lymphadenectomy could be associated with a worse outcome the more lymph nodes removed (; p=0·13 for overall survival and p=0·16 for recurrence-free survival). Results of the adjusted analyses by hospitals removing different median numbers of nodes () lends support to this conclusion.
Unadjusted and adjusted analysis classifying centres by median number of nodes harvested, with the Cox model for overall survival and recurrence-free survival
In the subgroups of women classified with low-risk early-stage disease, intermediate-risk and high-risk early-stage disease, and advanced disease (), we recorded no evidence of a difference in the relative effect of lymphadenectomy versus standard surgery (p=0·55 for overall survival and p=0·35 for recurrence-free survival).
Effect of lymphadenectomy on overall survival (A) and recurrence-free survival (B) in women in different risk groups of recurrence