Transcript
Efficacy of systematic pelvic lymphadenectomy in endometrial
cancer (MRC ASTEC trial): a randomised study
The writing committee on behalf of the ASTEC study group
‡
Summary
Background—Hysterectomy and bilateral salpingo-oophorectomy (BSO) is the standard surgery
for stage I endometrial cancer. Systematic pelvic lymphadenectomy has been used to establish
whether there is extra-uterine disease and as a therapeutic procedure; however, randomised trials
need to be done to assess therapeutic efficacy. The ASTEC surgical trial investigated whether pelvic
lymphadenectomy could improve survival of women with endometrial cancer.
Methods—From 85 centres in four countries, 1408 women with histologically proven endometrial
carcinoma thought preoperatively to be confined to the corpus were randomly allocated by a
minimisation method to standard surgery (hysterectomy and BSO, peritoneal washings, and palpation
of para-aortic nodes; n=704) or standard surgery plus lymphadenectomy (n=704). The primary
outcome measure was overall survival. To control for postsurgical treatment, women with early-
stage disease at intermediate or high risk of recurrence were randomised (independent of lymph-node
status) into the ASTEC radiotherapy trial. Analysis was by intention to treat. This study is registered,
number ISRCTN 16571884.
Findings—After a median follow-up of 37 months (IQR 24–58), 191 women (88 standard surgery
group, 103 lymphadenectomy group) had died, with a hazard ratio (HR) of 1·16 (95% CI 0·87–1·54;
p=0·31) in favour of standard surgery and an absolute difference in 5-year overall survival of 1%
(95% CI −4 to 6). 251 women died or had recurrent disease (107 standard surgery group, 144
lymphadenectomy group), with an HR of 1·35 (1·06–1·73; p=0·017) in favour of standard surgery
and an absolute difference in 5-year recurrence-free survival of 6% (1–12). With adjustment for
baseline characteristics and pathology details, the HR for overall survival was 1·04 (0·74–1·45;
p=0·83) and for recurrence-free survival was 1·25 (0·93–1·66; p=0·14).
Interpretation—Our results show no evidence of benefit in terms of overall or recurrence-free
survival for pelvic lymphadenectomy in women with early endometrial cancer. Pelvic
lymphadenectomy cannot be recommended as routine procedure for therapeutic purposes outside of
clinical trials.
Funding—Medical Research Council and National Cancer Research Network.
Introduction
Endometrial cancer is now the most common gynaecological malignancy in western Europe
and North America. About 6400 women are affected every year in the UK, 81 500 in the
European Union, and 40 100 women in North America. More than 90% of cases occur in
©2009 Elsevier Ltd. All rights reserved..
‡
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Lancet
Published as: Lancet. 2009 January 10; 373(9658): 125–136.
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women older than 50 years of age, with a median age of 63 years. The incidence in older women
(aged 60–69 years) increased in the UK by 19% between 1993 and 2001. It is the seventh most
common cause of death from cancer in women in western Europe, accounting for 1–2% of all
deaths from cancer. Roughly 75% of women survive for 5 years. This high survival rate is
attributable to most women being diagnosed at an early stage after postmenopausal bleeding.
At diagnosis, about three-quarters of women have disease confined to the uterine corpus.
Standard definitive surgery includes hysterectomy and bilateral salpingo-oophorectomy
(BSO). Most tumours are of endometrioid type; other histological types include serous,
mucinous, clear cell, and mixed epithelial. Endometrial tumours are graded as well (grade 1),
moderately (grade 2), or poorly (grade 3) differentiated, apart from clear cell and serous, which
are generally regarded as grade 3. Endometrial cancer spreads beyond the uterus by infiltrating
directly through the myometrium, extending into the cervix, and metastasising most often to
the pelvic nodes and less frequently directly to the para-aortic nodes. Pelvic lymph-node
metastases occur in about 10% of women with clinical stage I (ie, confined to the corpus)
endometrial cancer. Within stage I disease, 3–5% of women with well differentiated tumours
and superficial myometrial invasion will have lymph-node involvement. This proportion rises
to roughly 20% of women with poorly differentiated tumours and deep myometrial invasion.
In Europe, traditional management of women with stage I disease has consisted of surgery,
which is typically combined with adjuvant radiotherapy for women whose pathological
features suggest an increased risk of nodal metastases. Tumour type, grade, and depth of
myometrial invasion are key prognostic factors for recurrence, and are used to assess risk of
recurrence and need for adjuvant treatment. A systematic review and meta-analysis of 1770
patients from four randomised trials and data from the ASTEC/EN.5 radiotherapy trial show
that adjuvant radiotherapy results in a small reduction in risk of isolated pelvic recurrence
(2·9%), but no evidence that it affects overall or disease-specific survival.
Since 1988, the International Federation of Gynaecology and Obstetrics (FIGO) classification
of stage of endometrial cancer has required a full systematic pelvic and para-aortic
lymphadenectomy. Some propose that adjuvant radiotherapy can be avoided and treatment
morbidity reduced when lymphadenectomy shows no indication of disease in the nodes.
However, evidence is scarce of a therapeutic benefit for lymphadenectomy in terms of survival.
Lymphadenectomy is undertaken widely in North America and Australia, and data from non-
randomised studies and case series, which have shown an association between
lymphadenectomy and increased survival, lend support to the procedure. Other observational
studies, however, have not shown any such benefit. ASTEC (A Study in the Treatment of
Endometrial Cancer) was designed to assess the therapeutic benefit of lymphadenectomy in
endometrial cancer, independent of the effect of adjuvant radiotherapy.
ASTEC consisted of two trials with separate randomisations that were designed to answer a
surgical and a radiotherapy question (figure 1). The surgical trial investigated whether pelvic
lymphadenectomy could improve survival of women with endometrial cancer, which was
thought preoperatively to be confined to the corpus. The radiotherapy trial addressed whether
adjuvant external-beam radiotherapy (EBRT) could improve survival of women with
intermediate-risk and high-risk early-stage endometrial cancer. In this Article we report the
results of the surgical randomisation.
Methods
Study design and women
We undertook a randomised controlled trial between J uly 1, 1998, and March 31, 2005 in 85
centres in four countries (UK, South Africa, Poland, and New Zealand). We included women
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with histologically proven endometrial carcinoma that was thought preoperatively to be
confined to the corpus, and those who were able to undergo both systematic lymphadenectomy
and EBRT. Women who had a CT or MRI scan suggesting node enlargement were not excluded
from randomisation. Specialist gynaecological surgeons who were experienced in pelvic
lymphadenectomy undertook all surgical procedures. The same surgeon, who was specified
before randomisation, had to undertake surgery irrespective of whether the woman was
randomly assigned to the standard surgery group alone or the group with systematic
lymphadenectomy. All women provided written, informed consent at initial recruitment to both
the surgical and radiotherapy randomisation, in the event that they would be eligible for the
radiotherapy trial. We obtained ethics approval for the trial from the North West Multi-centre
Regional Ethics Committee (UK).
Interventions
We randomly allocated eligible women to the standard surgery group or lymphadenectomy
group. Women in the standard surgery group had a hysterectomy and BSO, peritoneal
washings, and palpation of para-aortic nodes. Nodes that were suspicious could be sampled if
the surgeon believed it to be in the woman's best interest. Women in the lymphadenectomy
group had standard surgery plus a systematic dissection of the iliac and obturator nodes. If the
nodes could not be dissected thoroughly because of obesity or anaesthetic concern, sampling
of suspect nodes was recommended and para-aortic node sampling was at the discretion of the
surgeon.
In both groups, a vertical incision was recommended, unless a transverse incision was preferred
by the surgeon because of gross obesity. Surgery could be undertaken by laparoscopic
technique provided that the procedure could be accomplished safely and as thoroughly as an
open procedure. The type of surgical access (open or laparoscopic) to be used was specified
before randomisation and was therefore independent of the type of surgery allocated. During
the trial we monitored the type of incision (vertical or transverse); when we noted an imbalance
in the type of incisions being undertaken between the groups, the incision type also had to be
specified before randomisation. Thromboprophylaxis and prophylactic antibiotics were
prescribed according to local practice.
Procedures
Randomisation was done by a telephone call to the Medical Research Council Clinical Trials
Unit (MRC CTU), and we used a method of minimisation. Stratification factors were centre,
WHO performance status (0–1 vs 2–4), time since diagnosis (≤ 6 weeks vs >6 weeks), and
planned surgical approach (open vs laparoscopic). We registered surgery and pathology details
(based on local reporting) with the MRC CTU after surgery. We used the minimum dataset of
the Royal College of Pathologists as the standard for pathology reporting. Women were
classified in three categories: low-risk, early-stage disease (FIGO IA or IB and low grade
pathology [G1, G2]); intermediate-risk and high-risk, early-stage disease (FIGO IA or IB with
high grade pathology [G3, papillary serous or clear cell], FIGO IC or IIA); and advanced
disease—ie, spread beyond the uterine corpus (FIGO stage IIB, IIIA, IIIB, and IV). Pelvic
lymph-node status was not taken into account; thus no FIGO stage IIIC category was included.
Further randomisation into the ASTEC radiotherapy trial (comparing EBRT and observation
with no EBRT or systemic treatment until recurrence) was required for women with
intermediate-risk and high-risk, early-stage disease, including those with positive lymph nodes.
Without this second randomisation, differences in postsurgical treatment could have arisen,
with women in the standard surgery group either having more radiotherapy (because their
lymph-node status was unknown) or less radiotherapy (because they were less likely to have
positive lymph nodes identified) than women in the lymphadenectomy group were having. We
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offered women with low-risk, early-stage disease and women with advanced disease further
treatment according to standard practice.
We assessed women before randomisation and surgery, 3 months after randomisation, then
every 3 months in the first year, every 6 months in years 2 and 3, and every year thereafter.
Follow-up data collected included details of endometrial cancer recurrence and treatment, vital
status, and short-term and long-term toxic effects. The primary outcome measure was overall
survival. Secondary outcome measures were recurrence-free survival, adverse effects from
treatment, and disease-specific survival.
Statistical analysis
We planned to randomise 1400 women to detect an improvement in 5-year overall survival
from 80% in the standard surgery group to 90% in the lymphadenectomy group (hazard ratio
[HR] 0·47) with 5% significance level and 90% power. We allowed for non-compliance of
roughly 20% in the sample size calculations to take account of women who would have no
lymph nodes removed or have lymph node sampling only in the lymphadenectomy group.
We compared Kaplan-Meier curves for all time-to-event outcome measures with the standard
(non-stratified) log-rank test. We defined overall survival as the time from randomisation to
death from any cause; women who were known to be still alive at the time of the analysis were
censored at the time of their last follow-up. We defined recurrence-free survival as the time
from randomisation to first reappearance of endometrial cancer or death from any cause;
women who were known to be alive and without recurrent disease at the time of analysis were
censored at the time of their last follow-up. Disease-specific survival was defined as time from
randomisation to death from endometrial cancer or death due to treatment. To compare disease-
specific survival we undertook a competing risk analysis by subtracting the log-rank statistic
for non-endometrial cancer deaths from the log-rank statistic for all deaths (ie, the two observed
values were subtracted from each other, the two expected values were subtracted from each
other, and the two variances were subtracted from each other).
The Chief Investigator, blinded to treatment group, made the assessment of cause of death, and
classified it as treatment related, disease related, treatment and disease related, or other (non-
endometrial cancer, non-treatment related). All deaths within 30 days of surgery were classified
as treatment related irrespective of their cause. All comparisons are expressed relative to
women in the standard surgery group; therefore an HR less than 1·0 indicates a decreased risk
of the event for women in the lymphadenectomy group. We modelled the absolute difference
between the treatment groups using the flexible parametric models of Royston and Parmar.
Although unadjusted HRs are presented for all outcome measures, we also calculated an
adjusted HR with the Cox model for disease-specific, overall, and recurrence-free survival.
Covariates included the characteristics: age (as a continuous variable), WHO performance
status (0, 1, 2, 3, or 4), weeks between diagnosis and randomisation (≤6 weeks vs >6 weeks),
surgical technique intended (open vs laparoscopic), and type of incision (vertical vs Pfannestiel
vs other transverse, two dummy variables used); and pathology details: extent of tumour
(confined vs spread), histology (endometrioid/adenocarcinoma vs other), depth of invasion
(inner half of myometrium vs endometrium only, outer half of myometrium vs endometrium
only), and differentiation (grade 1, 2, or 3). We assessed any benefits of lymphadenectomy on
survival in an exploratory manner in subgroups. Predefined subgroups included grouping
centres according to the median number of lymph nodes removed (<10, 10–14, ≥15) in the
lymphadenectomy group, and grouping women by risk of recurrence: low risk of recurrence,
intermediate and high risk of recurrence, and advanced disease (according to eligibility for the
radiotherapy randomisation). To test for differences in the relative size of effect in different
subgroups, we used a χ
2
test for interaction, or, when appropriate, a χ
2
test for trend. All analyses
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were done on an intention-to-treat basis. All p values are two-sided. Analyses were undertaken
with SAS System (version 9.10), apart from the flexible parametric models for which we used
stata (version 9.1). This study is registered, number ISRCTN 16571884.
Role of the funding source
The sponsor of the study reviewed and approved the trial design, and the execution was
overseen by an independent data monitoring committee and independent trial steering
committee. The sponsor of the study had no role in data collection, data analysis, data
interpretation, or writing of the report. The writing committee had full access to all the data in
the study, and the trial management group had final responsibility for the decision to submit
for publication.
Results
1408 women were randomly assigned: 704 to the standard surgery group and 704 to the
lymphadenectomy group (figure 2). Patient characteristics at randomisation were generally
much the same between the two groups (table 1).
Table 2 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 (table 2).
Almost all women in both groups had a total abdominal hysterectomy and BSO (table 3). 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 (table 3). The median length of operation was 50% longer
when lymphadenectomy was done (table 3). The proportion of women having laparoscopic
procedures was similar in both groups (table 3). 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%]).
Table 4 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 (table 4). A few women
with low-risk early-stage disease received radiotherapy and a smaller proportion received
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EBRT with or without brachytherapy (table 5). 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 (table 5).
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 (table 5). 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 (table 6). Overall survival curves showed no evidence of a difference between the
two groups (figure 3).
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 (table
6). 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 (table 6). 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 (figure 3), 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. Table 7 summarises the
site of recurrence.
Kaplan-Meier curves for recurrence-free survival showed a conventionally significant benefit
for the standard surgery group (figure 3). Figure 4 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 (figure 4). 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%
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(1–12) in favour of standard surgery (figure 4). 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 (figure 4).
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 (table 8) 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.
We also undertook analyses of disease-specific survival, adjusting for baseline characteristics
with the Cox model (table 8). Results were similar to the unadjusted analysis (table 8).
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 (table
9). Our results suggest that, if anything, lymphadenectomy could be associated with a worse
outcome the more lymph nodes removed (table 9; 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 (table 9) lends support to this conclusion.
In the subgroups of women classified with low-risk early-stage disease, intermediate-risk and
high-risk early-stage disease, and advanced disease (figure 5), 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).
Discussion
This randomised trial has shown no evidence of a benefit for systematic lymphadenectomy for
endometrial cancer in terms of overall, disease-specific, and recurrence-free survival. This
study is one of the largest reported surgical gynaecological cancer trials. We undertook searches
to identify other published randomised trials of lymphadenectomy in endometrial cancer and
searched the Cochrane database for systematic reviews of both randomised and observational
studies. None was found but a randomised trial (smaller than ASTEC) has just been reported,
which confirms that lymphadenectomy is not associated with a survival benefit in endometrial
cancer.
The proportion of women with pelvic-node metastases in ASTEC (9%) was consistent with
that in the Gynaecological Oncology Group (GOG) surgical study of disease spread. The
ASTEC trial design successfully randomised participants to postoperative EBRT independent
of lymph-node status, resulting in a balanced proportion of irradiated women in both groups.
Lymphadenectomy might otherwise have led to more women categorised as having high-stage
disease in the lymphadenectomy group, which would have resulted in more women in this
population receiving postoperative EBRT. Thus, any effect in favour of the lymphadenectomy
group would have been enhanced. Although more women in the standard surgery group than
in the lymphadenectomy group, apart from in the low-risk early-stage subgroup, received
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EBRT (which might favour standard surgery), differences were not large. Furthermore, a
greater proportion of women in the lymphadenectomy group with positive lymph nodes
received EBRT (which might favour lymphadenectomy), although numbers were small.
However, in view of the results of the systematic review and meta analysis of 1770 women
from four randomised trials and now data from the ASTEC/EN.5 radiotherapy trial showing
that even a very small benefit of radiotherapy (more than 3% in 5-year overall survival) can
be excluded, this slight imbalance in the use of EBRT is neither statistically nor clinically
significant.
Several observational studies have compared outcomes in women who have received
systematic lymphadenectomy and those who have not, with some studies supporting
lymphadenectomy for all grades of tumour, another supporting it for G3 tumours, and others
suggesting that benefit depends on the number of lymph nodes removed. However, these
studies of treatment benefit should be interpreted with caution since they are prone to bias
because of systematic differences in women who do and do not receive lymphadenectomy,
including comorbidity and obesity that can be related to poor survival. Additionally, non-
randomised studies will always have a higher proportion of node-positive women with occult
stage III disease in the group who have not been surgically staged versus those classified as
stage I after lymphadenectomy with negative nodes and a reduced risk of recurrence (stage
migration). Large cancer registries are invaluable for monitoring trends in cancer incidence
and outcomes, for hypothesis generation, and for planning the provision of cancer services,
but they are not reliable for assessment of treatment effects. Analysis of large observational
cohorts means that small associations could be significant but they can easily arise from very
modest bias and should not be misinterpreted as measuring a direct effect of an intervention.
No national or international accepted guidelines exist for what is regarded as an adequate
systematic lymphadenectomy in terms of node counts, and therefore no specific guidelines
were given in the protocol. The number of nodes identified might depend on the physical
characteristic of the women, surgical thoroughness, and pathological examination of the
tissues. ASTEC succeeded in comparing systematic lymphadenectomy with a more
conservative approach of standard surgery with lymphadenectomy in women who only had
potentially positive nodes on palpation. The median lymph-node count of 12 in the
lymphadenectomy group is broadly similar to that in a large single-institution case series from
the USA, in which 11 nodes were removed, as well as a study using data from an large
observational database in which a median of between seven and 12 nodes were removed.
We were unable to undertake an unbiased analysis of outcome according to the number of
nodes removed for individual patients, since we would have had to break the randomised
comparison with the same issues of selection bias (although less stage shift). We were,
however, able to do the exploratory analysis that considered standard surgery versus
lymphadenectomy in centres which routinely removed different numbers of nodes. Results
from this analysis suggested that, if anything, the lymphadenectomy group had poorer
outcomes when more nodes were removed than the standard surgery group did. This finding
and the trend of a slightly higher recurrence in the lymphadenectomy group is potentially
important, although an explanation is not obvious. Although some node sampling occurred in
the standard surgery group, only 35 (5%) women had any nodes removed and, of these, 26
women had four or fewer removed. This small amount of non-compliance could have biased
the point estimate for the HR very slightly towards 1 (ie, no effect of lymphadenectomy) but
the treatment effect would have to have been very large for this small amount of non-
compliance to affect the overall result.
One limitation of this study is that the lymphadenectomy specified in the protocol was not
comprehensive and did not include all pelvic and para-aortic nodes. At the time ASTEC was
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conceived, the systematic lymphadenectomy (ie, lymphadenectomy rather than sampling) was
considered to be a potentially therapeutic procedure that could be implemented in the range of
hospitals where women with endometrial cancer are treated and in the range of women needing
it, including those in whom more extensive surgery might be difficult because of lack of
surgical access due to obesity. More extensive lymphadenectomy could have had significantly
increased treatment-related morbidity and mortality. Data for sentinel nodes have given insight
into the totality of the lymph drainage pattern in endometrial cancer and might well direct future
surgical research. Improvements in imaging could also make selection of high-risk women
easier so that a more extensive lymphadenectomy could be done in the subset of women for
whom lymph-node metastases are more likely and a more extensive operation is feasible (those
with little comorbidity, including obesity).
Morbidity was low overall, but we noted a substantial increase in the incidence of
lymphoedema in the lymphadenectomy group compared with standard surgery. Clinicians
might not have noted or reported milder cases, since all reported cases of lymphoedema were
moderate and severe.
We acknowledge that although ASTEC is a very large trial, only 191 deaths were recorded.
Could a small but important treatment effect have been missed? Recurrence-free survival is
the most powerful outcome measure (with 251 events). The lower limit of the 95% CI for the
adjusted HR for recurrence-free survival (table 8) of 0·93 translates into a benefit of 1·5% at
5 years (adjusted). Thus we can reliably exclude an improvement in 5-year recurrence-free
survival from lymphadenectomy of 1·5% or greater.
ASTEC has important implications for both clinical practice and future trials. The balance of
risks and benefits for systematic lymphadenectomy does not favour this intervention, with no
clear evidence of benefit in terms of overall or recurrence-free survival and increased risk of
lymphoedema. Although the results do not invalidate the use of lymphadenectomy for surgical
staging to identify the need for adjuvant treatment, our results suggest that lymphadenectomy
in itself has no therapeutic effect and is therefore not justified as a therapeutic procedure in its
own right. Some argue that surgical staging allows the most rational use of adjuvant
radiotherapy, reserving it for women with proven extrauterine disease. In doing so, long-term
effects associated with radiotherapy can be reduced without affecting survival. This argument
might be an over simplified view of the evidence, since results of GOG99 study showed that
when surgically staged women with negative nodes were randomly assigned, a protective effect
of radiotherapy against pelvic recurrence was still recorded although no evidence of a
difference in overall survival was noted (incidence of recurrence was 12% in the no
radiotherapy group and 3% in the radiotherapy group, relative hazard 0·42 [90% CI 0·25–0·73];
p=0·007). Estimated overall 4-year survival was 86% in the no radiotherapy group and 92%
for group with radiotherapy (relative hazard 0·86 [90% CI 0·57–1·29]; p=0·56). This finding
suggests that the decision regarding adjuvant therapy for intermediate-risk and high-risk
disease should be made independently of lymph-node status.
In conclusion, this large randomised trial suggests that unless surgical staging will directly
affect adjuvant therapy, routine systematic pelvic lymphadenectomy cannot be recommended
in women undergoing primary surgery for stage I endometrial cancer outside of clinical trials.
Surgical interventions should be assessed through randomised trials, and surgical staging as
part of a management strategy is no exception.
ASTEC study group
Trial design: H Kitchener, P Blake, J Sandercock, M K B Parmar.
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Writing committee: H Kitchener (University of Manchester, School of Cancer and Imaging
Sciences, Manchester, UK); A M C Swart (UCL Centre for Clinical Pharmacology and MRC
CTU, London, UK); and W Qian, C Amos, M K B Parmar (Cancer Group MRC CTU, London,
UK).
Chief clinical investigator: H Kitchener.
Data analysis: W Qian.
Trial management group: C Amos, P Blake, A Branson, C H Buckley, H Kitchener, M K B
Parmar, W Qian, CWE Redman, J Shepherd, A M C Swart.
Independent data monitoring committee: G Dunn, P Heintz, J Yarnold (chair).
Trial steering committee: P J ohnson, M Mason (chair), R Rudd.
MRC Clinical Trials Unit Data Management: C Amos, P Badman, S Begum, N Chadwick, S
Collins, K Goodall, J J enkins, K Law, P Mook, J Sandercock, C Goldstein, B Uscinska.
UK centres—Aberdeen Royal Infirmary (M Cruickshank, D E Parkin); Addenbrookes
Hospital, Cambridge (R A F Crawford, J Latimer); Bassetlaw Hospital, Worksop (M Michel);
Belfast City Hospital incorporating Belvoir Park Hospital (J Clarke, S Dobbs, R J McClelland,
J H Price); Birmingham Women's Hospital (K K Chan, C Mann); Bradford Royal Infirmary
(R Rand); Brighton General Hospital (A Fish); Bromhead Hospital, Lincoln (M Lamb);
Broomfield Hospital, Chelmsford (C Goodfellow, S Tahir); Chelsea and Westminster Hospital,
London (J R Smith); Cheltenham General Hospital (R Gornall, R Kerr-Wilson, G R Swingler);
Churchill Hospital, Oxford (B A Lavery); City Hospital Birmingham (K K Chan, S Kehoe);
Clatterbridge Centre for Oncology, Wirral (A Flavin); Colchester General Hospital (J Eddy);
Countess of Chester Hospital, Chester (J Davies-Humphries); Coventry Maternity Hospital (M
Hocking, L J Sant-Cassia); Cumberland Infirmary, Carlisle (S Pearson); Derby City General
Hospital (R L Chapman, J Hodgkins, I Scott); Derbyshire Royal Infirmary (D Guthrie, M
Persic); Derriford Hospital, Plymouth (F N Daniel, D Yiannakis); Doncaster Royal Infirmary
(M I Alloub, L Gilbert, M R Heslip); Queen Elizabeth the Queen Mother Hospital, Margate
(A Nordin); Edinburgh Royal Infirmary (G Smart, V Cowie); Epsom General Hospital (M
Katesmark); Essex County Hospital (P Murray, J Eddy); Gloucestershire Royal Hospital (R
Gornall, G R Swingler); Good Hope District Hospital, Sutton Coldfield (C B Finn, M
Moloney); Hammersmith Hospital, London (A Farthing, J Hanoch, P W Mason, A McIndoe,
W P Soutter); Harold Wood Hospital, Romford (H Tebbutt); Ipswich Hospital (J S Morgan,
D Vasey); J ames Cook University Hospital, South Cleveland (D J Cruickshank, J Nevin); J ohn
Radcliffe Hospital, Oxford (S Kehoe, I Z McKenzie); King's Mill Hospital, Nottingham (C
Gie); Leicester General Hospital (Q Davies, D Ireland, P Kirwan); Leicester Royal Hospital
(Q Davies); Lincoln County Hospital (M Lamb); Liverpool Women's Hospital (R Kingston, J
Kirwan, J Herod); LLandough Hospital, Penarth (A Fiander, K Lim); Manor Hospital, Walsall
(A C Head); Milton Keynes General Hospital (C B Lynch); New Cross Hospital,
Wolverhampton (A J Browning, C Cox, D Murphy); Ninewells Hospital, Dundee (I D Duncan,
C Mckenzie); Norfolk and Norwich Hospital (S Crocker, J Nieto); Northern General Hospital,
Sheffield (M E L Paterson, J Tidy); Northampton General Hospital (A Duncan); Nottingham
City Hospital (S Chan, K M Williamson); Oldchurch Hospital, Romford (A Weekes); Pilgrim
Hospital, Boston (O A Adeyemi); Poole Hospital HNS Trust (R Henry, V Laurence, S Dean);
Princess Royal Hospital, Hull (D Poole, M J Lind, R Dealey); Queen Elizabeth Hospital,
Gateshead (K Godfrey, M M Hatem, A Lopes, J M Monaghan, R Naik); Royal Bournemouth
General Hospital (J Evans); Royal Hallamshire Hospital, Sheffield (A Gillespie, M E L
Paterson, J Tidy); Royal Marsden Hospital, London (T Ind); Royal Shrewsbury Hospital (J
Lane, S Oates, D Redford); Royal Surrey County Hospital, Guilford (M Ford); Royal Sussex
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County Hospital, Brighton (A Fish, P Larsen-Disney); Royal United Hospital, Bath (N
J ohnson); Royal Victoria Infirmary, Belfast (A Bolger); Royal Preston Hospital (P Keating, P
Martin-Hirsch); Somerset Nuffield Hospital, Taunton (L Richardson); Southmead Hospital,
Bristol (J B Murdoch); St Batholomew's Hospital, London (A J eyarajah); St Georges Hospital,
Lincoln (M Lamb); St Helier Hospital, Surrey (N McWhinney); St Mary's Hospital, London
(A Farthing, P W Mason); St Mary's Hospital, Manchester (H Kitchener); St Mary's Hospital,
Portsmouth (J L Beynon, P Hogston, E M Low, R Woolas); St Michaels Hospital, Bristol (R
Anderson, J B Murdoch, P A R Niven); St Pauls Hospital, Cheltenham (R Kerr-Wilson);
Staffordshire General Hospital, Stafford (K Chin); Singleton Hospital, Swansea (P Flynn, O
Freites); Sussex Oncology (O Freites, A Fish, G H Newman); Taunton and Somerset Hospital
(O McNally); The Great Western Hospital, Swindon (J Cullimore); University College
Hospital, London (A Olaitan, T Mould); University Hospital of North Staffordshire, Stoke on
Trent (V Menon, C W E Redman); University Hospital of North Tees, Cleveland (M George,
M H Hatem); University Hospital Wales, Cardiff (A Evans, A Fiander, R Howells, K Lim);
Whiston Hospital, Prescot (G Cawdell); Wordsley Hospital, Stourbridge (A P Warwick);
Wycombe General Hospital (D Eustace); Yeovil District Hospital (J Giles); Ysbyty Gwynedd
Hospital, Bangor (S Leeson).
International centres—Groote Schuur Hospital, South Africa (J Nevin, AL van Wijk); Marie
Curie Institute, Poland (K Karolewski, M Klimek, P Blecharz); Wellington Hospital, New
Zealand (D McConnell).
Conflict of interest statement
We declare that we have no conflict of interest.
Correspondence to: Ann Marie C Swart, MRC Clinical Trials Unit, 222 Euston Road,
London NW1 2DA, UK
[email protected]
Acknowledgements
Acknowledgments
We thank the women who participated in this trial; the research staff at the clinical centres who helped to recruit women
and provide data; and Babak Oskooei for providing statistical input into preliminary analyses. The trial was funded
by the MRC through core funding to the MRC CTU.
References
1. Cancer Research UKCancerStats: corpus uteri cancer. http://info.cancerresearchuk.org/cancerstats/
(accessed Aug 5, 2008).
2. Boyle P, Leon ME, Maisonneuve P, Autier P. Cancer control in women. Update 2003. Int J Gynaecol
Obstet 2003;83(suppl 1):179–202. [PubMed: 14763175]
3. Cancer facts and figures 2008. American Cancer Society; Atlanta: 2006. Available at http://
seer.cancer.gov/csr/1975_2005/results_single/sect_01_table.01.pdf(accessed Aug 5, 2008).
4. Sant M, Aareleid T, Berrino F. EUROCARE-3: survival of cancer patients diagnosed 1990–94—results
and commentary. Ann Oncol 2003;14(suppl 5):v61–118. [PubMed: 14684501]
5. Boronow RC, Morrow CP, Creasman WT. Surgical staging in endometrial cancer: clinical-pathologic
findings of a prospective study. Obstet Gynecol 1984;63:825–832. [PubMed: 6728365]
6. Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham J E, Heller PB. Surgical pathologic
spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer 1987;60(suppl):
2035–2041. [PubMed: 3652025]
Page 11
Published as: Lancet. 2009 J anuary 10; 373(9658): 125–136.
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t
S
p
o
n
s
o
r
e
d
D
o
c
u
m
e
n
t
7. Kong A, Simera I, Collingwood M, Williams C, Kitchener H, on behalf of Cochrane Gynaecological
Cancer Group. Adjuvant radiotherapy for stage I endometrial cancer: systematic review and meta-
analysis. Ann Oncol 2007;18:1595–1604. [PubMed: 17347128]
8. The ASTEC/EN.5 writing committee. Adjuvant external beam radiotherapy in the treatment of
endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results,
systematic review, and meta-analysis.
9. Shepherd J H. Revised FIGO staging for gynaecological cancer. Br J Obstet Gynaecol 1989;96:889–
892. [PubMed: 2775686]
10. Kilgore LC, Partridge EE, Alvarez RD. Adenocarcinoma of the endometrium: survival comparisons
of patients with and without pelvic node sampling. Gynecol Oncol 1995;56:29–33. [PubMed:
7821843]
11. Morrow CP, Bundy BN, Kurman RJ . Relationship between surgical-pathological risk factors and
outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group
study. Gynecol Oncol 1991;40:55–65. [PubMed: 1989916]
12. Trimble EL, Kosary C, Park RC. Lymph node sampling and survival in endometrial cancer. Gynecol
Oncol 1998;71:340–343. [PubMed: 9887227]
13. Wells, M. Minimum dataset for the histopathological reporting of atypical hyperplasia and
adenocarcinoma in endometrial biopsy and curettage specimens and for endometrial cancer in
hysterectomy specimens. Standards and Minimum Datasets for Reporting Cancers. Royal College
of Pathologists; London: 2001.
14. Lefebvre, C.; Clarke, M. Identifying randomised trials. In: Egger, MSG.; Altman, DG., editors.
Systematic reviews in healthcare: meta-analysis in context. Vol. 2nd edn. BMJ Publishing Group;
London: 2001. p. 69-87.
15. Panici PB, Basile S, Maneschi F. Systematic pelvic lymphadenectomy vs no lymphadenectomy in
early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst 2008;100:1707–
1716. [PubMed: 19033573]
16. Cragun J M, Havrilesky LJ , Calingaert B. Retrospective analysis of selective lymphadenectomy in
apparent early-stage endometrial cancer. J Clin Oncol 2005;23:3668–3675. [PubMed: 15738538]
17. Fanning J . Long-term survival of intermediate risk endometrial cancer (stage IG3, IC, II) treated with
full lymphadenectomy and brachytherapy without teletherapy. Gynecol Oncol 2001;82:371–374.
[PubMed: 11531297]
18. Mohan DS, Samuels MA, Selim MA. Long-term outcomes of therapeutic pelvic lymphadenectomy
for stage I endometrial adenocarcinoma. Gynecol Oncol 1998;70:165–171. [PubMed: 9740684]
19. Lutman CV, Havrilesky LJ , Cragun J M. Pelvic lymph node count is an important prognostic variable
for FIGO stage I and II endometrial carcinoma with high-risk histology. Gynecol Oncol 2006;102:92–
97. [PubMed: 16406063]
20. Chan J K, Cheung MK, Huh WK. Therapeutic role of lymph node resection in endometrioid corpus
cancer: a study of 12333 patients. Cancer 2006;107:1823–1830. [PubMed: 16977653]
21. Keys HM, Roberts J A, Brunetto VL. A phase III trial of surgery with or without adjunctive external
pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology
Group study. Gynecol Oncol 2004;92:744–751. [PubMed: 14984936]
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Figure 1.
ASTEC trial design
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Figure 2.
Profile of ASTEC surgical trial
We did not collect logs of patients assessed for eligibility. TAH=total abdominal hysterectomy.
BSO=bilateral salpingo-oophorectomy. H=hysterectomy.
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Figure 3.
Overall survival (A), disease and treatment-related deaths (B), and recurrence-free survival
(C) by treatment group
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Figure 4.
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
A and B show Kaplan-Meier estimates, with Royston-Parmar parametric model fitted. C and
D show the absolute difference over time (95% CI) in survival from Royston-Parmar
parametric model.
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Figure 5.
Effect of lymphadenectomy on overall survival (A) and recurrence-free survival (B) in women
in different risk groups of recurrence
O–E=observed minus expected. Outer bars show 99% CI, inner bars show 95% CI.
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Table 1
Baseline characteristics
Standard surgery (N=704) Lymphadenectomy (N=704)
Age (years) 63 (36–89) 63 (34–93)
WHO performance status
0 520 (74%) 537 (76%)
1 156 (22%) 139 (20%)
2 23 (3%) 22 (3%)
3 4 (1%) 5 (1%)
4 1 (<1%) 1 (<1%)
Time between diagnosis and randomisation
(weeks)
4 (0–16) 4 (0–26)
≤6 weeks 576 (82%) 588 (84%)
>6 weeks 128 (18%) 116 (16%)
Surgical technique intended
Open 650 (92%) 659 (94%)
Laparoscopic 54 (8%) 45 (6%)
Body-mass index 29 (16–79) 29 (10–69)
Unknown 161 177
Data are median (range) or number (%) unless otherwise specified.
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Table 2
Pathology details
Standard surgery (N=683)
*
Lymphadenectomy (N=686)
*
Extent of tumour
Confined to corpus uteri 553 (81%) 538 (79%)
Spread beyond corpus uteri 128 (19%) 146 (21%)
Extension to endocervical glands 33 (27%) 34 (24%)
Extension to cervical stroma 53 (43%) 57 (40%)
Extension beyond uterus 38 (31%) 52 (36%)
Unknown 4 3
Unknown 2 2
Histology
Endometriod 545 (80%) 541 (79%)
Adenocarcinoma NOS 46 (7%) 37 (5%)
Clear cell 10 (1%) 17 (2%)
Papillary serous 21 (3%) 32 (5%)
Squamous 6 (1%) 5 (1%)
Mucinous 1 (<1%) 4 (1%)
Mixed epithelial stromal 7 (1%) 8 (1%)
Sarcoma 10 (1%) 9 (1%)
Other epithelial 4 (1%) 6 (1%)
Mixed epithelial 31 (5%) 25 (4%)
Unknown 2 2
Differentiation or grade
Well (G1) 225 (33%) 213 (31%)
Moderate (G2) 300 (44%) 290 (43%)
Poor (G3)
†
139 (20%) 158 (23%)
Not applicable
‡
16 (2%) 16 (2%)
Unknown 3 9
Depth of invasion
Endometriumonly 96 (14%) 89 (13%)
Inner half of myometrium 369 (55%) 310 (46%)
Outer half of myometrium 212 (31%) 274 (41%)
Unknown 6 13
Lymphovascular permeation
Present 125 (19%) 140 (22%)
Not present 407 (63%) 377 (59%)
Not stated 111 (17%) 127 (20%)
Unknown 40 42
Nodal involvement (if nodes harvested)
Yes 9 (27%) 54 (9%)
No 23 (72%) 560 (91%)
Unknown 0 1
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Standard surgery (N=683)
*
Lymphadenectomy (N=686)
*
Number of involved nodes
1 5 (56%) 28 (52%)
2 3 (33%) 12 (22%)
3 0 6 (11%)
4 0 2 (4%)
5 1 (11%) 4 (7%)
6 0 2 (4%)
Position of involved nodes
Unilateral 6 (67%) 31 (58%)
Bilateral 2 (22%) 19 (36%)
Para-aortic 1 (11%) 3 (6%)
Unknown 0 1
FIGO stage
§
IA 88 (13%) 84 (12%)
IB 318 (47%) 261 (39%)
IC 147 (22%) 187 (28%)
IIA 33 (5%) 34 (5%)
IIB 53 (8%) 57 (8%)
III/IV 38 (6%) 52 (8%)
Unknown 6 11
Data are number (%) or number. NOS=not otherwise specified.
*
Excludes patients whose pathology details did not confirmendometrial cancer: 39 women (21 standard surgery group, 18 lymphadenectomy group) who
had no other tumour in the surgical specimen; atypical hyperplasia; or cervical, ovarian, or colorectal cancer.
†
Including clear cell and serous papillary.
‡
Sarcoma and mixed epithelial sarcoma.
§
FIGO IIIC is not included here. Women with positive lymph nodes are classified irrespective of nodal status.
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Table 3
Surgery details
Standard surgery (N=702)
*
Lymphadenectomy (N=701)
*
Surgery received
Total abdominal hysterectomy/BSO 685 (99%) 693 (99%)
Subtotal hysterectomy/BSO 6 (1%) 2 (<1%)
Unknown 11 6
Nodes harvested
Yes 35 (5%) 630 (92%)
No 652 (95%) 58 (8%)
Unknown 15 13
Number of nodes harvested
1–4 26 (76%) 72 (12%)
5–9 4 (12%) 142 (23%)
10–14 1 (3%) 153 (25%)
>14 3 (9%) 243 (40%)
Unknown 1 20
Median (range) 2 (1–27) 12 (1–59)
Required blood transfusion
Yes 30 (4%) 39 (6%)
Unknown 18 12
Number of units
1 2 (7%) 1 (3%)
2 13 (45%) 21 (54%)
3 6 (21%) 5 (13%)
4 6 (21%) 9 (23%)
≥5 2 (7%) 3 (8%)
Unknown 1 0
Median (range) 2 (1–6) 2 (1–7)
Length of operation (min)
†
≤60 336 (52%) 83 (13%)
60–90 220 (34%) 285 (44%)
90–120 69 (11%) 190 (29%)
>120 25 (4%) 94 (14%)
Unknown 52 49
Median (range) 60 (10–255) 90 (10–390)
Number of postoperative days in hospital
Median (range) 6 (2–120) 6 (2–106)
Unknown 22 23
Surgical technique used
Laparoscopic 42 (6%) 45 (6%)
Open 647 (94%) 648 (94%)
Vertical incision 287 (45%) 384 (60%)
Published as: Lancet. 2009 J anuary 10; 373(9658): 125–136.
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Standard surgery (N=702)
*
Lymphadenectomy (N=701)
*
Pfannenstiel 311 (49%) 208 (32%)
Other transverse 43 (7%) 49 (8%)
Unknown 6 7
Unknown 13 8
Data are number (%) unless otherwise specified. BSO=bilateral salpingo-oophorectomy.
*
Five women (two standard surgery group, three lymphadenectomy group) were unable to complete surgery.
†
Defined as “fromknife to skin”.
Published as: Lancet. 2009 J anuary 10; 373(9658): 125–136.
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Table 4
Adjuvant radiotherapy received (within 3 months after surgery)
Standard surgery (N=704) Lymphadenectomy (N=704)
Radiotherapy received 227 (33%) 228 (33%)
External beam+/− brachytherapy 173 (25%) 165 (23%)
Brachytherapy only 54 (8%) 63 (9%)
Radiotherapy not received 471 (67%) 469 (67%)
Unknown 6 7
Published as: Lancet. 2009 J anuary 10; 373(9658): 125–136.
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Table 5
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
Standard surgery (N=683)
*
Lymphadenectomy (N=686)
*
Low-risk early-stage endometrial cancer
Total 330 (49%) 282 (42%)
Radiotherapy received
Yes 22 (7%) 24 (9%)
No 305 (93%) 257 (91%)
Unknown 3 1
External beam+/− brachytherapy 12 (4%) 9 (3%)
Brachytherapy only 10 (3%) 15 (5%)
Nodes removed
Yes 8 (2%) 255 (92%)
No 314 (98%) 22 (8%)
Unknown 8 5
Median number of nodes (range) 2 (1–3) 12 (1–59)
Nodal involvement
Yes (received EBRT) 1 (1) 6 (2)
No 7 249
Intermediate-risk and high-risk early-stage endometrial cancer
Total 243 (36%) 264 (39%)
Radiotherapy received
Yes 137 (56%) 138 (53%)
No 106 (44%) 124 (47%)
Unknown 0 2
External beam+/− brachytherapy 102 (42%) 98 (37%)
Brachytherapy only 35 (14%) 40 (15%)
Nodes removed
Yes 14 (6%) 244 (93%)
No 226 (94%) 17 (7%)
Unknown 3 3
Median number of nodes (range) 1 (1–16) 12 (1–51)
Nodal involvement
Yes (received EBRT) 4 (1) 21 (12)
No 10 233
Advanced endometrial cancer
Total 103 (15%) 124 (19%)
Radiotherapy received
Yes 62 (61%) 64 (53%)
No 40 (39%) 56 (47%)
Unknown 1 4
External beam+/− brachytherapy 55 (54%) 55 (46%)
Published as: Lancet. 2009 J anuary 10; 373(9658): 125–136.
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Standard surgery (N=683)
*
Lymphadenectomy (N=686)
*
Brachytherapy only 7 (7%) 8 (7%)
Nodes removed
Yes 10 (10%) 103 (85%)
No 91 (90%) 18 (15%)
Unknown 2 3
Median number of nodes 2 (1–6) 13 (1–38)
Nodal involvement
Yes (received EBRT) 4 (0) 25 (8)
No 6 78
Unknown, unable to classify risk group
Total 7 16
*
Excludes patients whose pathology details did not confirmendometrial cancer.
Published as: Lancet. 2009 J anuary 10; 373(9658): 125–136.
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Table 6
Cause of death
Standard surgery (N=704) Lymphadenectomy (N=704)
Total deaths 88 (13%) 103 (15%)
Disease related 56 (65%) 64 (63%)
Treatment related
*
4 (5%) 7 (7%)
Disease and treatment related
*
0 2 (2%)
Not disease or treatment related 26 (30%) 28 (28%)
Unknown 2 2
*
Details of treatment related, and disease and treatment related, cause of death: standard surgery group—renal failure (n=1), perforated ulcer (1), pulmonary
oedema (1), bowel ischaemia (1); lymphadenectomy group—pulmonary embolism(2), perforated duodenal ulcer (1), perforated diverticular disease (1),
bowel obstruction (1), bowel infarction (1), deep-vein thrombosis and infection (1), aspiration (1), no details (1).
Published as: Lancet. 2009 J anuary 10; 373(9658): 125–136.
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Table 7
Site of recurrence
Standard surgery (N=704) Lymphadenectomy (N=704)
Total recurrences 75 (11%) 98 (14%)
Local/vaginal 18 (25%) 24 (27%)
Pelvic 11 (15%) 10 (11%)
Distal 38 (53%) 49 (54%)
Local/vaginal and distal 0 3 (3%)
Pelvic and distal 5 (7%) 4 (4%)
Unknown 3 8
Published as: Lancet. 2009 J anuary 10; 373(9658): 125–136.
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Published as: Lancet. 2009 J anuary 10; 373(9658): 125–136.
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Table 9
Unadjusted and adjusted analysis classifying centres by median number of nodes
harvested, with the Cox model for overall survival and recurrence-free survival
Overall survival Recurrence-free survival
Centres with median LN count <10
Unadjusted (n=489) 0·81 (0·50–1·31) 1·01 (0·67–1·54)
Adjusted
*
(n=481)
0·54 (0·31–0·95) 0·72 (0·45–1·16)
Centres with median LN count 10–14
Unadjusted (n=314) 1·40 (0·74–2·64) 1·72 (1·00–2·96)
Adjusted
*
(n=307)
1·39 (0·67–2·90) 1·81 (0·99–3·27)
Centres with median LN count ≥15
Unadjusted (n=553) 1·57 (1·00–2·45) 1·71 (1·14–2·56)
Adjusted
*
(n=536)
1·37 (0·83–2·26) 1·50 (0·95–2·37)
Data are hazard ratio (95% CI). LN=lymph node.
*
Adjusted by covariates (with imputation by mean for unknown baseline) for age (continuous), WHO performance status (0, 1, 2, 3, or 4), weeks between
diagnosis and randomisation (≤6 weeks vs >6 weeks), surgical technique intended (open vs laparoscopic), type of incision (vertical vs Pfannenstiel vs
other transverse), extent of tumour (confined vs spread), histology (endometrioid/adenocarcinoma vs other), depth of invasion (inner half vs endometrium,
outer half vs endometrium), and differentiation (grade 1, grade 2, grade 3).
Published as: Lancet. 2009 J anuary 10; 373(9658): 125–136.