Keywords
neoplasms - uterus - endometrium - sentinel lymph node - biopsy - endometrial neoplasms
Palavras-chave
neoplasias - útero - endométrio - linfonodo sentinela - biópsia - neoplasias endometriais
Introduction
Endometrial cancer is the most common gynecological cancer in rich countries.[1] Overall survival is considered good because its diagnosis usually happens in the
early stages, with the disease confined to the uterus, and surgery is often curative.[2]
The standard surgical procedure, when indicated, is an extra-fascial total hysterectomy
with bilateral salpingo-oophorectomy.[1] Lymphadenectomy is included for staging; it used to be performed in all cases, but,
now, a more selective approach is preferred.[3] Node-positive documentation identifies a high-risk population and helps tailor adjuvant
therapy for node-negative results, potentially reducing the need for external radiation
therapy.[4] The therapeutic utility of lymphadenectomy is controversial; two randomized controlled
trials showed no therapeutic benefit in early endometrial cancer,[5]
[6] but, instead, it is associated with significant morbidity, up to a 50% risk of lymphedema,[7] increased risk of bleeding, intraoperative injury, and increased surgical time.[8] Sentinel node biopsy offers relevant information, and it is a useful procedure to
determine lymph node involvement in cases of early endometrial cancer,[3]
[9] with a lower risk of lymphedema.[9]
To evaluate the quality of each meta-analysis included in this study, the A Measurement
Tool to Assess Systematic Reviews (AMSTAR 2) tool, which allows critical evaluation
of systematic reviews that include randomized or non-randomized studies as well as
those with both designs in care interventions, was used.[10] This instrument considers that all its items used to assess systematic reviews are
important, but that seven of them can critically affect the validity of a review and
its conclusions. These items correspond to the existence of a protocol registered
before the beginning of the review, adequate bibliographic search, justification for
the exclusion of each of the studies, the risk of bias of each study included in the
review, suitability of the methods of meta-analysis, consideration of risk of bias
when interpreting the results of the review, and assessment of the presence and possible
impact of publication bias.[10]
Methods
A search of publications was conducted using the MeSH terms endometrial neoplasm and sentinel lymph node biopsy in the PubMed and Embase databases on October 21, 2020, and, again, on November 10,
2021, with the filters of meta-analysis and publication date set to since 2015. The
retrieved articles were screened by the title and abstract independently, with another
evaluator agreeing to read the entire article in case of discrepancy and make their
decision after this reading. The articles selected for this screening were studied
by the author, who read the complete articles and determined their relevance for the
review; those that were finally extracted were classified with the AMSTAR 2 evaluation
tool.
Results
The database searches found 17 articles, 7 of which were selected, after the screening,
for full review by the author. Finally, six of them were included for quality analysis.
[Figure 1] shows that the excluded publication did not report the results of the sentinel node
biopsy in endometrial cancer separately (the results were combined with those for
cervical cancer).[11]
Fig. 1 Information flow through the different phases of the systematic review.
A meta-analysis that included prospective cohort studies to evaluate sentinel lymph
node biopsy in stage I high-grade endometrial cancer patients found a false negative
rate of 8% (95% confidence interval [CI], 4–16%).[12] Other results of this study, as well as those of a study in laparoscopic surgery,[13] and two meta-analyses from 2017[14]
[15] are shown in [Chart 1]. The study by Lin et al.[14] also evaluated the laparoscopic surgery subgroup that had the best sensitivity within
the sentinel node mapping surgical options with 96% (95% CI: 88–99%).
Chart 1
Meta-analyses reporting the detection rate and sensitivity of sentinel node biopsy
in endometrial cancer
|
Author
|
Detection rate (%)
(95% CI)
|
Sensitivity (%)
(95% CI)
|
|
Marchocki et al.[12]
|
91
(85–95)
|
92
(84–96)
|
|
Wang and Liu[13]
|
96
(95–98)
|
96.3
(94–98)
|
|
Lin et al.[14]
|
83
(80–86)
|
91
(87–95)
|
|
Bodurtha Smith et al.[15]
|
81
(77–84)
|
96
(91–98)
|
Abbreviation: CI, confidence interval.
Sentinel node biopsy was superior to lymphadenectomy in detecting positive pelvic
nodes, but there was no difference in detecting positive para-aortic nodes in two
meta-analyzes that analyze this issue.[16]
[17]
[Chart 2]. The classification of the items with the AMSTAR 2 assessment tool are shown for
each study in [Chart 3].
Chart 2
Detection of pelvic and para-aortic nodes comparing sentinel node biopsy with lymphadenectomy
in endometrial cancer
|
Author
|
Pelvic nodes
Odds ratio (95% CI)
|
Paraortic nodes
Odds ratio (95% CI)
|
|
Gu et al.[16]
|
2.00
(1.21–3.32); p = 0.007
|
0.62
(0.24–1.64); p = 0.34
|
|
Bogani et al.[17]
|
2.03
(1.30–3.18); p = 0.002
|
0,93
(0,39–2.18); p = 0.86
|
Abbreviation: CI, confidence interval.
Chart 3
Assessment of each domain in the meta-analyses rated with the critical evaluation
tool for reviews AMSTAR 2
|
Question/author
|
1
|
2
|
3
|
4
|
5
|
6
|
7
|
8
|
9
|
10
|
11
|
12
|
13
|
14
|
15
|
16
|
Classification
|
|
Marchocki et al.[12]
|
Y
|
Y
|
N
|
N
|
Y
|
N
|
Y
|
Y
|
N
|
N
|
N
|
N
|
N
|
N
|
N
|
Y
|
CL
|
|
Wang and Liu[13]
|
Y
|
N
|
N
|
N
|
Y
|
Y
|
N
|
N
|
P
|
N
|
Y
|
Y
|
N
|
N
|
Y
|
Y
|
CL
|
|
Lin et al.[14]
|
N
|
N
|
N
|
N
|
Y
|
Y
|
N
|
P
|
P
|
N
|
N
|
N
|
N
|
N
|
N
|
N
|
CL
|
|
Bodurtha Smith et al.[15]
|
N
|
Y
|
N
|
N
|
Y
|
Y
|
N
|
Y
|
P
|
N
|
N
|
N
|
Y
|
Y
|
N
|
Y
|
CL
|
|
Gu et al.[16]
|
Y
|
Y
|
N
|
N
|
Y
|
Y
|
Y
|
N
|
N
|
N
|
N
|
N
|
N
|
N
|
N
|
Y
|
CL
|
|
Bogani et al.[17]
|
Y
|
P
|
N
|
P
|
N
|
N
|
Y
|
Y
|
N
|
N
|
N
|
N
|
N
|
N
|
N
|
Y
|
CL
|
Abbreviations: CL, critically low; N, no.; P, partial yes; Y, yes
Discussion
Most patients with endometrial cancer present without lymph node metastases, with
tumor confined to the uterus (about 75% stage I of the International Federation of
Gynecology and Obstetrics [FIGO] classification) that has a rate of overall survival
greater than 90%.[18]
The acceptance of sentinel node mapping within the National Comprehensive Cancer Network
(NCCN) guidelines as a procedure to be considered in the surgical staging of endometrial
cancer apparently confined to the uterus, without evidence of metastasis in the images
and without evidence of extrauterine disease in surgery,[3] confirms the indication of this procedure in surgical practice given the difficulty
in selecting cases for lymphadenectomy, as well as the lack of benefit in early stages
when this surgical procedure is performed, evidenced in randomized studies, and its
high rate of complications. Sentinel node mapping can allow staging with a simple,
rapid procedure and a lower risk of complications.[1] However, the speed of its acceptance does not seem consistent with the currently
available evidence. The inclusion of sentinel node mapping in endometrial cancer in
clinical practice has a low level of evidence derived mainly from observational studies,
and it is desirable to have more randomized studies to support its acceptance as an
alternative in the staging of this pathology. However, it is a story that begins to
seem to the current standard use of the sentinel node in the staging of axillary nodes
in clinically node-negative early breast cancer,19 in which its use was extended to the clinical setting, without high-level studies,
despite the insistence on the need for randomized studies but that was able to demonstrate
their advantages in the following years.[20] For greater safety with this new surgical option, it is recommended that surgeons
developing this technique adhere to an algorithm that includes a thorough evaluation
of retroperitoneal lymph nodes, selective or side-specific lymphadenectomy, if there
is no identified mapping within a hemipelvis, and removal of all suspicious lymph
nodes regardless of the mapping.[21]
The quality evaluation of each study found the general confidence of their results
to be critically low according to the AMSTAR 2 tool. This means that the review has
more than one critical flaw and should not be relied upon to provide an accurate and
complete summary of the available studies.[10] Among the critical domains, those corresponding to items 9 and 13 of the AMSTAR
2 listing refer to the risk of biases, which are present in all the meta-analyses
evaluated here in different magnitudes, except for the one by Bodurtha Smith et al.[15] for the consideration of these risks in the analysis of the results of the review.
These items that assess the risk of bias are given priority in the classification
because of the inclusion in the reviews of non-randomized studies.
Meta-analyses are important components of scientific information in evidence-based
medicine.[22] The number of these reviews has increased steadily, but their quality has not always
kept pace with this number.[23] To this issue, many instruments have been designed to evaluate the different aspects
of a review, AMSTAR 2 allows a more detailed evaluation of systematic reviews that
include non-randomized studies, which are increasingly being incorporated into these
studies.[10]
The limitations of this study are due to the design of the AMSTAR 2 tool in the evaluation
of the planning and performance of the reviews. As a new tool that includes non-randomized
studies in systematic reviews, it is necessary to wait for the feedback of users of
the instrument to consider making modifications.[10]
Conclusion
The current study found that the quality of recent meta-analyses on the utility of
sentinel node biopsy in the staging of endometrial cancer, evaluated by the AMSTAR
2 assessment tool — which allows evaluating systematic reviews that include non-randomized
studies — is classified as critically low, and, therefore, these meta-analyses are
not reliable to be used in the summary of their studies.
