Journal of

Clinical Medicine

Systematic Review
The Role of Adjuvant Therapy for the Treatment of
Micrometastases in Endometrial Cancer: A Systematic Review
and Meta-Analysis
Carlo Ronsini 1, * , Stefania Napolitano 2 , Irene Iavarone 1 , Pietro Fumiento 1 , Maria Giovanna Vastarella 1 ,
Antonella Reino 1 , Rossella Molitierno 1 , Lugi Cobellis 1 , Pasquale De Franciscis 1 and Stefano Cianci 3, *

1 Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi
Vanvitelli”, 80138 Naples, Italy; [email protected] (I.I.); [email protected] (P.F.);
[email protected] (M.G.V.); [email protected] (A.R.);
[email protected] (R.M.); [email protected] (L.C.);
[email protected] (P.D.F.)
2 Division of Medical Oncology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”,
80138 Naples, Italy; [email protected]
3 Gynecologic Oncology Unit, Women Wealth Area, Department of Woman and Child Health and Public
Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00136
Rome, Italy
* Correspondence: [email protected] (C.R.); [email protected] (S.C.)

Abstract: Endometrial cancer is the most incident gynecological cancer. Lymph node dissemination
is one of the most important factors for the patient’s prognosis. Pelvic lymph nodes are the primary
site of extra-uterine dissemination in endometrial cancer (EC), setting the 5-year survival to 44–52%.
It is standard practice for radiation therapy (RT) and/or chemotherapy (CTX) to be given as adjuvant
treatments to prevent the progression of micrometastases. Also, administration of EC patients
with RT and/or CTX regimens before surgery may decrease micrometastases, hence the need for
Citation: Ronsini, C.; Napolitano, S.; lymphadenectomy. The primary aim of the systematic review and meta-analysis is to assess whether
Iavarone, I.; Fumiento, P.; Vastarella, adjuvant RT and/or CTX improve oncological outcomes through the management of micrometastases
M.G.; Reino, A.; Molitierno, R.; and nodal recurrence. We performed systematic research using the string “Endometrial Neoplasms”
Cobellis, L.; De Franciscis, P.; Cianci, S. [Mesh] AND “Lymphatic Metastasis/therapy” [Mesh]. The methods for this study were specified
The Role of Adjuvant Therapy for the a priori based on the recommendations in the Preferred Reporting Items for Systematic Reviews
Treatment of Micrometastases in and Meta-Analyses (PRISMA) statement. Outcomes were 5-year overall survival, progression-
Endometrial Cancer: A Systematic
free survival, recurrence rate, and complications rate. We assessed the quality of studies using
Review and Meta-Analysis. J. Clin.
the Newcastle–Ottawa Scale (NOS). A total of 1682 patients with stage I-to-IV EC were included.
Med. 2024, 13, 1496. https://doi.org/
Adjuvant treatment protocols involved external-beam RT, brachytherapy, and CTX either alone or
10.3390/jcm13051496
in combination. The no-treatment group showed a non-statistically significant higher recurrence
Academic Editors: Jacek Szamatowicz risk than any adjuvant treatment group (OR 1.39 [95% CI 0.68–2.85] p = 0.36). The no-treatment
and Farr R Nezhat
group documented a non-statistically significant higher risk of death than those who underwent
Received: 15 January 2024 any adjuvant treatment (RR 1.47 [95% CI 0.44–4.89] p = 0.53; I2 = 55% p = 0.000001). Despite the fact
Revised: 15 February 2024 that early-stage EC may show micrometastases, adjuvant treatment is not significantly associated
Accepted: 1 March 2024 with better survival outcomes, and the combination of EBRT and CTX is the most valid option in the
Published: 5 March 2024 early stages.

Keywords: endometrial cancer; micrometastases; radiation therapy; chemotherapy; adjuvant

Copyright: © 2024 by the authors.

Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
1. Introduction
conditions of the Creative Commons Endometrial cancer (EC) is the most diffuse gynecological neoplasia worldwide, oc-
Attribution (CC BY) license (https:// curring in 2–3% of patients [1]. The main risk factor for endometrial cancer is exposure
creativecommons.org/licenses/by/ to an excessive estrogenic environment that is not balanced by an adequate amount of
4.0/). progesterone; therefore, obese patients are more at risk due to the production of estrogen

J. Clin. Med. 2024, 13, 1496. https://doi.org/10.3390/jcm13051496 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2024, 13, 1496 2 of 13

by aromatase in adipose tissue, patients affected by PCOS due to chronic anovularity with
deficiency in progesterone production with relative hyperestrogenism, patients suffering
from diabetes mellitus and arterial hypertension, early menarche, late menopause, nulli-
parity, patients being treated with tamoxifen, and patients after the fourth and fifth decade
of life [1,2]. Vaginal bleeding is the most common sign of endometrial malignancy, and
thanks to it, more than 75% of women are diagnosed with early-stage disease. Following
abnormal uterine bleeding, especially in menopausal women, it would be necessary to
carry out a transvaginal pelvic ultrasound, which will detect endometrial thickening (where
endometrial thickening in a menopausal woman means a thickness greater than 4 mm).
From here, it would be necessary to carry out a diagnostic hysteroscopy with targeted
biopsy near the areas suspected of malignancy (for example, areas with vascular atypia).
Histological examination will give definitive confirmation.
There is also a family predisposition to develop endometrial carcinoma. Among
them, we remember Lynch syndrome type II, in which there is a greatly increased risk
of developing malignant tumors of the colon, endometrium, and ovary. Therefore, it is
of fundamental importance to search for hereditary tumors when a young patient with
endometrial cancer is found.
This leads to a favorable prognosis with an overall 80–85% survival at 5 years [2,3].
Only 10% of patients with clinical early-stage EC have lymph node involvement [4,5].
Otherwise, it would be appropriate to establish standard treatment protocols to appraise
the risk of relapse and the adverse effects of unnecessary treatments [6–9]. Nowadays, the
main issue regards the extent of surgical dissection—also for staging purposes—especially
for lymph nodes [2,6,7]. Macrometastases are defined as those with dimensions >2 mm;
micrometastases are defined as those with dimensions between 0.2 and 2 mm or greater
than 200 cells; isolated tumor cells are released if <0.2 mm or <200 cells [6].
The presence of micrometastases into the pelvic lymph nodes—when EC is limited
to the uterine corpus—is estimated to be 5%-to-18% [2]. The involvement of retroperi-
toneal lymph nodes—embracing pelvic and/or para-aortic nodes—shows worse prognosis,
with 44%–to-52% overall survival (OS) at 5 years [2]. The standard treatment for EC con-
fined to the uterus is class A radical hysterectomy—according to the Querleu–Morrow
classification—with bilateral salpingo-ooforectomy [2,10,11]. Pelvic lymph nodes are the
main site of extra-uterine dissemination of the disease, setting the prognosis to 44–52% at
5 years [2]. Indeed, lymphadenectomy may be recommended for all EC stages, whereas
some may recommend selective pelvic and para-aortic lymph node dissection based on
tumor grading and myometrial invasion [5]. The extension of the surgical intervention
suggests that the incidence of regional lymph node involvement in EC could be 10%-to-34%
in high-risk women but up to 5% in low-risk categories [5]. Internationally accepted clinical
and pathological risk factors estimating prognosis are lymph node involvement, lympho-
vascular space invasion (LSVI), tumor grading, patient age, and T classification [12,13].
Data from PORTEC 1 and 2 trials also recognized LVSI as a risk factor for pelvic nodal
relapse [14]. LVSI is represented by neoplastic cells entering uterine lymphatic or vascular
spaces and occurs in 15% of stage I-II EC [15,16]. It is standard practice for radiation therapy
(RT) and/or chemotherapy (CTX) to be given as adjuvant treatments. Administration of
EC patients with radiation therapy (RT) and/or chemotherapy (CTX) regimens—before
surgery also—may decrease the rate of micrometastases, hence the need for lymphadenec-
tomy [17,18]. Nowadays, sentinel lymph node (SLN) mapping is considered a valid
alternative to systematic lymphadenectomy in order to assess nodal involvement [19–21].
The sentinel lymph node technique consists of identifying the first drainage lymph node
station of the uterus through an endocervical injection of indocyanine green, which thus
allows us to easily identify the sentinel lymph node and then remove and analyze it. In
some cases, this technique fails, and therefore a systematic pelvic lymphadenectomy, which
is certainly a more invasive procedure, is necessary for staging.
The potential management of micrometastases remains unclear. In addition, SLNs may
be evaluated for pathologic ultrastaging because it provides prognostic details [14,15,19,20].
J. Clin. Med. 2024, 13, 1496 3 of 13

The primary objective of the present systematic review and meta-analysis is to assess
whether adjuvant RT and/or CTX regimens improve oncological outcomes through the
management of micrometastases and lymph node relapse. Secondarily, we aim to determine
whether there is a suitable and optimal combination of those treatment regimens for
different categories of patients.

2. Materials and Methods

The present study was exempted from ethical approval because it does not include
interventions on human subjects. The methods for this study were specified a priori
based on the recommendations in the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) statement [22]. The review is registered on PROSPERO as
ID431489.

2.1. Search Method

We performed systematic research for records about the eventual use of different
therapeutic regimens in managing micrometastases in EC via PubMed, EMBASE, Scopus,
Google Scholar, Clinical-trials.gov, and the Cochrane Central Register of Controlled Trials
in April 2023. We made no restriction on country or year of publication and considered
only English-entirely published studies. We adopted the following string of idioms in each
database to identify studies fitting to our review’s topic: “Endometrial Neoplasms” [Mesh]
AND “Lymphatic Metastasis/therapy” [Mesh].

2.2. Study Selection

Study selection was made independently by I.I. and P.F. In cases of discrepancy, C.R.
decided on inclusion or exclusion. Our population included patients with histological
diagnoses of EC and lymph node involvement. No restrictions concerning FIGO stage,
tumor grading, or the site of lymph node recurrence were applied. Recurrence and survival
outcomes were analyzed, and treatment options—RT, CTX, and HT—were compared.
The inclusion criteria were the following: (1) studies that included patients histologically
diagnosed with EC with microscopic involvement of at least one lymph node (<2 mm);
(2) studies reporting at least one outcome of interest: OS, recurrence rate (RR); progression-
free survival (PFS) after either observation or adjuvant treatment of micrometastases;
and (3) peer-reviewed articles, published originally. We excluded the following: non-
original studies, pre-clinical trials, animal trials, abstract-only publications, and articles
in a language other than English. If possible, the authors of studies that were published
as conference abstracts were contacted via e-mail and asked to provide their data. We
mentioned the studies selected and all the reasons for exclusion in the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart (Figure 1). We
assessed all the included studies concerning potential conflicts of interest.

2.3. Statistical Analysis

Heterogeneity among comparative studies was tested using the Chi-square test and
I-square tests [23]. Risk rates and 95% confidence intervals (CI) were used for dichotomous
variables. Statistical analysis was conducted using fixed-effect models without significant
heterogeneity (I2 < 50%) or using random-effect models if I2 > 50%. The 5-year OS, 5-year
PFS, 5-year RR, and complications rate were the clinical outcomes calculated in each study
as percentages. The chi-square test was used to compare continuous variables. Review
Manager version 5.4.1 (RevMan 5.4.1) and IBM Statistical Package for Social Science (IBM
SPSS version 25.0) for MAC were used for statistic calculation. For all the performed
analyses, a p-value < 0.05 was considered significant.
J. Clin. Med. 2024, 13, 1496 4 of 13

Identification

Records identified through PubMed Records identified through EMBASE Records identified through
database searching database searching Scopus, Cochrane Library, and
n=21 n=38 ScienceDirect database searching
n=35

Records removed by selection from title

n=54
Screening

Record titles screened Duplicates removed

n=40 n=12

Article abstracts screened Records excluded by

n=28 selection from abstract
n=14
Eligibility

Full-text articles excluded,

Full-text articles assessed
with reasons:
for eligibility
n=3, not in English;
n=14
n=2, full-text not available.

Studies included in
qualitative synthesis
Included

n=9

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart.

Figure 1. Preferred Reporting Items

2.4. Quality for Systematic Reviews and Meta-Analyses (PRISMA)
Assessment
flowchart. We assessed the quality of the included studies using the Newcastle–Ottawa Scale
(NOS) [24]. That assessment scale uses three broad factors (selection, comparability, ex-
2.3. Statistical Analysis posure), with scores ranging from 0 (lowest quality) to 9 (best quality). Two authors (I.I.
Heterogeneity among and comparative
P.F.) independently rated
studies wasthe studies’
tested quality.
using Any disagreement
the Chi-square test andwas resolved by
discussion or consultation with C.R. We have reported the NOS
I-square tests [23]. Risk rates and 95% confidence intervals (CI) were used for dichotomousscale in Appendix A. We
used a funnel plot analysis to establish publication bias.
variables. Statistical analysis was conducted using fixed-effect models without significant
heterogeneity (I2 < 50%)3.or using random-effect models if I2 > 50%. The 5-year OS, 5-year
Results
PFS, 5-year RR, and complications rate were the clinical outcomes calculated in each study
3.1. Studies’ Characteristics
as percentages. The chi-square After the was
test usedsearch,
database to compare continuous
40 articles matched variables.
the search Review
criteria. After removing
Manager version 5.4.1 (RevMan 5.4.1)
records with no and IBM duplicates,
full-text, Statistical Package
and wrong forstudy
Socialdesigns
Science(e.g.,
(IBM reviews), 14 were
SPSS version 25.0) for MAC were
eligible. used
Nine for statistic
articles matchedcalculation.
the inclusionFor all the
criteria performed
and anal-in the systematic
were included
yses, a p-value <0.05 was review. Four articles
considered were non-comparative, single-armed studies evaluating only adjuvant
significant.
treatment regimens for micrometastases [25–28]. The other five were comparative studies
2.4. Quality Assessment between observation and adjuvant treatments for micrometastases and were included in
quantitative analysis (Figure 1) [29–33]. The countries where the studies were conducted,
We assessed the quality of the included
the publication studies
year range, using the
the studies’ Newcastle–Ottawa
design, Scale Federation of
the FIGO (International
(NOS) [24]. That assessment scale uses three broad factors (selection, comparability,
Gynecology and Obstetrics) stage of disease, the number of participants, ex- and adjuvant
posure), with scores ranging from
treatment 0 (lowest
protocols are quality) to 9in(best
summarized Tablequality). Two authors
1. The quality (I.I. was assessed by
of all studies
and P.F.) independently rated the studies’ quality. Any disagreement was resolved by dis-
NOS [24] (Appendix A). Overall, the publication years ranged from 2014 to 2021 [25–33].
cussion or consultationInwith
total,C.R.
1682Wepatients
havewith EC were
reported theincluded [25–33].
NOS scale The follow-up
in Appendix A. We(FU) period ranged
from 17.8 to 84.8 months on average
used a funnel plot analysis to establish publication bias. [25–33].
J. Clin. Med. 2024, 13, 1496 5 of 13

Table 1. Characteristics of included studies.

Median FU
Author, Year of Period of FIGO No. of Adjuvant
Country Study Design Period
Publication Enrollment Stage Participants Treatment
(Months)
Single-arm studies
Retrospective
Raimond, 2014 [25] France 2000–2012 observational I 156 EBRT, BT N/A
multi-center cohort study
Perspective
Lee, 2017 [26] USA 1990–2015 interventional IIIC2 72 EBRT ± CTX 43.0
mono-center cohort study
Retrospective
Piedimonte, observational
Canada 2012–2018 I 23 EBRT + CTX 24.0
2018 [27] mono-center case-control
study
Perspective EBRT, BT,
Forsse, 2020 [28] Norway 2001–2019 interventional I-IV 445 CTX ± RT, 49.0
mono-center cohort study HT
Comparative studies—adjuvant treatment vs. LN-included for meta-analysis
Prospective
interventional
Ignatov, 2019 [29] Germany 2000–2017 N/A 126 EBRT 84.8
multi-center case-control
study
Retrospective
observational
Onal, 2019 [30] Turkey 2000–2016 IIIC1 167 EBRT ± CTX 49.0
mono-center case-control
study
Retrospective
observational High-dose
Ito, 2020 [31] Japan 2008–2018 N/A 113 17.8
multi-center case-control salvage RT
study
Retrospective
observational EBRT ± BT
Son, 2020 [32] USA 2005–2015 IA-IB-II 405 69.0
multi-center case-control ± CTX, HT
study
Retrospective
EBRT ± CTX,
Backes, 2021 [33] USA 2005–2017 observational IA-IB-II 175 31.0
BT
multi-center cohort study
FIGO: International Federation of Gynecology and Obstetrics; FU: follow-up; EBRT: external-beam radiation
therapy; BT: brachytherapy; CTX: chemotherapy; HT: hormone therapy.

3.2. Outcomes
A total of 1682 patients with stage I-to-IV EC were included in the review [25–33].
Adjuvant treatment protocols included external beam (EB) RT, BT, and CTX either alone
or in combination [25–33]. The studies by Raimond et al. and Backes et al. presented the
highest PFS rates at 5 years (91% and 95%, respectively), together with the lowest 5-year RR
(9% and 5.1%, respectively) [25,33]. Those articles showed data neither about OS nor about
the adverse effects of adjuvant therapy [25,33]. In both cohorts, patients were at an early
stage of the disease, and adjuvant treatment protocols for pelvic nodal relapse included
EBRT or BT [25,33]. Backes et al. used EBRT ± CTX in order to treat the para-aortic site of
recurrence as well [33]. The Forsse et al. cohort included patients with FIGO I-to-IV stages
of the disease, and nodal relapse was located on pelvic and para-aortic lymph nodes [28].
Patients were administered EBRT ± CTX, BT, or HT [28]. The 5-year PFS and OS rates were
81.5% and 75%, respectively, whereas the 5-year RR was 17% [28]. No data were shown
regarding iatrogenic toxicities [28]. In the study by Piedimonte et al., nodal recurrence
was located on the iliac, obturator, and para-aortic lymph nodes [27]. Patients at FIGO
stage I were administered EBRT ± CTX, and the 5-year PFS, OS, and RR were 77.5%, 50%,
and 8.7%, respectively [27]. Adverse events were 9.1%, according to the National Cancer
J. Clin. Med. 2024, 13, 1496 6 of 13

Institute Common Toxicity Criteria ≥ 3. In addition, Onal et al. described recurrence in

pelvic and para-aortic lymph nodes [30]. Although PFS and OS at 5 years were 77% and
J. Clin. Med. 2024, 13, x FOR PEER REVIEW 7 of 15
71%, respectively, the 5-year RR was 34.7%. In that case, patients were administered EBRT
± CTX, and the FIGO stage of the disease was IIIC1 [30]. Lee et al. presented the lowest
5-year PFS and OS rates (51% and 48%, respectively) [26]. Women with para-aortic lymph
node recurrence were administered
Single-arm EBRT ± CTX, and the FIGO stage of the disease was
studies
IIIC1 [26]. Those results are summarized in Table 2.
Raimond, 2014 [25] Pelvic 91.0 N/A 9 N/A
Table 2. Outcomes.
Lee, 2017 [26] Para-aortic 51.0 48.0 51.4 0.0
Iliac, obturator, National Cancer
Piedimonte, 2018 [27] 77.5 50.0 8.7 9.1 Common
Institute
Author, Year of para-aortic
LNs 5-Year PFS (%) 5-Year OS (%) 5-Year RR (%) Toxicity Criteria
Publication
Forsse, 2020 [28] Pelvic, para-aortic 81.5 75.0 17.0 N/A
for Adverse
Events ≥3 (%)
Comparative studies—adjuvant treatment vs. LN-included for meta-analysis
Single-arm studies
Ignatov,
Raimond, 20142019
[25] [29] Pelvic, para-aortic 91.0
Pelvic 70.0 N/A
N/A 30.0 9 N/A
N/A
Onal,
Lee, 2017 2019
[26] [30] Pelvic, para-aortic 51.0
Para-aortic 77.0 48.071.0 34.751.4 N/A0.0
Piedimonte, 2018 Iliac, obturator,
Para-aortic, iliac, 77.5 50.0 8.7 9.1
[27] para-aortic
Ito, 2020 [31] presacral, obtura- 17.5 74.8 25.1 0.0
Forsse, 2020 [28] Pelvic, para-aortic
tor 81.5 75.0 17.0 N/A
Comparative studies—adjuvant treatment vs. LN-included for meta-analysis
Son, 2020 [32] Pelvic, para-aortic 77.2 81.5 18.0 N/A
Ignatov, 2019 [29] Pelvic, para-aortic 70.0 N/A 30.0 N/A
Backes, 2021 [33] Pelvic, para-aortic 95.0 N/A 5.1 N/A
Onal, 2019 [30] Pelvic, para-aortic 77.0 71.0 34.7 N/A
LNs: lymph nodes; PFS: progression-free survival; OS: overall survival; RR: recurrence rate.
Para-aortic, iliac,
Ito, 2020 [31] presacral, 17.5 74.8 25.1 0.0
3.3. Meta-Analysis
obturator
Son, 2020 [32] The five studies
Pelvic, para-aortic 77.2 comparing no treatment
81.5 for micrometastases
18.0 with anyN/A
other adju-
vant treatment were enrolled in the meta-analysis. A total of 986 patients were analyzed.
Backes, 2021 [33] Pelvic, para-aortic 95.0 N/A 5.1 N/A
A total of 300 patients in the no-treatment arm were compared with 686 patients who
LNs: lymph nodes; PFS: progression-free survival; OS: overall survival; RR: recurrence rate.
underwent any adjuvant treatment, as described in Table 1, by exploring the DFS outcome.
Because of the high heterogeneity (I2 > 50%; p < 0.00001), a random-effects model was
3.3. Meta-Analysis
applied.
The five studies comparing
The no-treatment no treatment
group showed for micrometastases
a non-statistically with recurrence
significant higher any other adjuvant
risk than
treatment
any adjuvant were enrolledgroup
treatment in the(OR
meta-analysis.
1.39 [95% CIA0.68–2.85]
total of 986
p =patients
0.36), aswere
shownanalyzed.
in FigureA2.total
of 300We
patients in theano-treatment
performed sub-analysis arm were
for the compared
patients withat686
looking thepatients
risk of who underwent
death. Unfortu-
any adjuvant treatment, as described in Table 1, by exploring the DFS
nately, only three of the five comparative studies reported useful data: 193 patients outcome. Because of
for the
the high heterogeneity (I2 > 50%; p < 0.00001), a random-effects model
no-treatment group and 492 for any other adjuvant treatment group. In addition, in that was applied.
The no-treatment
analysis, the no-treatmentgroup showed
group a non-statistically
documented significant
a non-statistically higher recurrence
significant higher riskrisk
of
than adjuvant treatment group (OR 1.39 [95% CI 0.68–2.85] p
death than those who underwent any adjuvant treatment (RR 1.47 [95% CI 0.44–4.89] pin=
any = 0.36), as shown
Figure
0.53; I22.= 55% p = 0.000001), as documented in Figure 3.

Figure 2.
Figure 2. Risk
Risk of
of recurrence.
recurrence.
J. Clin. Med. 2024, 13, 1496 7 of 13

We performed a sub-analysis for the patients looking at the risk of death. Unfortu-
nately, only three of the five comparative studies reported useful data: 193 patients for
the no-treatment group and 492 for any other adjuvant treatment group. In addition, in
that analysis, the no-treatment group documented a non-statistically significant higher risk
J. Clin. Med. 2024, 13, x FOR PEER REVIEW
of death than those who underwent any adjuvant treatment (RR 1.47 [95% CI 0.44–4.89] 8 of 15

p = 0.53; I2 = 55% p = 0.000001), as documented in Figure 3.

Figure 3.
Figure 3. Risk
Risk of
of death.
death.

4. Discussion
4. Discussion
The
The cohorts
cohorts analyzed
analyzed in in our study were
our study were principally
principally administered
administered with with aa combination
combination
of
of EBRT and CTX [25–27,30,33]. Raimond et al. and Backes et al. documented the
EBRT and CTX [25–27,30,33]. Raimond et al. and Backes et al. documented the highest
highest
PFS rates (91% and 95%, respectively) and the lowest RR (9%
PFS rates (91% and 95%, respectively) and the lowest RR (9% and 5.1%, respectively) and 5.1%, respectively) [25,33].
In particular, the Raimond et al. cohort included patients with
[25,33]. In particular, the Raimond et al. cohort included patients with FIGO stage I only, FIGO stage I only, whereas
in the Backes
whereas in the et al. study,
Backes etpatients
al. study, were FIGO were
patients stage I-II
FIGO [25,33].
stageThose data demonstrate
I-II [25,33]. Those data
that EBRT ± CTX may be a valid adjuvant treatment
demonstrate that EBRT ± CTX may be a valid adjuvant treatment option for option for patients with early-stage
patients with
EC and micrometastases in pelvic and para-aortic lymph nodes.
early-stage EC and micrometastases in pelvic and para-aortic lymph nodes. In parallel, In parallel, EBRT ± CTX
showed lower survival outcomes in the Lee et al. study [26].
EBRT ± CTX showed lower survival outcomes in the Lee et al. study [26]. In that case, In that case, patients had FIGO
IIIC2
patientsEC had
and FIGO
metastases
IIIC2 inECpara-aortic
and metastases nodes,inrevealing
para-aortic thatnodes,
adjuvant therapy
revealing may
that not be
adjuvant
sufficient in advanced stages of disease [26]. The diagnosis
therapy may not be sufficient in advanced stages of disease [26]. The diagnosis of mi- of micrometastases in women
with apparent node-negative EC could be crucial for prognosis [34]. In fact, the presence of
crometastases in women with apparent node-negative EC could be crucial for prognosis
isolated tumor cells (ITCs) and nodal metastases is related to an increased number of breast,
[34]. In fact, the presence of isolated tumor cells (ITCs) and nodal metastases is related to
colon, and prostate cancers [35–39]. Results regarding SLN pathologic ultrastaging confirm
an increased number of breast, colon, and prostate cancers [35–39]. Results regarding SLN
that women with ITCs may be managed as node-negative [40]. In that specific context,
pathologic ultrastaging confirm that women with ITCs may be managed as node-negative
adjuvant treatment can be assessed according to uterine risk factors. Whereas women with
[40]. In that specific context, adjuvant treatment can be assessed according to uterine risk
micrometastases can be managed as node-positive [40]. Based on our study, due to the
factors. Whereas women with micrometastases can be managed as node-positive [40].
heterogeneity of the data and the exiguous number of fitting records, it is impossible to
Based on our study, due to the heterogeneity of the data and the exiguous number of
determine the correct sequence of RT and CTX [25–27,30,40]. In order to avoid that bias,
fitting records, it is impossible to determine the correct sequence of RT and CTX [25–
the extent of the sample size for each category of treatment could allow authors to perform
27,30,40]. In order to avoid that bias, the extent of the sample size for each category of
further trials to assess recurrence and survival outcomes after the use of RT, CTX, and
treatment could allow authors to perform further trials to assess recurrence and survival
combinations of those regimens, respectively. However, the molecular profile of EC patients
outcomes
should after thewhen
be assessed use of RT, CTX, adjuvant
considering and combinations of those regimens,
treatment regimens respectively.
[40]. For example, there
However,
is evidencethe thatmolecular
cytokeratin profile of EC patients
expression in regional should
lymph benodes
assessed when to
is related considering
the positivityad-
juvant treatment regimens [40]. For example, there is evidence
of LVSI (p = 0.011), deep myometrial invasion, and disease recurrence (p < 0.0001) [41,42].that cytokeratin expression
in addition,
In regional lymph nodes isofrelated
the expression to theinpositivity
cytokeratin metastaticoflymph LVSI (p = 0.011),
nodes did notdeep myometrial
concern tumor
invasion, and disease recurrence (p < 0.0001) [41,42]. In addition,
cells, and it was related to disease recurrence in early-stage EC (p = 0.0096) [41]. Recent the expression of cy-
tokeratin in metastatic lymph nodes did not concern tumor
evidence demonstrated that the molecular subtype was significantly related to nodal metas- cells, and it was related to
disease
tases (p =recurrence
0.004) [43].inIn early-stage
particular,EC the(pexpression
= 0.0096) [41]. Recent
of p53abn evidence
presents nodaldemonstrated
involvement that
in
the molecular subtype was significantly related to nodal
44.8% of patients; POLEmut shows nodal metastases in 14.2% of cases; MMRd in 14.9%; metastases (p = 0.004) [43]. In
particular, the expression of p53abn presents nodal involvement
and NSMP in 10.8% [43]. Regarding metastases’ entity, subsequent evidence compared in 44.8% of patients;
POLEmut shows
oncological outcomesnodal in metastases
women with in ITCs,
14.2%micrometastases,
of cases; MMRd in and 14.9%; and NSMP in[44–46].
macrometastases 10.8%
[43]. Regarding metastases’ entity, subsequent evidence
Women with micrometastases showed significantly better survival outcomes compared tocompared oncological outcomes
in women
women with with ITCs, micrometastases,
macrometastases, and macrometastases
and the difference [44–46]. Women
between micrometastases and with
negativemi-
crometastases
lymph nodes in showed
PFS was significantly
not significant,betterdemonstrating
survival outcomes comparedlymph
that negative to women nodeswith are
macrometastases,
not a better prognostic and the difference
factor compared between micrometastases
to micrometastases and negative
[44–46]. lymphPineda
In the García nodes
in al.
et PFSanalysis,
was not the significant,
authorsdemonstrating
provide information that negative
regarding lymphthenodes are not a better
histopathological prog-
features
nostic factor compared to micrometastases [44–46]. In the
of EC patients with micrometastases [46]. For example, most micrometastases showed García Pineda et al. analysis, the
authors provide information regarding the histopathological features of EC patients with
micrometastases [46]. For example, most micrometastases showed endometrioid histol-
ogy and low grading, and no difference between patients with and without nodal metas-
tases was noticed [46]. Instead, myometrial invasion appeared as an independent risk fac-
tor for nodal metastases [46]. The strength of our analysis is that it embraces all studies
J. Clin. Med. 2024, 13, 1496 8 of 13

endometrioid histology and low grading, and no difference between patients with and
without nodal metastases was noticed [46]. Instead, myometrial invasion appeared as an
independent risk factor for nodal metastases [46]. The strength of our analysis is that it
embraces all studies assessing whether adjuvant EBRT and/or CTX regimens improve
oncological outcomes through the management of micrometastases and lymph node re-
lapse. One limitation of our study is the exiguous number of available records in the
scientific literature. Another point of weakness is the heterogeneity of the data; in fact,
patients are not stratified according to either the FIGO stage of the disease or the site of
micrometastases. Moreover, most studies included in our systematic review did not specifi-
cally distinguish their patients in EBRT + CTX and EBRT without CTX arms, jeopardizing
the consistency of their analyses [26–28,30,32]. To date, our meta-analysis documents that
there is no consistent benefit from adjuvant treatment. It could depend on the lower risk of
positive lymph nodes in patients with micrometastases—especially for ITCs—compared to
macrometastases. In parallel, recent evidence shows that patients with ITCs in SLNs could
not benefit from adjuvant treatment [33]. In parallel, an issue concerning distant sites of EC
dissemination is loco-regional recurrence [47]. It could be attributed to molecular pathways
of tumor instability [48–50]. The tumor microenvironment, involving, for example, LVSI,
shows a crucial role in EC relapse [51,52]. Moreover, the effectiveness of surgical staging
may be confounding [53,54]. However, improvement of SLN mapping to the detriment of
systematic lymphadenectomy can understage EC [55]. In our opinion, that issue partially
justifies loco-regional recurrence and is connected to lymph nodes or distant relapse. In the
case of fertility-sparing treatment (FST), grading mainly predicts the response to hormonal
therapy (HT) [56]. In fact, Medroxyprogesterone Acetate (MPA) leads to a 37% response
rate (RR) in well-differentiated EC, whereas it leads to a 9% RR in G3 neoplasm [57]. In
addition, HT can be influenced by the expression of the cell adhesion molecule L1-CAM,
which is prone to invasiveness, metastatization, and relapse [58]. Although early-stage ECs
may present micrometastases, adjuvant treatment regimens are not significantly associated
with better survival outcomes, and the combination of EBRT and CTX is the most valid
option in the early stage of disease. Molecular biomarkers could predict the efficacy of
FST on EC. For example, deep myometrial invasion (DMI) is not independent of The
Cancer Genome Atlas (TCGA) in assessing OS in EC, but it influences RR [59]. Moreover,
similarly to other conditions—such as endometriosis—new strategies may be applied to
detect micrometastases through liquid biopsy [60]. This allows for identifying in the serum
of patients with EC, or in different cellular compartments, specific micro-RNAs that could
be used as biomarkers of the disease [60]. In addition, knowledge of lymph node status,
even if microscopic, could help modulate surgical aggressiveness, minimizing the risks of
iatrogenic comorbidities [61–63].
Similarly, microbial signatures may subtend a specific pattern of clinical and onco-
logical outcomes in women with EC [64]. The above-mentioned molecular methods for
outcome prediction—as the miRNAs and the microbiota—might also be taken into account
in a risk prediction model, even though the data allowing for establishing an optimal
distinction of risk groups are still extremely poor. There is little evidence of that issue
in endometriosis-affected patients, and it would be appropriate to investigate whether a
similar mechanism could distinguish EC. In the end, the presence of micrometastases is
a risk factor that should be contextualized in the patient’s clinical presentation in order
to optimize the personalization of treatment. Avoiding adjuvant treatments where they
should not be necessary has clinical and sociological value. Conversely, the goal of chroni-
cizing oncologic disease and minimizing the risk of recurrence is the moral duty of the
clinician. The importance of detecting micrometastases is highlighted by the pathological
ultrastaging obtained through SLN mapping [65]. The SLN mapping procedure is gaining
consensus in EC staging because it avoids unnecessary surgery-related morbidity, preserv-
ing the advantages of surgical staging [65]. There is increasing evidence that SLNs with
ICG during laparoscopy assures a safe and valid mapping compared to methylene blue
and radiolabeled albumin nanocolloid [65]. This might be fundamental for preoperative
J. Clin. Med. 2024, 13, 1496 9 of 13

imaging [65]. Moreover, ICG fluorescence shows efficiency in terms of timing and nodal
detection rates [65].
Today, with the new molecular classification, the presence of POLmut (polymerase-
mutated), MMRd (mismatch repair deficient), NSMP (non-specific molecular profile), and
p53abn (p53 abnormal) takes on a key role from a prognostic point of view [66].
The present study has several limitations. First of all, the authors made a very limited
stratification of patients according to the FIGO stages and the sites of micrometastases.
Therefore, as difficult as it is to establish the exact weight exerted by micrometastases in
the oncologic history of patients with CE, it turns out to be a clinical fact that should not
be disregarded. Unfortunately, we do not have enough evidence supporting the role of a
specific combination of adjuvant treatment regimens in the different histological subtypes
of EC. Moreover, due to the paucity of data, it is impossible to assess the optimal strategy
of combining RT and CTX in different categories of EC patients. Another limitation of the
analysis lies in heterogeneity. In particular, further studies are needed to address or mitigate
that bias. Heterogeneity would be diminished by the setup of prospective multicenter
studies involving a wider sample size, to be stratified based on the FIGO stage, site of nodal
recurrence, and longer FU time. Those issues may fill the gaps in knowledge and suggest
potential directions for future investigations.

5. Conclusions
Despite the fact that early-stage EC may show micrometastases, especially in pelvic
and para-aortic lymph nodes, the use of adjuvant treatment is not significantly associated
with better survival outcomes. However, those data highlight the importance of targeted
therapy conforming to the FIGO stage of the disease. The combination of EBRT and CTX is
the most diffuse and valid option for early-stage EC patients, although further evidence is
needed to optimize and standardize adjuvant treatment protocols based on SLN mapping.
It would also be appropriate to perform further trials in order to analyze survival outcomes
according to the stage of the disease and the site of recurrence and to perform a more
detailed stratification of advanced-stage patients.

Author Contributions: C.R.: validation, methodology, and data curation; S.N.: validation; I.I.: data
curation, writing—original draft, and writing—review and editing; P.F.: data curation, and writing—
review and editing; M.G.V.: data curation; A.R.: writing—review and editing; R.M.: writing—review
and editing; L.C.: conceptualization; P.D.F.: methodology; S.C.: validation. All authors have read and
agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data supporting conclusions of the study can be found in the Refer-
enct List.
Conflicts of Interest: The authors declare no conflicts of interest.
J. Clin. Med. 2024, 13, 1496 10 of 13

Appendix A

Table A1. Newcastle–Ottawa Scale.

Single-arm studies
Author, Year of
Country Selection Comparability Exposure Total
Publication
Raimond, 2014 [25] France 3 2 2 7
Lee, 2017 [26] USA 3 2 3 8
Piedimonte, 2018 [27] Canada 3 2 3 8
Forsse, 2020 [28] Norway 3 2 2 7
Comparative studies—adjuvant treatment vs. LN-included for meta-analysis
Ignatov, 2019 [29] Germany 3 3 2 8
Onal, 2019 [30] Turkey 3 3 3 9
Ito, 2020 [31] Japan 3 3 2 8
Son, 2020 [32] USA 3 3 3 9
Backes, 2021 [33] USA 3 3 3 9

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