The effect of waiting time for surgical staging on survival outcome
for endometrial cancer is controversial. It has been suggested that a
longer waiting time for surgical staging was associated with worse
survival outcomes in uterine cancer43 and the delay between diagnosis
and surgery should not exceed 6 weeks.44 However, when focusing
on type 1 endometrial cancer only, the waiting time for surgical
staging was not associated with decreased survival outcome, presumably
owing to its indolent growth and resulting excellent prognosis.45
7 | IS LYMPHADENECTOMY
THERAPEUTIC?
Lymphadenectomy is required for accurate staging, yet its therapeutic
benefits remain controversial. Historically, one case–control study
suggested that lymphadenectomy may be beneficial therapeutically46
and another showed it improved prognosis even in node-positive
women.47 Another retrospective study suggested that complete lymphadenectomy
increases survival in patients with grade 3 tumors.48
In contrast, two major trials of large-scale
cohorts have shown that
pelvic lymphadenectomy offers no therapeutic benefits compared
with no lymphadenectomy.49,50 These studies, however, have been
criticized for several limiting factors. First, limited effort with respect
to the extent of dissection and lymph node evaluation was made.
Second, a high proportion of low-risk
patients in these studies might
have skewed the results. Finally, no direct decision on adjuvant therapy
based on lymphadenectomy was designed as part of the protocols.
At present, lymphadenectomy is primarily used for staging and
should be considered in women with high-risk
factors.51 An international
trial of the role of lymphadenectomy to direct adjuvant therapy
for high-risk
endometrial cancer (STATEC) has recently started. The
ongoing ENGOT-EN2-
DGCG
trial (NCT01244789) aims to shed light
into this issue by comparing survival in patients with Stage I grade 3
endometrioid endometrial cancer, Stage I and II type 2 endometrial
cancer, or Stage II endometrioid endometrial cancer and without metastatic
node after randomization for adjuvant chemotherapy.
In a retrospective study, para-aortic
lymphadenectomy resulted
in an improved outcome in intermediate and high-risk
patients when
compared with pelvic lymphadenectomy alone.52 A limiting factor of
this study was that adjuvant therapy was not comparable in the two
groups. In patients who underwent both pelvic and para-aortic
lymphadenectomy,
77% received chemotherapy as opposed to only 45% in
the pelvic lymphadenectomy group. This uncertainty is the reason why
addition of para-aortic
lymphadenectomy is recommended if pelvic
lymphadenectomy is being done, and explains different approaches
among different centers.
Sentinel lymph node mapping has been introduced into the surgical
staging of endometrial cancer with the goal to reduce morbidity
associated with comprehensive lymphadenectomy and to obtain
prognostic information from lymph node status. A recent meta-analysis
reported overall detection rates higher than 80%, with 50%
bilateral pelvic node detection rate and 17% para-aortic
detection
rate.53 Use of indocyanine green increases the bilateral detection rate
compared with blue dye. Additionally, cervical injection increases the
bilateral sentinel lymph node detection rate but decreases the para-aortic
detection rate compared with alternative injection techniques.
The sensitivity of sentinel lymph node mapping to detect metastases
is higher than 90%, reaching almost 100% in a meta-analysis.
53
Randomized studies have suggested that sentinel lymph node mapping
can safely replace lymphadenectomy in the staging of endometrial
cancer.54,55
Apart from the historical distinction between type 1 and 2 endometrial
cancer, various approaches (genomic and immunochemistry)
have been conducted to better predict prognosis and subsequently
adapt therapy. The Cancer Genome Atlas Research Network identified
four groups of endometrial carcinomas based on genomic features.4
Similarly, many immunohistochemical markers have been studied to
differentiate between low-and
high-risk
endometrial carcinomas.
Several studies have tried to develop more applicable variants of the
TCGA classification by using immunohistochemical markers and DNA
sequencing techniques that can be done on formalin-fixed,
paraffin
embedded tissues.56,57 L1 cell adhesion molecule (L1CAM) was introduced
as a promising biomarker for identification of patients with
poor outcome, which has been confirmed in subsequent studies.58–60
Markers of the p53 pathway,16 hormone receptor expression,61 and
microsatellite instability,62 are several of the other relevant biomarkers
to predict prognosis of endometrial cancer. Various approaches combining
genomic characterization and biomarkers expression provide
promising results to tailor adjuvant therapy.63–65
8 | ADJUVANT TREATMENT
At present, the indication for adjuvant radiation therapy is based on
the presence of risk factors. Low-risk
disease (Stage I, grade 1 or 2
with no or superficial myometrial invasion) does not require adjuvant
radiation therapy. This was demonstrated in a Danish cohort study
of low-risk
women, in which surgery alone resulted in a 96% 5-year
survival.66 A seminal Norwegian trial,67 which included 621 women
treated after surgery with vaginal brachytherapy, indicated that overall
survival was not improved by additional external beam radiation
therapy (EBRT). This study, however, showed that adjuvant radiotherapy
reduced the risk of pelvic recurrence. Three other large randomized
trials (PORTEC-1
trial,68 the US GOG#99 trial,69 and the UK
MRC ASTEC trial70) studying the benefits of pelvic radiation therapy
as adjuvant therapy to surgery have supported its indication only for
high-risk
patients. The main finding from these trials is the significant
reduction in the rates of vaginal and pelvic recurrence after EBRT, but
without added survival benefit. In contrast, EBRT added to the risk
of long-term
morbidity. The patients without lymphadenectomy analyzed
in the PORTEC and ASTEC trials presented similar recurrence
and survival rates to those with documented node-negative
disease in the GOG#99 trial. Additionally, PORTEC-1
illustrated that most pelvic
relapses were located in the vaginal vault (75%), and that salvage rates
were high in women who had not had previous radiation therapy.

9 | PROGESTOGEN THERAPY
Although the use of progesterone therapy has been widely
recognized in the past, a meta-analysis
of six randomized trials
totalizing 3339 women has shown no survival benefit for
adjuvant progestogen therapy in endometrial cancer.81 A subsequently
published randomized trial of 1012 women also failed to
demonstrate any survival benefit.82 However, hormonal therapy
can provide prolonged remission of metastatic disease in women
with grade 1 and/or ER/PR receptor-positive
disease. Where
possible, ER/PR should be determined on a biopsy of the recurrent
tumor because the hormone receptor status may change
over time.83
10 | STAGE II
10.1 | Occult Stage II disease
Therapeutic management of patients with clinically occult Stage II disease
is similar to that of patients with Stage I disease.
10.2 | Clinical overt Stage II disease
In these cases, radical hysterectomy, bilateral salpingo-oophorectomy,
bilateral pelvic lymphadenectomy, and selective
aortic node dissection have been historically used as primary
treatment. However, it is important to note that this strategy has
been poorly supported by the medical literature. Results of one of
the few retrospective studies could not find any survival benefit
from radical hysterectomy for patients with suspected gross cervical
involvement in comparison with simple or modified radical
hysterectomy.31,84 Surgical treatment in patients with suspected
gross cervical involvement is currently under evaluation, as radical
hysterectomy increases the risk of adverse events. Preoperative
MRI scanning is advisable to exclude bladder involvement and
ensure local resectability. Studies indicate excellent results for this
approach, with no benefit from the addition of radiation for patients
with negative nodes.85,86 Adjuvant radiotherapy is usually reserved
for patients with involved nodes or other adverse factors and/or
close or involved surgical margins.
However, neoadjuvant therapy followed by a less extensive simple
hysterectomy can represent an alternative. If surgery is not considered
feasible because of tumor extension and/or in medically inoperable
patients, full pelvic radiotherapy and intracavitary brachytherapy, as in
cervical cancer, may be employed either preoperatively or definitively
with high disease control and survival rates.87,88
11 | STAGE III
Most patients with Stage III endometrial cancer are managed by complete
surgical resection of all pelvic and/or nodal disease, followed by
postoperative EBRT and/or chemotherapy.
As primary tumors of both the ovary and the endometrium may
be present in patients with presumed Stage III disease with adnexal
involvement, full surgical staging and expert pathologic examination
of the specimen is recommended in these cases.
Adjuvant treatment is indicated for women with Stage III disease
as detailed in Section 8 above.
Patients with clinical Stage III endometrial carcinoma in which
surgical resection is not possible are treated primarily by pelvic irradiation,
with or without chemotherapy.89 Once therapy has been
completed, exploratory laparotomy should be considered for those
patients whose disease now appears to be resectable.
12 | STAGE IV
Optimal management in women with Stage IV endometrial cancer
includes cytoreductive surgery, which is associated with superior
overall survival outcome.90 In advanced disease, neoadjuvant chemotherapy
is also an option, particularly if postoperative morbidity is
considered likely and/or ascites is present.91 After surgery, platinum-based
chemotherapy should be considered, based on the trials cited
above. Patients with evidence of extra-abdominal
metastases are usually
managed with systemic platinum-based
chemotherapy, or hormonal
therapy if grade 1 and/or receptor positive.
As neoadjuvant chemotherapy is the treatment of choice in
advanced-stage
disease, as well as in relapsed disease, several studies
have investigated the optimal combinations of chemotherapeutic
agents that represent the most effective neoadjuvant therapy for
Stage IV endometrial cancer patients. As the combinations of doxorubicin,
cisplatin, and paclitaxel (TAP)92 and carboplatin and paclitaxel have
been shown to be most effective, these have been the most studied.
The former, however, is much more toxic and resulted in treatment-related
deaths. A comparative trial of the GOG, randomizing to either
TAP or carboplatin-paclitaxel
chemotherapy has shown both schedules
to have similar efficacy, while carboplatin-paclitaxel
was preferred for
lower morbidity; full results have not yet been published.93
Two randomized trials have compared doxorubicin monotherapy
versus doxorubicin–cisplatin doublet.94,95 Superiority of the combination
chemotherapy in terms of progression-free
and overall survival,
with manageable toxicity, was confirmed in both studies. Doxorubicin–
cisplatin doublet versus doxorubicin–cisplatin–paclitaxel triplet was
tested in a phase III randomized trial.92 The triplet regimen resulted
in a significantly superior progression-free
survival, although this regimen
proved to be too toxic, with treatment-related
deaths despite the
use of growth factors.
The carboplatin–paclitaxel doublet has been tested in several
phase II studies in advanced-stage
or relapsed disease, demonstrating
a response rate of 65%–75% and progression-free
survival of about
14 months.96–98 The interim results of the GOG-0209
trial, a noninferiority
trial comparing the combination of doxorubicin, cisplatin, and
paclitaxel (TAP) and G-CSF
versus carboplatin and paclitaxel, show
that the carboplatin and paclitaxel doublet is not inferior to TAP.98
The better tolerability profile of carboplatin–paclitaxel has led to the

RECOMMENDATIONS F OR PRA CTICE
1. A definitive tissue diagnosis must be obtained preoperatively.
This will result in better selection of the surgical approach,
and help to differentiate tumors at low- and high-risk of lymph
node metastasis. Imaging might be used to determine depth
of myometrial invasion, cervical involvement, and lymph node
enlargement. Level of Evidence C
2. Although lymphadenectomy in clinical Stage I endometrial cancer
decreases recurrence, it has no impact on overall or relapsefree
survival. Level of Evidence A. In the clinic, lymphadenectomy
should be performed for staging only in high-risk cases. There is
little evidence to support a therapeutic benefit, but it may be
used to select women with positive nodes for adjuvant therapy
and reduce the need for EBRT in node-negative patients. Level
of Evidence C
3. In patients with Stage I endometrial cancer with low-, intermediate-,
or high/intermediate risk features, adjuvant radiotherapy
has no impact on survival, but significantly reduces the rate of
pelvic recurrence. Level of Evidence A. In high-risk patients, vaginal
brachytherapy effectively reduces the risk of vaginal relapse.
Level of Evidence A. EBRT should be considered in patients with
presumed Stage I–II disease with strong adverse factors, positive
nodes, or advanced stage disease to ensure pelvic control. Level
of Evidence A
4. The addition of adjuvant chemotherapy to radiotherapy in patients
with high-risk disease improves progression-free survival, but an
overall survival benefit is unproven. Level of Evidence A
5. Adjuvant chemotherapy for patients with early stage, high-risk
disease should only be considered for those with serous cancers
and after individual patient counseling (no proven benefit in overall
survival), and preferably be done within clinical trials.
6. Chemotherapy is a more effective strategy compared with whole
abdominal radiation in patients with Stage IV disease and abdominal
disease with residual nodules less than 2 cm diameter. Level
of Evidence A
7. Targeted therapy in endometrial cancer should be further developed
and only considered within clinical trials.
8. The use of adjuvant hormonal therapy (progestogen) has not been
properly substantiated. Level of Evidence A
9. High-risk and advanced stage endometrial cancer patients should
be managed where possible by a gynecological oncologist, working
within a multidisciplinary team. Level of Evidence A
10. Patients with endometrial cancer are frequently old and frail, and
this should be taken into consideratio