169 JPOG JUL/AUG 2014CONTINUING MEDICAL EDUCATIONEndometrial Carcinoma

TH Cheung, MBBS(HK), MRCOG(UK), MHKCOG, FHKAM(O&G)

INTRODUCTION
Endometrial cancer (EC) is the fourth
most common malignancy in women
worldwide. About 290,000 cases are
diagnosed annually, leading to 74,000
deaths.1 The standard treatment has
been total abdominal hysterectomy
and bilateral salpingo-oophorectomy
(THBSO), and pelvic and aortic lymphadenectomy, followed by adjuvant
pelvic irradiation for those with high
clinical-pathological risk factors. Recent clinical studies have raised queries and challenges to the conventional
treatment approach. This article gives
an overview of this malignant disease,
discusses the controversies, summarizes the current position, and highlights
the possible treatment strategies in the
future.
PATHOLOGY
Two distinct types of EC have been defined based on histology and molecular
characteristics of the tumour (Table 1).
Type I tumour or endometrioid carcinoma accounts for 80 90% of all EC.2
It is related to unopposed oestrogen
stimulation and is preceded by atypical
hyperplasia. The typical molecular alterations include PTEN gene silencing and
defects in DNA mismatch repair genes.3
Patients with type I EC are usually diagnosed at early stage and have a 5-year
survival rate of 74%.
Type II tumour includes clear cell,
papillary serous adenocarcinoma and
carcinosarcoma. It is not oestrogen-related and develops from atrophic endometrium. In contrast to type I tumours, p53
gene mutation, p16 gene inactivation
and Her-2/neu overexpression are often found. Patients are more often diagnosed at late stage because the tumour
spreads early, and the overall 5-year survival rate is between 27% and 42%.3
RISK FACTORS
Chronic anovulation in premenopausal
women and peripheral conversion of
androstenedione secreted from the adrenal gland in the adipose tissue of overweight postmenopausal women are the
common sources of unopposed oestrogen. Breast cancer survivors taking
tamoxifen also has a sevenfold higher
relative risk of developing EC.4 A recent
cohort study suggests that increased
EC risk is associated with the use of
combined oestrogen and progestogen

replacement for more than 10 years

among women with body mass index
below 25 kg/m2 . 5
Table 1. Comparison of FIGO 1988 with FIGO 2009 staging systems for
endometrial carcinoma
FIGO 1988 FIGO 2009
Limited endometrium Stage IA Stage IA
< myoinvasion Stage IB Stage IA
> myoinvasion Stage IC Stage IB
Cervical glands involvement Stage IIA Not relevant
Cervical stromal involvement Stage IIB Stage II
Tumour invades the serosa and/or
adnexae
Stage IIIA Stage IIIA
Positive peritoneal washing Stage IIIA Not relevant
Vaginal and/or parametrial
involvement
Stage IIIB Stage IIIB
Pelvic node metastasis Stage IIIC Stage IIICI
Aortic node metastasis Stage IIIC Stage IIIC2
Bladder and/or bowel mucosa
involvement
Stage IVA Stage IVA
Distant metastasis Stage IVB Stage IVB
5 SKP

170
a c
Figure 1. Endometrial carcinoma with full thickness infiltration. a) Magnetic re
sonance imaging. b) Intraoperative finding: tumour invades
through the serosa of the anterior uterine wall. c) Uterine specimen cut open.
b
Lynch syndrome, or hereditary
non-polyposis colon cancer (HPNCC),
is due to germline mutation of one of
the mismatch repair genes, and it accounts
for 2 3% of all EC and 9% of EC
diagnosed before the age of 50. The
cumulative risk of a HPNCC patient developing
EC reaches 60% by the age of
70.6
A positive association between EC
and metabolic syndrome factors including
obesity, hypertension, hyperglycaemia
and hyperlipidaemia, alone or in
combination, has also been suggested
by a prospective study.7
CLINICAL PRESENTATION
AND DIAGNOSIS
EC patients usually present with abnormal
uterine bleeding. Occasionally,
EC may be diagnosed in asymptomatic
women who have atypical glandular
cells on Papanicolaou smear. The median
age of EC patients is 61, and 20% of
EC patients are premenopausal.8
Dilatation and curettage (D&C) under
general anaesthesia used to be performed
for patients with abnormal uterine
bleeding,9 but outpatient procedures
including Vabra aspirator and Pipelle
are preferred nowadays. Although the
Vabra aspirator can sample a larger
endometrial surface,10 a meta-analysis
showed that Pipelle outperforms the
Vabra aspirator and offers a sensitivity
of 99.6% and 91% for diagnosing EC in
postmenopausal and premenopausal
women, respectively.11
Hysteroscopy offers visual-guided
biopsy of the lesion inside the uterus.
A meta-analysis showed that hysteroscopy
had a high diagnostic accuracy
rate and low serious complication rate,
and the failure rate of the procedure
was 3.6%.12 The increased incidence
of positive peritoneal cytology in patients

with EC after hysteroscopy raises

concerns even though there is no evidence
that the procedure promotes
dissemination of cancer and worsens
the prognosis.13,14
Further investigations may not
be necessary for postmenopausal
women with endometrial thickness <
5 mm or < 4 mm measured by transvaginal
ultrasonography, as the negative
predictive value is 99% and 100%,
respectively.15,16 Whether transvaginal
ultrasonography, endometrial biopsy,
and hysteroscopy, alone or in combination,
is used to investigate abnormal
uterine bleeding depends on the
availability of expertise. Since none of
the tests is 100% sensitive, further investigation
is indicated if the symptom
persists.
PREOPERATIVE
INVESTIGATION
Many EC patients are old, obese and
have significant medical problems including
diabetes mellitus and hypertension.
Thorough health assessment and
optimization are essential before treatment
to minimize complications.
Contrast-enhanced magnetic resonance
imaging (MRI) is preferred to computed
tomography (CT) in assessing the
uterine and tumour size, myoinvasion,
cervical invasion, and nodal metastasis17
(Figure 1). The overall staging accuracy
rate is 85 93%. Positron emission tomography/
CT is the most sensitive method
in detecting nodal metastasis but
does not provide accurate information
on the primary tumour and is therefore
not routinely recommended.18
CA-125 may be checked before
surgery, and the level is raised in a third
of EC patients.19 Patients with abnormal
CA-125 are more likely to have higher tumour
grade and deep myoinvasion, nodal
metastasis, and poor survival.20
The International Federation of Gynecology
and Obstetrics (FIGO) adopted
a surgical staging system for EC in 1988
to replace the previously used clinical
staging system that failed to categorize
patients into different prognostic groups
accurately. The surgical staging sys

171 JPOG JUL/AUG 2014CONTINUING MEDICAL EDUCATIONtem has been revised in 2009, a
nd the
changes are shown in Table 1.21
Based on the FIGO staging together with histopathological risk factors
such as tumour grade, histological type
and lymph vascular space invasion,
EC patients can be roughly assigned to
three risk groups to guide the treatment22
(Table 2).
MANAGEMENT OF
ENDOMETRIAL CARCINOMA
Surgical Treatment
Hysterectomy and Bilateral
Salpingo-oophorectomy
Surgery is the mainstay of treatment,
and THBSO is recommended not only
to patients with early-stage disease but
also to the 10 25% patients diagnosed
with stage III or IV disease. Bilateral salpingo-oophorectomy is recommended
because of the potential risk of tumour
metastasis to the ovary. Radical hysterectomy may be offered to surgically fit
EC patients with cervical involvement,
but clear survival benefit from aggressive
surgery is not available.21 Preoperative
irradiation has not been shown to offer
any benefit and has largely been abandoned.
Staging Lymphadenectomy
Since only 10% of stage I EC patients
have pelvic nodal metastasis and about
50% of the nodal metastasis are noticeable intraoperatively,22 routine pelvic and
para-aortic lymphadenectomy to all patients including those with no enlarged
nodes may represent an overtreatment
because the chance of finding nodal metastasis is low. Performing pelvic
lymphadenectomy only is insufficient
to ascertain the nodal status because
metastasis to the aortic node can occur
without involving the pelvic node. Omitting lymphadenectomy for patients with
FIGO stage IA disease, grade 1 to 2 tumour is justifiable because the risk of
nodal metastasis is well below 10% and
their 5-year survival rate is above 95%
after THBSO. Restricting pelvic and para-aortic lymphadenectomy up to the level of renal vein in EC patients with high
tumour grade and deep myoinvasion appears to more appropriate. However, the
current technology is imprecise in determining these two tumour characteristics
before or during surgery. Among 181
clinical stage I EC patients that had grade
1 tumour, 18% of the patients needed an

upstage and 19% had tumours upgraded

in the final pathology.23 High-quality and
efficient intraoperative frozen pathological assessment may provide the answer,
but such a service is not readily available.
Therapeutic Lymphadenectomy
Retrospective studies suggest that multiple-site lymphadenectomy, removal of
a larger number of lymph nodes, and
debulking of enlarged metastatic nodes
offer survival benefits.24 26 However, the
therapeutic benefit of pelvic lymphadenectomy was not supported by two recently published randomized clinical trials (RCTs). An Italian study randomized
FIGO clinical stage I EC patients to systematic pelvic lymphadenectomy or no
lymphadenectomy after hysterectomy.
Significantly more patients in the pelvic
lymphadenectomy group compared with
those in the no-lymphadenectomy group
were diagnosed to have nodal metastasis (13.3% vs 3.2%) and developed postoperative complications. However, the
5-year disease-free survival and overall
survival (OS) were similar between the
two groups.26
A Study in the Treatment of Endometrial Cancer (ASTEC) trial randomized
patients to THBSO with or without lymphadenectomy. Patients diagnosed to
have intermediate-/high-risk early-stage
disease were subjected to a second randomization to pelvic radiotherapy or no
radiotherapy postoperatively. The progression-free survival (PFS) and OS were
not different between the two groups.27
Surgical Approaches
The Gynecologic Oncology Group
(GOG) LAP2 study compared laparoscopic with open surgery for treating
patients with stage I to IIA EC. The surgical treatment consisted of extrafascial
hysterectomy, bilateral salpingo-oophorectomy, and pelvic and aortic node dissection. Laparoscopic approach was associated with longer operative time, less
postoperative morbidities, and shorter
hospital stay. There was no difference
in the intraoperative complication rates
and the numbers of nodes removed.
Table 2. Endometrial carcinoma classified into three different risk groups
Grade I Grade II Grade III
Stage IA Low Low Intermediate
(without LVSI)
Stage IB Intermediate Intermediate High
Stage II and above High High High
LVSI = lymph vascular space invasion.

172
Nodal metastasis was diagnosed in 9%
of patients in both groups. However, one
in four patients randomized to the laparoscopic
approach ended up requiring
conversion to open surgery, and the risk
increased with the body mass index and
age. It appears that laparoscopic surgery
was applicable to EC patients when
trained surgeons were available.28 A metaanalysis showed no difference in the
OS, disease-free survival and cancer-related
death between the laparoscopic
and open surgery.29
Robot-assisted technique is an
advanced mode of minimally invasive
surgery, and the major advantages of robotassisted surgery are a steep learning
curve and no association between an increase
in body mass index and a higher
conversion rate.30,31
Pelvic Irradiation
Adjuvant external beam pelvic radiation
therapy (RT) is often given to patients with
risk factor for nodal metastasis or patients
with documented nodal metastasis. However,
there has never been any evidence
to support that pelvic RT improves the
survival. Recently published studies have
further questioned the role of adjuvant
pelvic RT in intermediate-risk EC patients.
The Post Operative Radiation Therapy
in Endometrial Carcinoma (PORTEC)
study randomized intermediate-risk EC
patients to adjuvant pelvic RT and no
further treatment after THBSO.32 After a
median follow-up of 52 months, the locoregional recurrence rates were 4%
and 14% in the RT and control groups,
respectively, whilst the rates of distant
metastasis were not different. Because
of the higher rate of successful salvage
treatment in the control group (79% vs
21%), the actuarial 5-year OS rates (81%
vs 85%) and the EC-related death rates
(9% vs 6%) were not significantly different
between the two groups.
The GOG 99 study randomized
intermediate-risk node-negative EC
patients to external beam RT or observation.
33 The 24-month cumulative
recurrence rate was 3% in the RT

group and 12% in the control group,

and the difference was mostly attributable
to vault recurrence. Because
most patients with vault recurrence
could be salvaged and about 50% of
deaths were not related to the EC or
treatment, survival benefit of RT again
was not demonstrated.
A Study in the Treatment of Endometrial
Cancer (ASTEC) and EN.5 trials
were two distinct studies, and their
data were pooled in a planned analysis.
Primary surgery did not always include
lymphadenectomy, and the patients
were randomized to postoperative external
beam RT or observation. The
5-year survival rates were 84% in both
groups.34
The GOG 99, PORTEC and ASTEC+
EN.5 studies have shown no evidence
of survival benefit by giving external
RT, but the treatment-related morbidity
would be significantly higher.32 34
Since vaginal vault recurrence is
the most common site of recurrence, the
PORTEC-2 study randomized high-intermediaterisk patients to external beam
RT or vaginal brachytherapy (VBT). The
estimated rates of vaginal recurrence
were 1.8% for VBT and 1.6% for external
beam RT. There were no differences in
the overall and disease-free survival between
the two groups, but the acute gastrointestinal
toxicity was significantly lower
in the VBT group (13% vs 54%). VBT
is therefore recommended for high-intermediaterisk EC patients and routine
pelvic RT is not.35
Chemotherapy
Chemotherapeutic Regime
Recurrences that commonly occur outside
the pelvis or the pelvic irradiation
field suggest that systemic therapy may
be necessary. Phase II studies showed
that taxanes, anthracyclines, ifosfamide
and platinum drugs are the most effective
agents for EC, and a response rates
of 20% can be expected.36 38
One RCT showed higher response
rate and longer PFS with combined doxorubicin
and cisplatin than with doxorubicin

alone.39 The GOG 177 study further showed

that the paclitaxel, doxorubicin and cisplatin
(TAP) combination had higher response
rate (57% vs 34%) and prolonged PFS
(median, 8.3 vs 5.3 months) and OS (median,
15.3 vs 12.3 months) compared with
doxorubicin cisplatin.40 TAP has therefore
become the standard treatment in patients
with advanced stage or recurrent disease.
However, the toxicity of this three-drug
combination is significant.
Carboplatin combined with paclitaxel
(CP) is the standard outpatient regime
for ovarian cancer patients and achieves
a 40 63% response rate when used in
chemotherapy-naive EC patients.41 The
GOG 209 study is a RCT comparing the
performance of CP with TAP for stage
III and IV or recurrent EC, and the final
analysis is pending. Although CP has
not been proven to be superior to TAP, it
has already been widely used in EC patients
because of the high response rate,
ease of administration, and manageable
toxicity. A number of clinical trials have
commenced to determine the role of this
combination.
Radiotherapy Versus
Chemotherapy
An Italian multicentre study randomized
patients with high-risk EC (FIGO 1988

173
stage IC grade 3, stage IIA to IIB grade
3 with deep myoinvasion or greater, or
stage III) to pelvic RT or five cycles of cisplatin
and doxorubicin, and showed no
survival difference between the two treatment
arms.42
A Japanese Gynecologic Oncology
Group study randomized patients with
no residual disease after hysterectomy
and pelvic and para-aortic node dissection
to chemotherapy or pelvic RT, and
again showed no difference in the PFS
and OS between the two treatment arms.
However, in the subgroup analysis for
the high-intermediate risk subgroup defined
as stage IC grade 3 and stage II
and IIIA disease with deep myoinvasion,
PFS and OS were better after chemotherapy.
43
The GOG 122 study compared
postoperative adjuvant chemotherapy
consisting of eight cycles of doxorubicin
and cisplatin with whole abdominal irradiation
in stage III and IV EC patients with
residual disease < 2 cm, and showed
that the PFS and OS were better after
chemotherapy than whole abdominal irradiation.
44
It therefore appears that patients
with high-risk features are more likely
to benefit from chemotherapy whilst
adequately surgically staged low-risk
patients with low metastatic risk do
not.
Radiotherapy Followed By
Chemotherapy
Since chemotherapy appears more effective
in reducing distant metastasis
whilst radiotherapy is more effective in
reducing pelvic recurrence, a sequential
use of chemotherapy after RT appears
advantageous.42
The joint study by Nordic Society
of Gynaecological Oncology/European
Organisation for Research and Treatment
of Cancer (NSGO/EORTC-55991)
with Italian GOG at the Mario Negri Institute
(MaNGO ILIADE-III) showed that
EC patients with no residual disease

after surgery had improved PFS and

cancer-specific survival if chemotherapy
was given after the completion of pelvic
RT compared with those with RT alone;
however, the differences in OS were not
statistically significant.45
Meta-analysis of nine RCTs on the
role of chemotherapy after surgery for EC
showed that chemotherapy reduces the
risk of recurrence, and improves PFS and
OS.46 It has been estimated that 1 in every
25 patients treated with high-dose platinumbased chemotherapy was cured.
Although chemotherapy appears
to be effective when used alone or sequentially
after RT, further studies are
needed to define which patient groups
should receive chemotherapy and
which chemotherapy regime should be
used. Since EC patients might be old
and have significant co-morbidities, the
clinical benefits of chemotherapy have
to be weighed against the toxicity of
chemotherapy.
Endocrine Therapy
EC is considered as an oestrogen-dependent
tumour, and progesterone has
been used in EC patients after surgery.
No particular progestational agent has
been shown to be superior to the rest, and
the duration of usage varies from months
to an indefinite period of time. However,
there is no evidence that progestogen
treatment after surgery prolongs recurrencefree survival or OS.47 A Cochrane
review of progestogen therapy in patients
with advanced or recurrent EC showed
no evidence of survival improvement.48
When progestogen is used for palliation
in EC patients with advanced disease or
recurrence, a 11 56% response rate and
PFS time of 2.5 to 14 months might be
achieved.49 Tamoxifen and aromatase
inhibitors have been used in EC, but the
response rates were modest.
Fertility-sparing Therapy
About 3 5% of EC patients are below the
age of 40, and some of them may have

strong desire to preserve fertility.50,51 It

cannot be overemphasized that fertilitysparing treatment using high-dose
progestogen is not the standard treatment,
and 10% of EC patients below
the age of 45 have synchronous ovarian
cancer and fertility-sparing treatment is
not applicable.52
Fertility-sparing treatment should
only be considered for patients with
grade 1 tumour limited to the endometrium,
and D&C is needed to assess tumour
grade because significantly fewer
patients with grade 1 EC diagnosed after
D&C (10%) were upgraded to higher
tumour grade compared with office endometrial
biopsy (26%).53 Preoperative
MRI is performed to assess myoinvasion
although the negative predictive value of
MRI in predicting absence of myoinvasion
is only 42 49%.17
Daily 100 400 mg megestrol acetate
or 200 600 mg medroxyprogesterone
acetate are most commonly used.
Higher response rate was not observed
in patients with advanced or recurrent
EC treated with 1,000 mg medroxyprogesterone
acetate compared with those
receiving 200 mg per day.54 A 75% response
rate can be expected, and treatment
failure should be declared if no
response is recorded after a 3-month
treatment.55 The treatment duration often
extends beyond 6 months if a response
is observed.

174 JPOG JUL/AUG 2014CONTINUING MEDICAL EDUCATIONKey pointsD&C at 3-monthly inte

rval is mandatory after fertility-sparing treatment because 30% of patients would recur even
after complete response. About 30 50%
of responders achieve pregnancy, with
or without assistance from reproductive
technology.56 Hysterectomy is advisable
after completing the family.
Targeted Therapy
The PI3K/PTEN/AKT/mTOR pathway is
the most commonly activated pathway
in type I EC. Temsirolimus is a mTOR
inhibitor and can achieve a 4 14% partial response rate in heavily pretreated
and chemotherapy-naive EC patients.57
Bevacizumab demonstrated a 15.1%
response rate and a median PFS of 4.2
months in patients with persistent or
recurrent EC in a phase II study.58 It is
likely that targeted treatment should be
individualized according to the aberrant
genetic changes, and efforts to identify
markers that predict response to targeted therapy are important to maximize the
benefits of targeted therapy.
POSTOPERATIVE
SURVEILLANCE
About 15% of EC recur, and the commonest site of recurrence is at the vaginal vault.58 Most of the recurrences develop within the first 2 years and 75%
within 3 years after treatment.
The National Comprehensive Cancer Network guidelines recommend visits every 3 to 6 months for 2 years then
6 months or annually.59 More intense follow-up may be indicated if the patient has
high risk factor for recurrence or develops
morbidities related to the treatment. Patients who develop symptoms, particularly
vaginal bleeding or brownish discharge,
should be advised to return for early examination to ensure early diagnosis.
In the follow-up visits, physical examination of the genital tract is a must. The
cost-effectiveness of routine vaginal cytology in asymptomatic women has been
questioned.60 CA-125 may be used if the
marker is raised before treatment. Imaging studies at interval for asymptomatic
patients is not routinely recommended.
MANAGEMENT OF
RECURRENCES
A meta-analysis has shown that complete surgical cytoreduction in patients
with advanced-stage or recurrent EC
was associated with improved survival.59 Treatment of patients with recur-

rences has to be individualized according to the tumour size, tumour grade,

site of recurrence, and prior or no prior
irradiation.
For patients with vaginal vault recurrence and no prior RT, external beam
pelvic RT can effectively treat tumour < 2
cm. For tumour > 2 cm, surgical cytoreduction is advisable before radiotherapy
to increase the chance of cure.61 In the
PORTEC study, the 3-year survival rate
after vaginal relapse was 73%.32
For nodal recurrences that occur at
the pelvic sidewall or aortic areas, RT is
often used in radiotherapy-naive patients
with or without prior surgical debulking.
Relapse inside the prior irradiated field is uncommon and is more
difficult to treat. Ultra-radical surgery involving multi-visceral resecEndometrial carcinoma (EC) is a heterogeneous disease with different histological types characterized by different aberrant molecular
changes.
EC or type I EC is the commonest histological type that results from
unopposed oestrogen stimulation.
The cornerstone of treatment of curative intent is surgery for EC.
Conventional and minimally invasive surgeries are equally applicable
to patients with EC.
Lymphadenectomy provides important information for the staging but
its therapeutic benefit has not been proven.
Pelvic irradiation improves pelvic disease control with no survival
benefit.
Chemotherapy is the mainstay of treatment for metastatic and advanced
EC.
Combination chemotherapy is better than single-agent treatment.
The carboplatin and paclitaxel combination is commonly used because
of high response rate, ease of administration, and manageable toxicity.
Hormonal therapy is used for palliation only.
Progestogen treatment has more tolerable side effects compared with
chemotherapy and is effective mostly for grade 1 EC.
Fertility-sparing treatment can only be considered in selected cases
after detail counselling.
The most frequently altered molecular pathway that leads to uncontrolled cell proliferation and tumour survival is PI3K/PTEN/AKT/mTOR.
Vaginal examination is important during follow-up visits because
recurrence at the vaginal vault is most common and salvageable.

175
tion might be needed although most
might not be suitable for this highrisk aggressive approach. Among
44 patients with exenteration, 20% of
patients achieved long-term survival of
> 5 years.62
Systemic treatment is indicated
for patients with multiple-site disease.
Hormonal therapy might be used for
asymptomatic patients with receptorpositive grade 1 disease, and
chemotherapy is used for symptomatic
or receptor-negative patients. Currently,
there is no Food and Drug Adminis
tration approved agent for second-line
salvage therapy.
About the Author
Dr Cheung is Consultant and Chief of Service in the Department
of Obstetrics and Gynaecology at The Chinese
University of Hong Kong, Prince of Wales Hospital, Hong
Kong.
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