Annals of Oncology 21 (Supplement 5): v41–v45, 2010
doi:10.1093/annonc/mdq245clinical practice guidelines
Endometrial cancer: ESMO Clinical Practice Guidelines
for diagnosis, treatment and follow-up
G. Plataniotis1 & M. Castiglione2
On behalf of the ESMO Guidelines Working Group*
1Aberdeen Royal Infirmary, Aberdeen, UK; 2RGT, University of Geneva, Geneva, Switzerland
incidence and epidemiology
Endometrial cancer is now the most common gynaecological
malignancy in Europe and North America. 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. About 81 500 women are affected every year in the
European Union and the incidence is increasing. Median age
of occurrence is 63 years, while >90% of women are older
than 50.
Roughly 75% of women survive for 5 years as most women are
being diagnosed at an early stage because of irregular vaginal
bleeding. At diagnosis,�75% of women have disease confined to
the uterus (stage I). Five-year survival for stage I patients is 90%.
In some cases, a history of complex hyperplasia/atypia can be
demonstrated. The majority of endometrial cancers occur after
menopause, but up to 25% of cases may be premenopausal.
Risk factors for developing endometrial cancer are: obesity,
nulliparity, late menopause, diabetes melitus and prolonged,
unopposed estrogen exposure, tamoxifen and the oral
contraceptive pill.
endometrial cancer histological types
The most common type is endometrioid adenocarcinoma,
which is composed of malignant glandular epithelial elements.
Clear-cell and papillary serous carcinoma of the endometrium
are tumours that are histologically similar to those noted in the
ovary and the Fallopian tube, and the prognosis is worse
relative to adenocarcinomas.
1 Endometrioid (75%) (secretory, ciliated, papillary or
villoglandular)
2 Adenocarcinoma with squamous differentiation.
3 Adenoacanthoma (benign squamous component)
4 Adenosquamous (malignant squamous component)
5 Uterine papillary serous (5%–10%)
6 Clear cell (1%–5%)
7 Malignant mixed Mullerian tumours or carcinosarcomas
(1–2%)
8 Uterine sarcomas (leiomyosarcoma, endometrial stromal
sarcoma, undifferentiated) (3%)
9 Mucinous (1%)
10 Undifferentiated.
Based on histopathology, molecular profile and clinical course
of endometrial cancers are divided into two categories. Type I
are typically low-grade (I–II) adenocarcinomas that are usually
estrogen related, are diagnosed early and have a favourable
prognosis.
Type II endometrial cancers are not hormone dependent and
are usually grade III endometrioid adenocarcinomas, papillary
serous and clear cell carcinomas and carcinosarcomas
(malignant mixed Mullerian tumours). They have p53
mutations and loss of heterozygosity at several chromosomal
loci. They are associated with early spread and worse prognosis.
It is interesting that some type II tumours may have molecular
alterations found in type I tumours such as K-ras, PTEN,
b-catenine and microsatellite instability. This indicates that
type II tumours can arise from dedifferentiation of a pre-
existing type I cancer.
staging
The FIGO (International Federation of Gynecology and
Obstetrics) staging system for endometrial cancer has been
revised recently. The previous staging is shown in Table 1
and we have included it in this guideline, as the existing
literature and evidence are based on this. The new staging is
shown in Table 2, and hopefully it will be used in the next
guidelines.
The initial preoperative evaluation apart from history and
clinical examination and endometrial biopsy, includes complete
blood count, liver and renal function tests, and chest X-ray. If
cervical involvement is suspected, contrast-enhanced dynamic
magnetic resonance imaging (MRI) should be requested.
FIGO uses surgical and pathological staging for carcinoma of
the uterus (Tables 1 and 2). Pathological assessment includes:
� depth of myometrial invasion (ratio of invasion to total
myometrial thickness);
*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via
L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland;
E-mail: clinicalrecommendations@esmo.org
Approved by the ESMO Guidelines Working Group: October 2007, last update March
2010. This publication supercedes the previously published version—Ann Oncol 2009;
20 (Suppl 4): iv29–iv31.
Conflict of interest: The authors have reported no conflicts of interest.
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
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� cervical involvement (glandular/stromal invasion);
� tumour size and location (fundus, lower uterine segment/
cervix);
� extension of tumour to Fallopian tubes and ovaries;
� tumour grade and histological cell subtype (adenocarcinoma
versus clear cell, papillary serous);
� lymphovascular space invasion (LVSI);
� lymph node status. The approximate incidence of pelvic
lymph node involvement is for FIGO stage IA: 5%, IB: 10%,
IC: 15%, II: 20%, III: 55%.
treatment
surgery
Most patients (75%) with endometrial cancer are diagnosed
with stage I disease, as a result of an early investigation of
abnormal postmenopausal bleeding.
Patients are treated initially by total hysterectomy and
bilateral salpingo-oophorectomy (TH/BSO) [I, A]. Operation
may be either an open or a laparoscopic procedure. A pelvic/
para-aortic lymphadenectomy may be carried out, although the
practice varies between centres. Debate about the role of
lymphadenectomy is ongoing as it may increase the risk of
lymphoedema without a clear benefit. A randomized trial
of lymphadenectomy and adjuvant external beam
radiotherapy in the treatment of endometrial cancer conducted
by the Medical Research Council (MRC) and the National
Cancer Research Institute (NCRI) in the UK. There was no
evidence of benefit on overall survival or recurrence-free
survival for pelvic lymphadenectomy in women with early
endometrial cancer and it cannot be recommended as routine
procedure for therapeutic purposes. However, complete
surgical staging is suggested by others that may have an impact
on survival.
Abdominal organs such as the liver, diaphragm, omentum,
peritoneal surfaces are inspected and palpated during
operation. Peritoneal washings are also taken. Patients with
suspected cervical involvement (after an MRI or cervical
biopsy) would preferably be treated by radical total abdominal
hysterectomy and bilateral salpingo-oophorectomy (TAH/
BSO) and pelvic/para-aortic lymph node dissection is
considered.
Medically inoperable stage I/II patients (with comorbidities
common to those patients, obesity, cardiac morbidity, diabetes)
may be treated by external beam radiotherapy (RT) and/or
brachytherapy (BT) [I, A].
In patients with intra-abdominal disease (omental, nodal,
ovarian, peritoneal involvement, ascites) TAH/BSO and
maximal surgical debulking could be considered. In patients
with distant metastatic disease (e.g. liver, lung) palliative
hysterectomy could be considered depending on patient status,
expected benefits and multidisciplinary team decision. Surgery
may be followed by pelvic RT and/or chemotherapy (see
below).
adjuvant postoperative treatment
There is no definitive data supporting the routine use of
adjuvant treatment for patients with disease confined to the
uterus. There is uncertainty as to whether adjuvant RT
improves overall survival. Factors influencing the decision for
adjuvant treatment are mentioned above in the paragraph on
staging.
Data from randomized studies such as PORTEC-1
(Postoperative Radiation Therapy in Endometrial Carcinoma),
the GOG-99 (Gynecologic Oncology Group) and the recent
ASTEC/EN.5 trial have shown a reduction in locoregional
disease recurrence but not benefit in overall survival. Similar
findings were reported by others. Those studies have shown
that the majority of the initial recurrences for patients with
disease limited to the uterus were limited to the vagina,
suggesting that vaginal vault brachytherapy alone could be
used as an adjuvant treatment. To compare adjuvant pelvic
RT with vaginal BT alone in uterine-confined disease,
the PORTEC-2 study randomized patients between those
two modalities and showed very satisfactory vaginal
and pelvic control rates and equal survival with both
modalities.
Table 1. The ‘old’ FIGO staging for endometrial cancer: it is included
here as the currently existing literature is based on this and t would be
useful for the reader to take it into account when reading the present
guidelines
Stage
IA Tumour limited to endometrium
IB Invasion to <50% of the myometrium
IC Invasion to >50% of the myometrium
IIA Endocervical glandular involvement only
IIB Cervical stromal invasion
IIIA Tumour invades serosa and/or adnexa and/or positive peritoneal
cytology
IIIB Vaginal metastases
IIIC Metastases of pelvic and/or para-aortic lymph nodes
IVA Tumour invasion of bladder and/or bowel mucosa
IVB Distant metastases including intra-abdominal and/or inguinal
lymph nodes
Table 2. The new 2009-FIGO staging for endometrial cancer
Stage
I Tumour confined to the corpus uteri
IA No or <50% of the myometrium
IB Invasion ‡50% of the myometrium.
II Tumour invades cervical stroma but does not extend beyond the
uterus
III Local and/or regional spread of the tumour
IIIA Tumour invades serosa of the corpus uteri and/or adnexae
IIIB Vaginal and/or parametrial involvement
IIIC1 Positive pelvic lymph nodes
IIIC2 Positive para-ortic lymph nodes with or without pelvic nodes
IV Tumour invades bladder/bowel mucosa, and/or distant metastases
IVA Tumour invasion of bladder and/or bowel mucosa
IVB Distant metastases including intra-abdominal and/or inguinal
lymph nodes
clinical practice guidelines Annals of Oncology
v42 | Plataniotis & Castiglione Volume 21 | Supplement 5 | May 2010
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role of chemotherapy
adjuvant chemotherapy
Despite a traditional use of adjuvant radiotherapy, stage I/II
patients with high-risk factors may have a compromised
survival due to extrapelvic metastatic disease, suggesting the
need for an effective systemic adjuvant therapy. The EORTC
55991 randomized trial is a study of adjuvant RT with or
without chemotherapy in high-risk patients stage I/II tumours
with deep myometrial invasion and grade 3, clear cell, serous
papillary, undifferentiated pathology. Initially chemotherapy
consisted of four courses of cisplatin 50 mg/m2 + doxorubicin
50 mg/m2 or epirubicin 75 mg/m2 (AP). Subsequently several
chemotherapy regimens were allowed, of which AP, paclitaxel
175 mg/m2 + epirubicin 60 mg/m2 + carboplatin AUC 5, and
paclitaxel 175 mg/m2 + carboplatin AUC 5–6 were used. Data
from this trial showed that adjuvant chemotherapy given before
or after RT results in a hazard ratio (HR) for progression-free
survival of 0.58 in favour of RT + chemotherapy [95%
confidence interval (CI) 0.34–0.99; P = 0.046]. This translates to
an estimated 7% absolute difference in 5-year progression-free
survival from 75% (95% CI 67%–82%) to 82% (95% CI
73%–88%).
Two large randomized studies from Italy and Japan have
failed to show any difference in overall survival or progression-
free survival between chemotherapy and RT and there is an
ongoing debate on the methodology and the results of those
trials.
To resolve this issue an intergroup trial of the Dutch
Cooperative Gynaecologic Oncology Group and the UK NCRI
has conducted the PORTEC 3 study, a randomized trial
comparing concurrent chemoradiation and adjuvant
chemotherapy with pelvic radiation alone in high-risk and
advanced-stage endometrial carcinoma (stage IB grade 3 with
LVSI; stage IC or IIA grade 3; stage IIB; stage III; stage IB, IC, II
or III with serous or clear cell pathology).
chemotherapy for advanced or recurrent disease
Two large randomized studies (EORTC 55872 and GOG-107)
have compared doxorubicin and cisplatin (AP) with doxorubicin,
and found that the combination gave better response rates, but
no significant differences in survival. Mainly on the superior
response rates, the combination of doxorubicin and cisplatin has
been used as a standard treatment in endometrial cancer. Other
combinations with or without taxanes are being studied.
A recent Cohrane Review included trials accruing women
with advanced/recurrent/metastatic endometrial
adenocarcinoma (not amenable to potentially curative surgery
or radical RT) who were suitable for cytotoxic chemotherapy.
Meta-analysis has shown that progression-free survival was
significantly improved (HR = 0.80; 95% CI 0.71–0.90;
P = 0.004), but there was only a trend towards improved
survival (HR = 0.90; 95% CI 0.80–1.03). Addition of paclitaxel
to combination chemotherapy was at the expense of
increased toxicity [I, A]. Other randomized trials are currently
ongoing (e.g. GOG-209).
A study with an impact on the treatment of endometrial
cancer with chemotherapy was GOG-122. Four hundred
patients with FIGO stage III or IV endometrial carcinoma of
any histology (including serous and clear cell carcinomas) were
randomized. The study compared chemotherapy with whole
abdominal RT of 30 Gy in 20 fractions with an additional 15 Gy
pelvic boost. Eligibility required TAH and BSO, surgical
staging, tumour resection and no single site of residual tumour
greater than 2 cm. Nodal sampling was optional.
Chemotherapy consisted of doxorubicin (60 mg/m2) and
cisplatin (50 mg/m2) every 3 weeks for seven cycles, followed by
one cycle of cisplatin. Both overall survival and progression-free
survival were significantly better for patients treated in the
chemotherapy arm.
hormone therapy
Hormone therapy as an adjuvant treatment is not
recommended. For advanced or recurrent disease, oral
medroxyprogesterone acetate had an overall response rate of
25% and 200 mg/day works equally well as 1000 mg/day.
Patients with well-differentiated tumours and positive
progesterone receptor status have a higher response rate.
Tamoxifen (40 mg/day) combined with medroxyprogesterone
acetate (200 mg/day) may have a higher response rate.
papillary serous, clear cell carcinomas
Papillary serous and clear cell carcinomas are considered more
aggressive (type II endometrial cancers) and have a higher
incidence of metastatic disease (and patterns of failure with
a similarity to ovarian cancer), and lower 5-year survival rates
than patients with endometrioid carcinoma. The EORTC 55991
and the PORTEC 3 trials have included patients with these
histologies, so it is expected that the role of adjuvant
chemotherapy and RT in these patients will be answered by
these studies.
recurrent disease
Disease usually recurs within the first 3 years following initial
treatment. After the diagnosis of the recurrence a full staging
with complete blood tests and imaging for assessment of the
disease extent is important for discussion of therapeutic
options. Surgery is considered only in solitary/isolated
recurrences (e.g. single lung metastasis), and in cases where it is
hoped it will improve the patient’s symptoms and quality of
life. Pelvic exenteration can be considered in fit patients with an
isolated central recurrence.
However, RT is the most commonly used treatment modality
for pelvic recurrence of endometrial carcinomas. In fit patients
without extrapelvic disease, pelvic RT followed by vaginal BT
may offer a 5-year survival rate of 30%–80%. Pelvic recurrences
are most commonly found at the vaginal vault. If the remaining
tumour after pelvic RT is <3–5 mm, intracavitary BT can be
used. Otherwise, interstitial BT can be considered if available.
Chemotherapy can also be considered especially in the case of
disseminated extrapelvic disease. Options need to be examined
in the multidisciplinary meeting and discussed with the patient.
Decisions should be taken after balancing the expected benefits
and side-effects from cytotoxic chemotherapy. The most active
Annals of Oncology clinical practice guidelines
Volume 21 | Supplement 5 | May 2010 doi:10.1093/annonc/mdq245 | v43
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agents against recurrent endometrial cancer are doxorubicin
and cis-platinum.
Hormonal therapy may give response rates as high as 20%–
30% (see above).
guidelines for adjuvant treatment for endometrial
cancer could be as follows
Treatment guidelines for endometrial cancer cannot
incorporate all possible options and individual patients’ cases.
Controversy and lack of clear evidence characterize this
heterogeneous neoplasmatic disease. It is therefore
recommended that the decision for treatment of endometrial
cancer should be based on discussion in a multidisciplinary
team with participation of all the involved diagnostic and
therapeutic specialties.
(Staging is referred to according to the ‘old’ staging as trials
and evidence are based on this staging—Table 1.)
stage IA G1–2, IB G1–2. Observation.
stage IA G3, IB G3. Patients with stage IA G3 and IB G3 could
be considered for vaginal BT, depending on coexisting risk
factors (see above). In the case of LVSI and positive or no
lymph nodes dissected in a patient with a stage IB G3 tumour,
pelvic RT can be considered.
stage IC, G1–2. Observation or vaginal BT. Pelvic RT as above
in stage IB G3.
stage IC, G3. Vaginal BT alone or pelvic RT in case of LVSI,
positive nodes or no nodes dissection can be considered.
Chemotherapy should be discussed for those high-grade
patients.
stage II. Patients with stage IIA (cervical glandular involvement
only) without other risk factors are being treated as those with
stage I. It has to be mentioned that in the ‘new’ FIGO staging
system the involvement of cervical glands is not staged as
a stage II disease. Involvement of cervical stroma had been
staged as a stage IIB high-risk tumour, where both pelvic RT
and vaginal BT should be considered. In the case of grade I
tumour without LVSI and/or negative pelvic nodes after node
dissection, vaginal BT alone could be considered.
It has also been suggested that adjuvant chemotherapy may
reduce the rate of distant recurrences in these patients.
Therefore, it is reasonable to consider adjuvant chemotherapy
for high-grade (grade 3) tumours with cervical stromal
invasion.
stage III and IV. Treatment for patients with stage III–IV
disease should be individualized to the needs, prognosis and
clinical condition of each patient. A multimodality approach is
indicated, tailored to the extent of the disease and the
histological subtype. Maximal surgical cytoreduction is
considered if feasible, for patients without co-morbidities
[III, B]. Tumours that are outside the uterus but not
outside the pelvis (stage III) are approached with curative
intent.
Observation only could be an option for non-invasive grade
I–II, confined to fundus tumours with only positive cytology
(stage IIIA with the old staging). For all other stage III
tumours pelvic RT with vaginal BT (especially in case of
cervical stroma invasion) is recommended.
Adjuvant chemotherapy may reduce the rate of distant
recurrence in these patients. Therefore, it is reasonable to
consider adjuvant chemotherapy for stage III high-grade
tumours, particularly those with pelvic lymph node disease, in
addition to adjuvant RT.
Neoadjuvant chemotherapy can be considered for tumours
advanced at diagnosis. This may be followed by surgery. Pelvic
RT could be considered either to palliate symptoms or as
a high-dose palliative RT if it was felt it could offer a longer
free-of-symptoms interval.
papillary serous and clear cell carcinomas
No definite evidence could support the
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