Evidence-based review of the utility of radiation therapy in the treatment of endometrial cancer.

Abstract

Endometrial cancer is the most common cancer of the female genital tract in the USA and usually presents at an early stage. Most women are cured with surgery, however, some patients may require adjuvant therapy including radiation and/or chemotherapy. Risk factors determine the need for adjuvant treatment and, based on these risk factors, patients are categorized as being at low, intermediate or high risk for recurrence. In this article we will review the best level of evidence available for the use of radiation therapy within each risk stratum. The most controversy and debate is associated with patients stratified to the intermediate-risk group.

Full text

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ISSN 1745-5057
Women's Health (2010) 6(5), 695–704
10.2217/WHE.10.49 © 2010 Future Medicine Ltd
REVIEW
Evidence-based review of the utility
of radiation therapy in the treatment
of endometrial cancer
SB Dewdney†1 & DG Mutch1
Endometrial cancer is the most common cancer of the female genital tract in the USA and usually
presents at an early stage. Most women are cured with surgery, however, some patients may
require adjuvant therapy including radiation and/or chemotherapy. Risk factors determine the
need for adjuvant treatment and, based on these risk factors, patients are categorized as being
at low, intermediate or high risk for recurrence. In this article we will review the best level of
evidence available for the use of radiation therapy within each risk stratum. The most controversy
and debate is associated with patients stratified to the intermediate-risk group.
1Department of Obstetrics
& Gynecology, Washington University
School of Medicine and Siteman
Cancer Center, St Louis,
MO 63110, USA
†Author for correspondence:
Tel.: +1 314 362 3181
Fax: +1 314 362 2893
dewdneys@wustl.edu
Keywords
• adjuvant therapy
• endometrial cancer • radiation
therapy
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Learning objectives
Upon completion of this activity, participants should be able to:
• Describe risk factors for and the typical presentation of endometrial cancer
• Describe treatment options – including prognosis – for low-, intermediate-, and high-risk
endometrial cancer
Financial & competing interests disclosure
CME Author
Desiree Lie, MD, MSEd, Clinical Professor; Director of Research and Faculty Development, Department of Family
Medicine, University of California, Irvine at Orange.
Disclosure: Désirée Lie, MD, MSEd, has disclosed the following relevant financial relationship:
Served as a nonproduct speaker for: ‘Topics in Health’ for Merck Speaker Services.
Authors and Disclosures
Summer B Dewdney, MD, Department of Obstetrics & Gynecology, Washington University School of Medicine and
Siteman Cancer Center, St Louis, MO, USA.
Disclosure: Summer B Dewdney, MD, has disclosed no relevant financial relationships.
David G Mutch, MD, Department of Obstetrics & Gynecology, Washington University School of Medicine and Siteman
Cancer Center, St Louis, MO, USA.
Disclosure: David G Mutch, MD, has disclosed no relevant financial relationships.
Editor
Elisa Manzotti, Editorial Director, Future Science Group, London, UK.
Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.
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In the USA, endometrial cancer is the most com-
mon malignancy of the female genital tract. It
is estimated that 42,160 women were diagnosed
with this disease in 2009, resulting in 7780
deaths [1]. Fortunately, the majority of endome-
trial cancer cases are diagnosed at an early stage
and present with abnormal uterine bleeding and
most of these women are cured. The median age
at diagnosis is 62 years [101]. Approximately 70%
of endometrial cancer patients are diagnosed
with localized disease, resulting in a 5-year
survival of 95% in this subset of patients [1].
In addition, the mortality rate for endometrial
cancer continues to decline; in 1991 the mortal-
ity rate was 4.18 per 100,000 and in 2005 it was
4.10 per 100,000 [1]. Risk factors for develop-
ment of this disease include obesity, diabetes,
hypertension, endogenous or exogenous excess
estrogen, nulliparity, menopause, family history
and endometrial hyperplasia.
Treatment
Most endometrial cancers in the USA are ini-
tially surgically staged according to the crite-
ria established by the International Federation
of Obstetrics and Gynecology (FIGO). FIGO
announced that they had updated endometrial
cancer staging in October 2009 [2]. Although
most of the studies in this review use FIGO
staging from 1988, it is important to recognize
the new staging system because it will be used
for future studies. The National Comprehensive
Cancer Network (NCCN) and the American
College of Obstetricians and Gynecologists
(ACOG), standard definitive treatment includes
a hysterectomy, bilateral salpingo–oophorec-
tomy and pelvic/para-aortic lymph node dissec-
tion with pelvic washings and, for poor histo-
logic types, an omental biopsy [3,102]. The value
of pelvic/para-aortic lymph node dissection
in the staging of endometrial cancer has been
called into question by recent data published
in A Study in the Treatment of Endometrial
Cancer (ASTEC) and trials carried out by Panici
et al. [4,5]. Management and adjuvant treatment
after surgery depends upon a patient’s risk fac-
tors for recurrence. Options include vaginal
vault brachytherapy, pelvic external-beam radi-
ation therapy (EBRT) and/or chemotherapy.
The most significant risk factors considered in
any decision for adjuvant therapy include age of
the patient, grade, histologic type (i.e., serous,
clear cell or grade 2/3 endometrioid), depth of
myometrial invasion, tumor extension beyond
the uterus and lymphovascular space invasion.
Depending on the number and severity of these
risk factors, patients are categorized as being
at low, intermediate, or high risk for recur-
rence (Table 1). Most controversy and debate is
associated with the patients stratified to the
intermediate-risk group.
In this article we will review the best level
of evidence available for the use of radiation
therapy within each risk stratum.
Management after surgery
Should women with a low risk
of recurrence receive adjuvant
radiation therapy?
Low-risk disease is defined as cancer that is con-
fined to the uterus with little or no myometrial
invasion and low-grade histologies (i.e., disease
confined to the endometrium or with <50%
myometrial invasion, grades 1 and 2). These
patients have the lowest risk of recurrence and
therefore are generally felt not to need any
adjuvant treatment.
Historically, these patients have not received
treatment because of their overall excellent sur-
vival and the fact that morbidity from treat-
ment is greater than the expected benefit from
therapy. This was further verified by the findings
of prospective studies conducted between 1977
and 1983 by the Gynecologic Oncology Group
(GOG 33), which investigated the patterns of
failure for early-stage disease [6]. Of the women
who had no myometrial invasion with grade 1 or
2 histology, none experienced recurrence [7]. In
addition, a Cochrane review of the treatment for
stage I endometrial cancer found a statistically
significant greater risk for death in patients who
had EBRT versus no treatment with low risk fac-
tors (i.e., disease confined to the endometrium,
<50% myometrial invasion or grade 1/2) [8].
These data were confirmed again by meta-
analysis of seven randomized trials by Johnson
et al. showing that prophylactic EBRT could be
harmful or ineffective in improving survival in
women with low- or intermediate-risk cancer [9].
Sorbe et al. (2009)
A recent prospective trial evaluated patients
diagnosed with stages IA or IB using FIGO
1988 criteria with grade 1 or 2 histology. These
patients were randomized to surgery plus
intravaginal brachytherapy or surgery with-
out adjuvant treatment. The study enrolled
645 patients and found no statistical differ-
ence in survival or local regional control with
adjuvant treatment. The mean follow-up time
was 68 months. A total of 26 (4%) recurrences
were observed in the complete series and there

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was no difference between the two groups
(p = 0.114). Acute and late side effects in both
groups were few and mild [10].
Therefore, adjuvant treatment with radiation
is not recommended in this group of patients
and may expose women to unnecessary toxicity
(level 1 evidence).
Should women with an intermediate
risk for recurrence receive adjuvant
radiation therapy?
Patients with disease confined to the uterus but
with high risk factors for recurrence are defined
as having intermediate risk. The inclusion crite-
ria for this group vary slightly from trial to trial.
These risk factors include, but are not limited to,
age, lymphovascular space invasion, tumor size,
cervical involvement and deep myometrial inva-
sion. Despite multiple randomized studies, this
group is still the most controversial with regard
to adjuvant radiotherapy because it is not clear
whether the benefit of treatment outweighs the
risks (Table 2).
Aalders et al. (1980)
This trial was conducted before the introduction
of FIGO staging, between 1968 and 1974. A
total of 540 patients with clinical stage I endo-
metrial cancers were entered into a prospective
randomized clinical trial. All patients received
vaginal brachytherapy and then were random-
ized to no further treatment or EBRT. The
authors found a significant reduction in pelvic
and vaginal recurrences in patients who received
EBRT although these patients had more dis-
tant metastases. The 5-year overall survival
(OS) was not improved by EBRT, although a
more detailed ana lysis of the series concluded
that patients with higher risk factors such as
poorly differentiated tumors (grade 3), who have
greater than 50% myometrial invasion might
benefit from EBRT [11].
PORTEC‑1 (2000)
This multicenter trial randomized patients to
external radiation therapy versus no therapy and
included patients with stage IC grade 1, grade 2
with any invasion, and stage IB grade 3 (FIGO
1988 criteria). Following total abdominal hys-
terectomy salpingo–ooporectomy without rou-
tine lymphadenectomy patients (n =715) were
randomized to receive either EBRT or no further
treatment. Both arms of patients were allowed to
have vaginal brachytherapy. Median follow-up
Table 2. Comparison of randomized controlled trials in the treatment of endometrial carcinoma.
Studyn Inclusion criteria
(FIGO 1988)
Method
of staging
Arms of studyOverall
survival
Recurrence rate at
5 years
Ref.
Aalders et al.
540Stage I
(clinical stage)
Clinically VBT + EBRT vs
VBT alone
89 vs 91%;
p = NS
2 vs 7%; p <0.01
[11]
PORTEC 714 Stage IB (G2/3);
stage IC (G1/2)
Surgically, LND
not required
No treatment vs EBRT85 vs 81%;
p = 0.31
14 vs 4%; p <0.001
[12]
GOG 99 392 Stage IB–IIB (occult)Surgically,
LND required
No treatment vs EBRT
(no VBT)
86 vs 92%;
p = 0.557
12 vs 3%; p = 0.007
at 2 years
[13]
ASTEC/EN.5 906Stage IA–IIA Surgically, LND
not required
No treatment (51% VBT)
vs EBRT (52% + VBT)
84 vs 84%;
p = 0.77
6 vs 3%; p = 0.02
[14]
PORTEC-2 427>60 years of age stage
IC G1/2, stage IB G3; any
age stage IIA G3
Surgically, LND
exclusion criteria
EBRT vs VBT 80 vs 84%;
p = 0.57
2 vs 5%; p = 0.17
[16]
ASTEC: A Study in the Treatment of Endometrial Cancer; EBRT: External-beam radiation therapy; FIGO: International Federation of Gynecology and Obstetrics;
G: Grade; GOG: Gynecologic Oncology Group; LND: Lymph node dissection; NS: Not significant; VBT: Vaginal brachytherapy.
Table 1. Definitions of risk of recurrence in endometrial cancer.
Risk level Definition
Low risk Confined to the uterus with little or no myometrial invasion and low-grade histologies
Intermediate risk Confined to the uterus but with invasion into the myometrium, or demonstrates occult cervical involvement
Other poor prognostic factors include (the factors are used to categorize the high-intermediate-risk group): outer
third myometrial invasion, grade 2 or 3 differentiation and the presence of lymphovascular invasion
High-intermediate risk Includes patients of any age with all three adverse prognostic factors, patients who are 50–69 years old with two
adverse prognostic factors, and patients who are >70 years old with any one of the adverse prognostic factors
High risk Gross involvement of the cervix, stage III or IV, papillary serous or clear cell histologies

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was 52 months. The 5-year local regional recur-
rence rates were statistically different at 4% in
the treatment group and 14% in the control
group (p < 0.001). However, the 5-year OS rates
were similar, (p = 0.31). This study identified
significantly more complications in the EBRT
group – 25% compared with 6% of controls.
In a subgroup ana lysis, an age of 60 years and
above and deep myometrial invasion were both
identified as poor prognostic factors [12].
GOG 99 (2004)
Of the randomized studies, the GOG 99 study
is the only study that required FIGO surgical
staging. This Phase III trial included patients
with intermediate-risk disease, defined as
stage IB, IC, IIA (occult), and IIB (occult) of
any grade, excluding papillary serous and clear
cell histologies (FIGO 1988 staging criteria).
A total of 448 women were randomized to
adjuvant EBRT or no further treatment, and
neither group received vaginal brachytherapy.
The median follow-up was 68 months and the
primary outcome was recurrence-free interval
(RFI). The 24-month estimated cumulative
incidence of recurrence was 3% for the EBRT
group and 12% for the no adjuvant treatment
group. The trial found that EBRT reduces the
risk of recurrence by 58%, compared with the
no adjuvant treatment group; however a sta-
tistical significance for survival was not found
between the two groups. A subgroup ana lysis of
the high-intermediate risk (HIR) patients was
performed. HIR patients were defined as those
with grade 2 or 3 histology, deep myometrial
invasion (outer third) and lympho vascular space
invasion; age 50 years or older with any two of
these risk factors; or age of at least 70 years with
any risk factor. This HIR group accounted for
nearly 2/3 of the recurrences and 2/3 of the can-
cer-related deaths. This study was not powered
to analyze this subgroup; however, they con-
cluded that this trial provides strong evidence
for the use of EBRT in patients who fall into
this category [13].
ASTEC/EN.5 (2009)
The ASTEC/EN.5 trial is a pooled trial of
two studies and may be flawed for this reason.
These two trials, ASTEC and EN.5 were origi-
nally set up as individual trials that were later
combined, secondary to insufficient recruit-
ment in either trial. The trial was designed to
evaluate the benefit of postoperative adjuvant
EBRT in women with intermediate- and high-
risk early-stage endometrial cancer. High risk
was defined as papillary serous and clear cell
subtypes, all other subtypes in IC (grade 3)
and IIA (grade 3), and all women in stage IIB.
Intermediate risk included subtypes other than
papillary serious and clear cell, within stage IA
and IB (grade 3), and stage IC and IIA (grades 1
and 2). FIGO 1988 staging criteria was used in
this study. A total of 905 women were enrolled,
and eligibility included stage IA/IB grade 3;
IC all grades and papillary serous or clear cell
histologies [14]. Briefly, the ASTEC trial was
in two parts. The first randomization was to
lymphadenectomy or not, and the second part
was a randomization to receive postoperative
radiation or not. Lymphadenectomy was not a
requirement for randomization in EN.5 but was
part of the original randomization in the first
part of the ASTEC trial. Approximately half of
the patients in both arms (EBRT vs no treat-
ment) received vaginal brachytherapy. The trial
found no evidence of a benefit from EBRT for
early-stage endometrial cancer with intermedi-
ate or high risk of recurrence in terms of OS.
In addition, the authors performed a meta-ana-
lysis using the data from GOG 99, PORTEC-1
and the current combined trial and found no
significant difference in OS, or disease-specific
survival regardless of the histologic risk group
of the patient. However, EBRT did demonstrate
a small reduction in isolated local recurrences.
Controversy exists surrounding this trial,
and some critics would cite methodological
flaws, despite its large prospective randomized
study design [15]. These limitations have been
described as not including a para-aortic lym-
phadenectomy as part of the prescribed proto-
col, leading to inadequate lymphadenectomies
in less than half of the patients. In addition,
patients who had positive lymph nodes were
still randomized to no treatment and there was
possible selection bias in the nonrandomized
nature of almost half of the patients from both
arms receiving vaginal brachytherapy. Finally,
there was a significant heterogeneity of inclusion
criteria, especially when analyzing the adjuvant
radiation portion of the study.
PORTEC‑2 (2010)
This was the second trial in the PORTEC
series. This noninferiority multicenter trial
randomized patients with a HIR of endo-
metrial cancer to vaginal brachytherapy or
EBRT. FIGO 1988 staging was used in this
trial and HIR was defined as age 60 years and
above and stage IC grade 1 or 2 or stage IB
grade 3, and any age with stage IIA grade 1,

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2 or grade 3 with less than 50% invasion. A
total of 427 patients were recruited to this
trial between 2002 and 2006, with a median
follow-up time of 45 months. Routine lymph-
adenectomy was not performed and was a basis
for exclusion. There was no significant differ-
ence in OS and the 5-year loco-regional recur-
rence rate between treatment modalities. The
estimated 5-year vaginal recurrence rates were
1.8% (95% CI) after vaginal brachytherapy
and 1.6% (95% CI) after EBRT [16]. A second
article from these data was published regarding
the quality of life for patients enrolled in this
study. Through validated questionnaires, vagi-
nal brachytherapy was found to be preferred
to EBRT with regard to quality of life. The
EBRT group reported significant and clinically
relevant higher levels of diarrhea and fecal leak-
age, which limited social and daily activities for
the EBRT group (p <0.001) [17].
The preponderance of data suggest that
external beam radiotherapy does not improve
OS but provides a small but real improvement
in local control for patients with intermediate-
risk disease. Vaginal brachytherapy appears
equally effective, with an improved quality of
life compared with EBRT (level 1 evidence).
Should women with a high risk
of recurrence receive adjuvant
radiation therapy?
Women who have endometrial cancer with a high
risk for recurrence are defined as having myome-
trial invasion greater than 50% (grade 3), gross
involvement of the cervix or advanced-stage dis-
ease. Other high-risk prognostic factors include
lymphovascular space involvement and aggres-
sive histologic types, papillary serous and clear
cell. These histological types have a particularly
poor prognosis, and are known to have a higher
propensity for extra-abdominal and intraperito-
neal spread. In addition, the majority of these
tumors have extrauterine spread at the time of
presentation, therefore making these histological
subtypes difficult to treat with radiation.
There are no randomized controlled trials
that are specific to this exact subset of patients.
Although, as described above, Aalders et al. ana-
lyzed a subset of patients with clinical stage IC
grade 3 endometrial cancers and found that
EBRT decreased the cancer-related death rate
from 27.5 to 18.2% [11]. Significantly more
deaths and recurrences were identified among
patients with lymphovascular space invasion
compared with those without (26.7 vs 9.1%,
p = 0.01).
The GOG 99 trial, which was a randomized
controlled trial but did not have the power to
analyze the HIR subset of patients, demonstrated
a 19% decrease in recurrence and a 0.73 rela-
tive hazard of death in the EBRT arm defined
as HIR [13].
Maggi et al. (2006)
This randomized trial failed to show superiority
of adjuvant chemotherapy over radiation. This
trial enrolled 345 women with high-risk endome-
trial cancer. Most were stage III (approximately
two-thirds), with the remaining being stage
IC/grade 3 and stage II/grade 3 with more than
50% myometrial invasion (FIGO 1988 criteria).
Patients were randomly assigned to adjuvant cis-
platin, doxorubicin and cyclophosphamide versus
EBRT. The median follow-up was 95.5 months.
There were no significant differences between
the two groups for OS or PFS [18].
Hogberg et al. (2007)
This randomized Phase III trial presented at
ASCO in 2007 (abstract form) evaluated adju-
vant treatment with radiation and chemotherapy
versus radiation only in high-risk endometrial
cancer. Patients with surgical stage I, II, IIIA
(positive for peritoneal fluid cytology only) or
IIIC (positive pelvic lymph nodes only) were eli-
gible (FIGO 1988 criteria). Most patients had
two or more risk factors: grade 3, deep myo-
metrial invasion or DNA non diploidy. Serous,
clear cell or anaplastic carcinomas were eligible
regardless of risk factors. Lymphadenectomy
was not required as part of surgical staging.
Patients were randomized to EBRT ± vaginal
brachytherapy with chemotherapy or to pel-
vic EBRT ± vaginal brachytherapy only. The
study was terminated early, secondary to poor
recruitment; 367 patients were evaluable. The
median follow-up time was 3.5 years. Hazard
ratio (HR) for progression free survival (PFS)
was 0.58 in favor of EBRT and chemotherapy
(95% CI: 0.34–30.99; p = 0.046). The authors
concluded that EBRT plus chemotherapy was
better than EBRT alone [19].
Japanese GOG (2008)
This was a randomized study that enrolled
475 patients with stage IC–IIIC endometrial car-
cinoma with deeper than 50% myometrial inva-
sion (FIGO 1988 criteria). They were randomized
to receive adjuvant EBRT or cyclophosphamide,
doxorubicin and cisplatin. A pelvic lymphadenec-
tomy was performed in 96.1% of the patients and
a para-aortic lymphadenectomy was performed