Practical Radiation Oncology (2017) 7, 19-25

www.practicalradonc.org

Original Report

Long-term outcomes using adjuvant pelvic

intensity modulated radiation therapy (IMRT) for
endometrial carcinoma
Siping He BS a , Beant S. Gill MD b , Dwight E. Heron MD, MBA, FACRO, FACR b ,
Joseph L. Kelley MD c , Paniti Sukumvanich MD c , Alexander B. Olawaiye MD c ,
Robert P. Edwards MD c , John Comerci MD c , Sushil Beriwal MD b,
a
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
b
Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
c
Department of Gynecologic Oncology, Magee-Womens Hospital of University of Pittsburgh Medical Center,
Pittsburgh, Pennsylvania

Received 5 April 2016; revised 27 May 2016; accepted 8 June 2016

Abstract
Purpose: We evaluated the long-term outcome and toxicity of adjuvant intensity modulated
radiation therapy (IMRT) for high-risk endometrial carcinoma via a retrospective institutional
review of patients treated in this setting with extended follow-up.
Methods and materials: Patients with endometrial cancer who underwent comprehensive surgical
staging followed by adjuvant IMRT with or without sequential chemotherapy between 1999 and
2010 were reviewed. Median doses delivered with IMRT and brachytherapy were 45 Gy in 25
fractions and 10 Gy in 2 fractions; 10.2% received extended field and 94.5% received vaginal
brachytherapy. Kaplan-Meier estimates are provided for rates of locoregional (in-field) relapse,
distant metastasis, and disease-free survival, and overall survival. Gastrointestinal (GI) and
genitourinary (GU) toxicity reported were graded with the Common Terminology Criteria for
Adverse Events, version 4.03.
Results: A total of 128 patients were identified. Median age at diagnosis was 64 years. Most
patients (82.8%) had endometrioid adenocarcinoma followed by papillary serous (10.2%), clear
cell (4.7%), and carcinosarcoma (2.3%). International Federation of Gynecology and Obstetrics
staging distribution was as follows: IA, 13.3%; IB, 32.8%; II, 30.4%; IIIA, 5.5%; IIIC1, 9.4%; and
IIIC2, 8.6%. Most (85.9%) underwent nodal dissections (28.1% pelvic only and 57.8% pelvic and
para-aortic). Two patients (1.6%) experienced acute grade 3 GI toxicity; no other acute grade 3
GI/GU toxicities were noted. With a median follow-up of 57.0 months, 5-year locoregional relapse
was 2.5%: vagina (n = 3), parametrium (n = 1), pelvic node (n = 1). Five-year estimates of distant
metastasis, disease-free survival, and overall survival were 16.5%, 73.4%, and 77.4%, respectively.
Five-year actuarial rates of late grade 3 GI and GU toxicities were 3.2% and 0.0%. The 5-year rate
of symptomatic pelvic insufficiency fracture was 4.4%.

Conflicts of interest: None.

Corresponding author. Magee-Womens Hospital of UPMC, Department of Radiation Oncology, 300 Halket Street, Pittsburgh, PA 15232.
E-mail address: beriwals@upmc.edu (S. Beriwal).

http://dx.doi.org/10.1016/j.prro.2016.06.005
1879-8500/ 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
20 S. He et al
Conclusions: This study represents the largest cohort of endometrial cancer patients with extended
follow-up receiving adjuvant IMRT. High rates of pelvic disease control and limited late toxicities
demonstrate safety and efficacy of this approach in the setting of extended follow-up.
2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Introduction
Endometrial cancer is the most common gynecologic
malignancy and the second most common cancer in women
of developed countries, affecting predominantly postmen-
opausal women around 60 years of age. 1 The most common
type in the United States is the endometrioid type arising
from an excess of estrogen and carries a favorable prognosis.
The remaining 20% are aggressive cell types (ie, clear cell
and serous types) that yield poorer prognosis because of
higher metastasis and recurrence rate. Overall 5-year
survival rate for stage I endometrioid type is favorable at
80%, whereas higher stages III and IV range between 20%
and 60%. 2 Initial treatment of endometrial cancer includes
surgical staging via complete hysterectomy, bilateral
salpingo-oophorectomy, and pelvic and para-aortic lymph
node dissection. 3 For patients with an intermediate to high
risk for locoregional recurrence, external beam radiation
therapy with or without vaginal cuff intracavitary brachy-
therapy is used. Conventional pelvic 3-dimensional (3D)
conformal radiation therapy is associated with increased
acute and late gastrointestinal (GI), genitourinary (GU), and
bone marrow toxicities, with a subsequent detrimental
impact on quality of life, leading to refinement in the
indication for using adjuvant external beam radiation
therapy among only high-risk patients. 4
Intensity modulated radiation therapy (IMRT) enables
greater conformality compared with 3D-conformal radia-
tion therapy, allowing for sculpting of dose away from
nearby critical pelvic structures. IMRT utilization for all
cancers has increased over time, with use among
gynecologic cancers increasing from 1.5% in 2001 to
23.2% in 2007. 5,6 However, more widespread adoption of
IMRT is limited because of unknown tradeoffs between
increased cost and decreased toxicity and the potential risk
of target miss given greater conformality. Early prospec-
tive and single-institution retrospective studies have
suggested efficacy of IMRT, demonstrating favorable
outcomes. 7-9 Despite favorable outcomes and reduced
toxicity of IMRT as demonstrated by earlier studies, the
outcomes are limited by short-term follow-up, which may
fail to capture late presenting toxicities and recurrences.
This study aims to review a larger number of patients
who have undergone adjuvant IMRT treatment with or
without brachytherapy over the span of a decade. Analysis
of this patient cohort with long-term follow-up aims to
highlight long-term outcomes, including toxicities and
locoregional control following adjuvant IMRT for endo-
metrial cancer.
Practical Radiation Oncology: January-February 2017
Methods and materials
Study design
A retrospective review was conducted of endometrial
cancer patients treated at University of Pittsburgh Medical
Center (UPMC) Cancer Center between 1999 and
2010 following institutional review board approval.
Patients underwent initial surgical staging (total laparo-
scopic or abdominal hysterectomy and bilateral
salpingo-oophorectomy with or without pelvic and/or
para-aortic lymph node dissection). Patients were required
to have International Federation of Gynecology and
Obstetrics (FIGO) stage IA-IIIC endometrial cancer,
receiving adjuvant pelvic IMRT with or without intracav-
itary brachytherapy. Patients treated with definitive
(nonsurgical) or palliative intent, patients with no or
limited follow-up (b3 months), and/or patients with gross
residual/recurrent disease at the time of radiation therapy
were excluded. All primary uterine histologies were
included except endometrial stromal sarcomas and leio-
myosarcomas in light of differences in management
approach. Patients were risk-stratified based on Gyneco-
logic Oncology Group (GOG) 99 criteria and ongoing
GOG 258 definitions: high-intermediate risk (FIGO stage
IA-II endometrioid with age 70 and 1 adverse factor,
age 50-69 and 2 adverse factors, or age b50 and 3
adverse factors), low-intermediate risk (FIGO stage IA-II
endometrioid not included in high-intermediate risk), and
high risk (stage IIIA-IIIC2 endometrioid or any stage with
adverse histology). 10
Radiation therapy technique
The treatment approach utilized has been described in
detail. 7 To highlight a few key differences, patients treated
through 2007 had daily placement of a radiopaque,
cylindrical vaginal marker, SHADOWFORM vaginal
marker (IZI Corp, Baltimore, MD), to indicate vaginal
apex position. This vaginal marker was abandoned after
2007 because of concerns of internal anatomy reproduc-
ibility and patient discomfort. Second, following consen-
sus guidelines in 2008 that suggested accounting for
bladder-filling variations, 11 patients treated after 2008
underwent a planning computed tomography scan in both
the full and empty bladder state; an internal target volume
was subsequently created to correct for vaginal variations
from bladder filling. Third, the clinical target volume
(CTV) of the pelvic field included internal, external, and
Practical Radiation Oncology: January-February 2017 Endometrial IMRT: Long-term results 21

Table 1 Patient clinicopathological characteristics (n = 128) beam computed tomography) became available. Follow-
Characteristic n % ing image guidance integration, the planning target
volume was defined by a 7-mm margin around the nodal
Age at diagnosis (y) CTV and 7 to 10 mm around the paravaginal CTV. Last, if
Median 63.5 -
patients required extended field treatment because of
Range 31-85 -
pelvic and/or para-aortic nodal involvement, the nodal
FIGO stage
IA 17 13.3 CTV was extended to include the para-aortic lymph nodes
IB 42 32.8 region up to the level of the renal vessels instead of the
II 39 30.4 bony landmark of L1. Within the planning field, normal
IIIA 7 5.5 structures including small bowel (entire peritoneal cavity),
IIIC1 12 9.4 bladder, rectum, bone marrow, and kidneys (if para-aortics
IIIC2 11 8.6 were involved) were contoured as organs at risk.
Lymphovascular space invasion When brachytherapy was used, all patients received
Present 54 43.9 high-dose-rate (HDR) brachytherapy using predominantly
Absent 69 56.1 a 3.0-cm diameter vaginal cylinder. Dose was prescribed 5
Histology
mm from the vaginal surface, treating the proximal 3 cm of
Endometrioid adenocarcinoma 106 82.8
vagina to 5 Gy 2 fractions.
Adverse histologies 22 17.2
Papillary serous 13 10.2
Clear cell 6 4.7 Statistical analysis
Carcinosarcoma 3 2.3
FIGO grade Locoregional control, distant metastasis rate,
1 31 24.2 disease-free survival, and overall survival were calculated
2 45 35.2 using the Kaplan-Meier method. Locoregional relapse was
3 52 40.6
defined as recurrence located within the radiation therapy
Depth of myometrial invasion (%)
fields: pelvis for pelvic-only radiation and pelvis and
Median 55 -
Range 4-100 - para-aortics if an extended field was used. All locoregional
Type of surgery recurrences were confirmed histologically via biopsy. If a
TH/BSO (no nodal assessment) 18 14.1 patient developed simultaneous locoregional and distant
TH/BSO + pelvic nodal dissection 36 28.1 failure, both were counted independently for locoregional
TH/BSO + pelvic and para-aortic control and distant metastasis rate. For all others, relapse
nodal dissection 74 57.8 was defined as the first site of relapse. Events counted in
Lymph nodes dissected calculation of disease-free survival included locoregional
Median 13 failure, distant failure, cancer-related death, and/or death
Range 1-45 from any cause.
Lymph node status
Radiation-related toxicities were graded according to
Negative 87 79.1
the Common Terminology Criteria for Adverse Events
Positive 23 20.9
Pelvic 12 10.9 (version 4.03). Acute toxicities were captured from start of
Para-aortic 4 3.6 IMRT up to 3 months after the end of IMRT. Late
Pelvic + para-aortic 7 6.4 toxicities were all symptoms reported after 3 months from
Peritoneal cytology the end of IMRT. To avoid underreporting of toxicities
Negative 111 86.7 subject to reporting bias, only severe (grade 3 or greater)
Positive 17 13.3 GU and GI) toxicities are reported. Fistula and symptom-
Margin status atic pelvic fracture rates were also captured.
Negative 126 98.4
Positive (microscopic) 2 1.6
FIGO, International Federation of Gynecology and Obstetrics; TH/
BSO, total hysterectomy/bilateral salpingo-oophorectomy. Results

Patient, disease, and surgical treatment characteristics

entire common iliac nodal groups and the proximal part of
the vagina unless involved. Common iliac nodes were
initially contoured to L5-S1, which was subsequently
altered from 2009 onwards to be defined anatomically by
the bifurcation of aorta. Fourth, planning target volume
margins for nodal and paravaginal sites were reduced
when image guidance (kilovoltage imaging and/or cone
One hundred and twenty-eight patients were included
for analysis with a median age at diagnosis of 63.5 years
(range, 31-85 years) (Table 1). All patients underwent a
total hysterectomy and bilateral salpingo-oophorectomy,
with 36 patients (28.1%) also undergoing pelvic nodal
dissection and 74 (57.8%) undergoing pelvic and
22 S. He et al Practical Radiation Oncology: January-February 2017

Table 2 Radiation therapy treatment details margins. Excluding high-risk patients (25.8%), patients
Characteristic n % were further risk-stratified into low-intermediate risk (LIR,
10.9%) and high-intermediate risk (HIR, 63.3%).
IMRT dose (Gy)
Median (range) 45 (41.4-50.4) -
IMRT fractions Radiation therapy details
Median (range) 25 (2328) -
Treatment field Radiation therapy treatment details are summarized in
Pelvis 115 89.8 Table 2. Nearly all (94.5%) received adjuvant HDR
Extended field (pelvis vaginal cuff brachytherapy. Median pelvic IMRT dose
and para-aortics) 13 10.2 was 45 Gy (range, 41.4-50.4 Gy) given in 25 fractions.
Brachytherapy Median vaginal cuff brachytherapy dose was 10 Gy in 2
None 7 5.5 fractions prescribed to a 5-mm depth. A minority of
Vaginal cuff (HDR) 121 94.5
patients (10.2%) received extended field radiation therapy
Adjuvant chemotherapy
None 94 73.4
to cover para-aortic nodes.
Delivered 34 26.6
HDR, high-dose rate; IMRT, intensity modulated radiation therapy.
Clinical outcomes

Median follow-up for the entire cohort was 57 months

para-aortic nodal dissection before pelvic IMRT. The most
common surgical stage was IB (32.8%) followed by stage
II (30.4%) disease. Most patients (82.8%) had endometrial
adenocarcinoma of the endometrioid type, whereas a
minority of patients had unfavorable histologies: papillary
serous (10.2%), clear cell (4.7%), and carcinosarcoma
(2.3%). Twenty-three (20.9%) of the 110 patients who
underwent lymph node dissection were lymph node
positive, with nearly one-half (n = 12) occurring at the
pelvic nodes. Only 2 patients (1.6%) had positive surgical
(range, 3.6-153 months). Five-year estimated outcomes
are as follows: locoregional relapse, 2.5% (95% confi-
dence interval [CI], 0.0%-5.2%); distant metastasis, 16.5%
(95% CI, 9.6%-23.4%); disease-free survival, 73.4% (95%
CI, 65.4%-81.4%); and overall survival, 77.4% (95% CI,
69.8%-85.0%) (Fig 1). Among the 5 patients with
locoregional relapse, 3 recurred in the vagina, 1 in the
parametrium, and 1 in a pelvic node.
All 3 patients with isolated vaginal recurrence, all
occurring at the apex, underwent successful salvage using

Figure 1 Kaplan-Meier estimates for locoregional relapse, disease-free survival, and overall survival.
Practical Radiation Oncology: January-February 2017
Table 3 Risk-stratified 5-year Kaplan-Meier estimated outcomes
Low-intermediate risk
(n = 14)
% 95% CI
Locoregional failure 7.1 0.0-20.6
Distant metastasis 7.1 0.0-20.6
Disease-free survival 85.7 67.3-100.0
Overall survival 91.7 76.0-100.0
CI, confidence interval.
multicatheter vaginal cylinder (MCVC) HDR brachyther-
apy. Specifically, the first patient failed at 6.8 months after
adjuvant sequential chemotherapy and IMRT alone with
initial stage IIIC2, grade 3, papillary serous carcinoma.
After MCVC salvage, this patient had no evidence of
disease at time of death from unrelated causes (8.5 months
after salvage therapy). The second patient had stage IA,
grade 1, endometrial adenocarcinoma with lymphovascu-
lar space invasion (LVSI) and failed treatment at 77.4
months after pelvic IMRT and brachytherapy. After
salvage MCVC, this patient remained in remission at last
follow-up (19.5 months). The last patient had stage IA,
grade 1, endometrial adenocarcinoma without LVSI,
developing isolated vaginal recurrence at 30.8 months
after pelvic IMRT and brachytherapy. After MCVC
salvage, this patient remains in remission at last
follow-up (4.2 months).
The 5-year rate of locoregional failure was low across
risk groups (Table 3). Rates of distant metastases,
disease-free survival, and overall survival trended toward
worse outcomes among higher risk patients.
Acute and late toxicities
Severe acute toxicities were limited to GI toxicity,
where 2 patients (1.6%) developed partial small bowel
obstruction. No patients developed acute grade 3 or greater
acute GU toxicities. Severe late toxicity (grade 3 or
greater) occurred at a 5-year actuarial rate of 3.2% (95%
CI, 0.1%-6.3%), again all consisting of grade 3 GI
toxicities (small bowel obstruction). No patients suffered
grade 3 or greater GU toxicities or fistulas. Pelvic
insufficiency fracture occurred at a 5-year estimated rate
of 4.4% (95% CI, 0.7%-8.0%). Pelvic insufficiency
fractures were associated with older age (mean 68 vs 63
years of age, P = .29) and chemotherapy delivery
(unadjusted hazard ratio, 5.4; P = .028).
Discussion
An enlarging body of data for the use of pelvic IMRT,
particularly in gynecologic patients, lends support to this
Endometrial IMRT: Long-term results 23
High-intermediate risk
(n = 81) High risk (n = 33)
% 95% CI % 95% CI
0.0 0.0-0.0 6.2 0.0-14.6
16.8 8.0-25.6 20.8 5.9-35.7
71.6 61.2-82.0 72.0 56.5-87.5
76.2 66.2-86.2 73.6 57.7-89.5
technique to reduce the risk of acute and potentially late
toxicities. With overlying concerns regarding variation
in contouring and the risk of target miss with increased
conformality, the long-term efficacy of IMRT in the
setting of pelvic malignancies such as endometrial
cancer remains less established. In this largest published
series with extended follow-up of endometrial cancer
patients treated with adjuvant IMRT, high locoregional
control with low rates of late severe toxicities confirm
long-term efficacy of this approach.
The postoperative use of pelvic radiation therapy and
intracavitary brachytherapy for endometrial carcinoma
has been successfully demonstrated in 5 prospective
randomized trials in the past, leading to a reduction in the
risk of locoregional relapse. 4,10,12-15 Interest in more
conformal radiation therapy techniques was driven by
exploratory findings of Post Operative Radiation Ther-
apy in Endometrial Carcinoma 1 (PORTEC-1) trial,
where pelvic radiation therapy improved local disease
control but also increased GI toxicity, particularly in
those treated with anteroposterior-posteroanterior or
3-field techniques. 4 With the advent of more conformal
techniques such as IMRT, initial dosimetric studies had
identified a reduction in small bowel dose that may result
in lesser toxicities. 16,17 Two single-arm prospective trials
have since established the utility of IMRT for endometrial
cancer patients by demonstrating favorable rates of acute
toxicity compared with historical controls and comparable
3-year outcomes. 18,19
Widespread adoption of IMRT in this setting has been
limited by concerns for target miss and contouring errors,
which may lead to inferior disease-related outcomes.
Target motion can be considerable in the postoperative
setting, where bladder filling and rectal distension
variations can be considerable and unpredictable. 20,21
Such findings have resulted in recommendations for using
an internal target volume as conducted here to account for
motion. 11 Similarly, with the intricacy of pelvic anatomy,
particularly in the postoperative setting, variation in
contouring can lead to target miss or overtreatment of
surrounding normal tissues. For example, in Radiation
Therapy Oncology Group (RTOG) 0418, only 26% of
patients were initially contoured per protocol. 8 With these
concerns, although early outcomes may appear favorable,
24 S. He et al Practical Radiation Oncology: January-February 2017

Table 4 Summary of past and present studies evaluating adjuvant IMRT among endometrial cancer patients
Current Shih 2012 Beriwal 2006 Mundt 2003 RTOG Barrilot 2014
study (MSKCC) 9 (UPMC) 7 (Chicago) 29 04188,18 (France)19
n 128 46 47 66 (36 vs 30) 43 47
Type of study Retrospective Retrospective Retrospective Retrospective case control Prospective Prospective
Modality IMRT IMRT IMRT IMRT vs 3D-CRT IMRT IMRT
Median
follow-up 57 (3.6-153) 52 (17-91) 20 (6-52) 19.6 (8-33) vs 30.2 (13-70) 42 (12-52.8) 3.45
(range), mo
2 vaginal (5-y)
LRF, % 2.5 (5-y) 0 (3-y) 7 (3-y)
4 paraaortic (5-y)
DM, % 16.5 (5-y) 7 (5-y)
DFS, % 73.4 (5-y) 88 (5-y) 84 (3-y) 91 (3-y)
OS, % 77.4 (5-y) 97 (5-y) 90 (3-y) 92 (3-y)
Acute GI 21 (G2) 27.1 (G2)
1.6 (G3) 2 (G3)
toxicity, % 7 (G3) 0 (G3)
Late GI 3.2 2.0 3.3 2.8 vs 16.7 (G2, crude)

toxicity, % (G3; 5-y rate) (G3; crude) (G2+; 3-y rate) 0 vs 3.3 (G3; crude)
3D-CRT, 3-dimensional conformal radiation therapy; DFS, disease-free survival; DM, distant metastases; G2, grade 2; G3, grade 3; GI, gastrointestinal; IMRT,
intensity-modulated radiation therapy; LRF, locoregional failure; MSKCC, Memorial Sloan Kettering Cancer Center; OS, overall survival; RTOG, Radiation
Therapy Oncology Group.

long-term results could theoretically reveal increased
locoregional failure because of target miss. The finding of
a 5-year locoregional relapse rate of 2.5% in this large
cohort should reassure clinicians of the efficacy of
adjuvant IMRT when adhering to established contouring
guidelines and with careful quality assurance. These
results additionally are comparable to conventional
radiation therapy outcomes (2.0%-4.2%) and validate a
prior retrospective analysis, which confirmed a 5-year rate
of locoregional relapse (2.0%) albeit in a smaller cohort of
patients (Table 4). 9,10,14
Despite a suggested benefit of IMRT being a reduction
in toxicities, our study demonstrated equivalent to
reduced rates of late grade 3 or greater toxicities (5-year
rate, 3.2%) to historical rates (2.5%-14.2%) using
conventional radiation therapy. 10,13-15 Although limited
by cross-trial comparisons, these findings suggest a
potential benefit in reducing late toxicities, particularly
GI, through a reduction in small bowel volume receiving
high doses. 16,17 Because the rates of severe long-term
toxicities remain low in this population, detecting this
difference between conventional radiation therapy and
IMRT may be challenging. Alternatively, assessment of
patient-reported, quality-of-life outcomes and acute toxicity
rates may be more sensitive and relevant parameters. Such
endpoints are the key focus of a recently completed
randomized trial (RTOG 1203), which may ultimately
provide a clear answer to this question.
In comparison, the rate of symptomatic pelvic fractures
has long been underappreciated, with recently reported
rates ranging from 13% to 45.2% with conventional
2-dimensional/3D radiation therapy. 9,22-26 The 5-year rate
of 4.4% seen in the present study is notably lower
and similar to the 6.5% rate published by Shih et al. 9
These data allude to lower fracture rates with IMRT,
potentially as a result of applied bone marrow constraints
and increased conformity of high-dose regions, the
latter of which having been associated with the risk of
fracture in the setting of sarcoma radiation therapy. 27
Nonetheless, in a retrospective analysis such as this one,
the true rate of both symptomatic and asymptomatic pelvic
insufficiency fractures can be underreported because of
dependence of patient-reported pain to lead to further
imaging.
Although unique and encouraging, these findings
should be taken in the context of the study limitations.
Most appreciably, the present study reflects a retrospective
review of patients treated with IMRT and thus is unable to
directly compare with patients treated with conventional
methods. Second, low-grade radiation toxicities captured
from physician-reported data cannot be reliably distin-
guished in retrospective analyses and thus were not
collected. The impact of grade 1 to 2 toxicities can
significantly influence a patients quality of life, as shown
previously in long-term results from PORTEC-1. 28 The
recently completed RTOG 1203 is better poised to answer
this question directly because patient-reported toxicities
will be standardized with validated query tools and
patient quality-of-life surveys will be collected at various
time points.
Practical Radiation Oncology: January-February 2017
Conclusions
The use of IMRT for gynecologic malignancies is
increasing, although limited long-term data exist to
support comparable efficacy and a reduction in toxicities.
In this large retrospective series with extended follow-up,
adjuvant IMRT with or without vaginal brachytherapy for
patients with endometrial cancer retained high rates of
locoregional control while maintaining low rates of severe
late toxicities, suggesting efficacy of this technique with
careful treatment planning.
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