YGYNO-976198; No.

of pages: 7; 4C:
Gynecologic Oncology xxx (2016) xxxxxx

Contents lists available at ScienceDirect

Gynecologic Oncology
journal homepage: www.elsevier.com/locate/ygyno

Treatment related outcomes in high-risk endometrial carcinoma:

Canadian high risk endometrial cancer consortium (CHREC)
Marcus Q. Bernardini a,, Lilian T. Gien a, Susie Lau b, Alon D. Altman c, Blake Gilks d, Sarah E. Ferguson a,
Martin Kbel e, Vanessa Samoulian g, Mina Wesa k, Anna Cameron f, Gregg Nelson f, Guangming Han h,
Blaise Clarke h, T.C. Ho a, Tony Panzarella i,j, Eshetu G. Atenafu i, Jessica N. McAlpine k
a

Division of Gynecologic Oncology, University of Toronto, Canada

Division of Gynecologic Oncology, McGill University, Canada
c
Division of Gynecologic Oncology, University of Manitoba, Canada
d
Department of Pathology and Laboratory Medicine, University of British Columbia, Canada
e
Department of Pathology and Laboratory Medicine, University of Calgary, Canada
f
Division of Gynecologic Oncology, University of Calgary, Canada
g
Division of Gynecologic Oncology, CHUM, Universit de Montral, Canada
h
Department of Pathology and Laboratory Medicine, University of Toronto, Canada
i
Biostatistics Department, Princess Margaret Cancer Centre, Canada
j
Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Canada
k
Division of Gynecologic Oncology, University of British Columbia, Canada
b

H I G H L I G H T S

Surgical staging and adjuvant treatment is varied in high-risk endometrial cancer.

Benets of adjuvant treatment in histotypes of endometrial cancer are varied.
Adjuvant radiation results in improved OS in clear cell and endometrioid cancers.
Adjuvant chemotherapy results in improved OS in serous cancers and carcinosarcoma.
Recurrence rates in women with comprehensively staged, stage 1 serous cancers is high.

a r t i c l e

i n f o

Article history:
Received 25 November 2015
Received in revised form 2 February 2016
Accepted 3 February 2016
Available online xxxx
Keywords:
Endometrial cancer
Serous cancer
Adjuvant treatment
High risk histology

a b s t r a c t
Objective. The lack of randomized clinical data pertaining to optimal surgery and adjuvant treatment in
women with high-risk histotypes of endometrial cancer has resulted in selective management based on institutional policies. The objective of this study was to assess differences in treatment strategies and their outcomes
among various institutions.
Method. High-risk endometrial cancer cases (20002012) with corresponding clinicopathologic data were
collected from 7 academic cancer centers. Histotypes included grade 3 endometrioid (EC3), serous (ESC), clear
cell (CCC) and carcinosarcoma (CS). Associations with overall survival were performed using Cox proportional
hazard regression.
Results. 1260 patients treated between 2000 and 2012 were included in the study: 398 EC3, 449 ESC, 91 CCC,
236 CS and 83 other. The use of adjuvant chemotherapy, adjuvant radiation, and extent of surgical staging were
statistically different among the 7 centers (P b 0.001). Histotype was independently associated with overall survival (OS) in patients with stage 1 and 2 disease who underwent surgical staging (P = 0.0324). Adjuvant radiation was associated with improved OS for EC3 and CCC and adjuvant chemotherapy was associated with
improved OS for ESC and CS. There was a high rate of recurrence (17.8% and 21.4%) in completely staged, stage
1A patients with ESC and CS respectively.
Conclusion. There exists a wide variation in practice and outcomes for high-risk histotypes of endometrial
cancer. The relative impact of adjuvant therapy appears to be histotype dependent and prospective studies examining adjuvant treatment in high-risk histotypes should use caution combining them together.
Crown Copyright 2016 Published by Elsevier Inc. All rights reserved.

Corresponding author at: University of Toronto, Princess Margaret Hospital, M700 610 University Ave, Toronto, Ontario M5G 2M9, Canada.
E-mail address: Marcus.Bernardini@uhn.ca (M.Q. Bernardini).

http://dx.doi.org/10.1016/j.ygyno.2016.02.002
0090-8258/Crown Copyright 2016 Published by Elsevier Inc. All rights reserved.

Please cite this article as: M.Q. Bernardini, et al., Treatment related outcomes in high-risk endometrial carcinoma: Canadian high risk endometrial
cancer consortium (CHREC), Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.02.002

M.Q. Bernardini et al. / Gynecologic Oncology xxx (2016) xxxxxx

1. Introduction
There are roughly 50,000 newly diagnosed cases per year of endometrial carcinoma in North America. Although this is generally thought
of as an indolent cancer with low mortality, 1520% (10,000 women) of
these women will die of their disease [1]. Disease specic survival rates
for low grade (grade 1) endometrioid cancers of the endometrium are
reported at over 90% [2, 3] whereas 5 year survival rates for highgrade endometrioid (EC3) and high-risk histologic types serous (ESC),
clear cell (CCC), carcinosarcoma (CS) have been reported between 45
and 70% [49].
Standard protocols for the management of endometrial cancer have
been developed and guided by the results from large randomized control trials [1012]. Although high-risk histotypes are included in these
studies, their numbers are too small to make meaningful conclusions
from the data. As such, it remains challenging to follow algorithms
with the small number of high-risk histotypes represented in randomized data.
It is estimated that high-risk endometrial cancer histotypes comprise b35% of all cancers of the uterine corpus. These include endometrial serous cancer (ESC), clear cell cancer (CCC), endometrioid
carcinoma grade 3 (EC3), and de-/undifferentiated carcinomas. Carcinosarcoma (CS), originally classied with other sarcomas of the uterus, are
now separately classied as mixed epithelial-mesenchymal tumors but
considered to be a metaplastic carcinoma by most [13].
The uncommon nature of these cancers is the primary reason why
robust data and optimal management is lacking. Collaborative multiinstitutional efforts will be required to obtain the critical mass of cases
to be able to make meaningful analyses. GOG 249, EORTC 55102 and
STATEC are 3 randomized control trials examining adjuvant treatment
in high-risk endometrial cancer that are either actively accruing or
have recently completed accrual [1416]. In all three studies the various
high-risk histologic types are all part of the inclusion criteria.
This study was designed to examine the management and outcome
of a large collection of high-risk histologic types of endometrial cancer
across multiple cancer centers within the Society of Gynecologic Oncology of Canada (GOC).
Through newly formed national communities of practice, there was
concern of inconsistency of management of high-risk EC across centers.
We hypothesized that in addition to a wide variation in practice there
would be a range in reported clinical outcomes.
2. Materials and methods
2.1. Study patients
A retrospective analysis of endometrial cancer cases between 2000
and 2012 was performed at 7 cancer centers across Canada (British Columbia Cancer Agency, Tom Baker Cancer Centre, Cancercare Manitoba,
Oddette Cancer Center, Princess Margaret Cancer Centre, Jewish General
Hospital, Centre Hospitalier de l'Universit de Montral).
REB approval was obtained at each participating center under a
larger collaborative project known as CHREC (Canadian High-Risk Endometrial Cancer) consortium. The analysis included all cases of the following histotypes for which accurate surgico-pathologic and follow-up
data was available: Endometrioid carcinoma grade 3 (EC3), endometrial
serous carcinoma (ESC), clear cell carcinoma (CCC) and carcinosarcoma
(CS). Data on mixed tumors and un/dedifferentiated cancers was collected but were not included in the analysis and were classied as
other. All cases were reviewed by specialty trained gynecologic pathologists. Use of immunohistochemistry to dene the histotypes was
center dependent.
Data was veried by 2 physicians at each participating center and
the data was collected in a central database. Complete surgical staging
was dened as hysterectomy, bilateral salpingo-oophorectomy, pelvic
lymphadenectomy, +/ para-aortic lymphadenectomy, +/

omentectomy. Data on adjuvant chemotherapy and radiation was collected. Radiation therapy included any combination of whole pelvic external beam treatment with standard 45Gy in 25 fractions, vaginal
brachytherapy, or a combination of both. Chemotherapy was predominantly carboplatin and paclitaxel but included regimens involving
doxorubicin, cyclophosphamide and ifosfamide.
For data presentation the names of the individual centers were
anonymized.
2.2. Statistical analysis
Summary statistics were used to describe patient and treatmentrelated characteristics. Categorical variables such as center, stage, histology, extent of surgical staging, para-aortic lymphadenectomy, and adjuvant treatment were expressed as count and proportions, whereas
continuous variables such as Age and follow-up were expressed as
mean and standard deviation and/or median and range as appropriate.
Chi-square/Fisher's exact test, as appropriate, was used to assess any association of the categorical variables of interest among centers. Analysis
of variance (ANOVA) was also used to compare mean age of patients
among centers. Overall survival (OS) rates were calculated using the
Kaplan-Meier product-limit method. The log-rank test was used to assess any impact of covariates of interest to the outcome OS. Covariates
with a signicance level of 0.20 at univariate level were examined in
a multivariable proportional hazards model. All P-values were 2-sided
and for the statistical analyses, P b 0.05 will be considered to indicate
a statistically signicant result. Statistical analysis was performed
using version 9.4 of the SAS system for Windows, Copyright 2002
2012 SAS Institute, Inc., Cary, NC.
3. Results
Data was collected on a total of 1260 cases diagnosed between 2000
and 2012. At the time of the analysis 672 (53.3%) were alive, 476 were
dead (37.8%) and 112 (8.9%) were lost to follow-up. Median time to follow up was 34.2 months with range 0158.1 months. Table 1 shows the
difference among centers with regard to stage, histology, presence of
lymphovascular space invasion (LVI), extent of surgical staging, paraaortic lymphadenectomy, and adjuvant treatment. A multivariate Cox
regression analysis was performed on variables associated with OS
(Table 2). Final stage (FIGO 2009), histotype, age at diagnosis, presence
of LVI, use of surgical staging, use of adjuvant radiation and adjuvant
chemotherapy were all statistical predictors of overall survival. There
was no statistically signicant difference in OS between treatment centers, controlling the statistical predictors listed above, despite variations
in practice (P = 0.15).
Fig. 1a shows the OS in the series based on histologic type. Women
with EC3 cancers had a statistically higher survival than those diagnosed
with ESC, CCC and CS cancers. The improved survival for women with
EC3 was also seen in the subgroup of women with stage 1 and 2 cancers
that underwent surgical staging. (Fig. 1b).
As histotype was an independent predictor of OS, the analyses of factors associated with improvements in OS were repeated examining individual histotypes. There were sufcient cases of ESC and EC3 to
examine only early stage disease whereas for CCC and CS all stages
were included in the analysis due to insufcient numbers.
Using multivariate Cox regression analysis of patients with stage 1
and 2 disease in women with EC3, predictors of OS were absence of
LVI (P = 0.0003), use of adjuvant radiation (P = 0.0079), use of adjuvant chemotherapy (P = 0.012) and treatment center (P = 0.0295)
(Table 3a). Use of adjuvant chemotherapy however was associated
with a decrease in overall survival. When the same analysis was performed including only surgically staged, stage 1 and 2 women with
EC3, the only factor associated with improved overall survival was the
absence of LVI (P = 0.0029) (Table 3b).

Please cite this article as: M.Q. Bernardini, et al., Treatment related outcomes in high-risk endometrial carcinoma: Canadian high risk endometrial
cancer consortium (CHREC), Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.02.002

M.Q. Bernardini et al. / Gynecologic Oncology xxx (2016) xxxxxx

Table 1
This table shows the differences in practice and representative histotypes at each of the participating centers. The centers are numbered 17. All parameters were statistically varied except
the presence of LVI.

Mean age (std)

Stage (%)

Histology (%)

IA
1B
II
IIIA or IIIB
IIIC1 or C2
IV
EC3
ESC
CCC
CS

Surgical staging (%)

Pelvic lymphadenectomy (%)
PA lymphadenectomy (%)
Adjuvant radiation (%)
Adjuvant chemotherapy (%)
Adjuvant radiation + chemotherapy (%)
LVI positive (%)

1 (n = 142)

2 (n = 241)

3 (n = 195)

4 (n = 415)

5 (n = 88)

6 (n = 74)

7 (n = 105)

66.5 (11.04)
43 (30.28)
21 (14.79)
13 (9.15)
17 (11.97)
30 (21.13)
18 (12.68)
62 (50.41)
47 (38.21)
14 (11.38)
NA
134 (94.37)
125 (88.03)
71 (50)
36 (25.90)
85 (60.71)
25 (18.12)
75 (53.57)

67.95 (10.2)
72 (31.44)
33 (14.41)
31 (13.54)
33 (14.41)
28 (12.23)
32 (13.97)
74 (30.71)
86 (35.68)
NA
81 (33.61)
200 (82.99)
163 (67.63)
76 (31.54)
92 (41.07)
62 (27.07)
23 (10.36)
128 (53.33)

68.28 (10.9)
79 (41.36)
19 (9.95)
12 (6.28)
22 (11.52)
31 (16.23)
28 (14.66)
64 (33.16)
65 (33.68)
14 (7.25)
50 (25.91)
145 (79.23)
117 (61.90)
12 (6.25)
92 (51.40)
101 (66.01)
72 (47.06)
105 (58.99)

66.83 (11.1)
146 (35.18)
58 (13.98)
54 (13.01)
54 (13.01)
48 (11.57)
55 (13.25)
119 (29.97)
163 (41.06)
38 (9.57)
77 (19.40)
296 (71.33)
203 (49.03)
80 (19.32)
210 (55.41)
203 (53.14)
113 (29.89)
194 (47.55)

70.59 (10.6)
30 (34.09)
18 (20.45)
8 (9.09)
6 (6.82)
20 (22.73)
6 (6.82)
30 (37.50)
32 (40)
9 (11.25)
9 (11.25)
88 (100)
87 (98.86)
53 (60.23)
63 (72.41)
68 (78.16)
52 (59.77)
45 (54.22)

68.73 (11.5)
21 (29.58)
15 (21.13)
8 (11.27)
13 (18.31)
11 (15.49)
3 (4.23)
23 (38.33)
28 (46.67)
9 (15)
NA
49 (69.01)
36 (50.70)
1 (1.41)
44 (59.46)
41 (55.41)
28 (37.84)
33 (46.48)

65.11 (9.32)
32 (30.48)
25 (23.81)
5 (4.76)
11 (10.48)
16 (15.24)
16 (15.24)
26 (32.50)
28 (35)
7 (8.75)
19 (23.75)
101 (96.19)
92 (87.62)
15 (14.29)
74 (71.15)
80 (76.92)
58 (55.77)
54 (51.43)

Multivariable Cox regression analysis for stage 1 and 2 disease in

women with ESC revealed that increasing patient age and presence of
LVI were predictors of decreased OS. The use of adjuvant radiation
was not signicantly associated with an improvement in OS. The associated improvement in OS with the use of adjuvant chemotherapy did not
reach statistical signicance (P = 0.062) (Table 4a). When the same
analysis was performed including only surgically staged, stage 1 and 2
women with ESC, the absence of LVI and use of adjuvant chemotherapy
were associated with improvements in overall survival (P = 0.0029 and
P = 0.0366 respectively, Table 4b).
For women with CCC, the multivariable Cox regression analysis revealed that decreasing age (P = 0.0110), lower stage (P = 0.0006)
and use of adjuvant radiation (P = 0.0008) were associated with an improvement in OS while the use of adjuvant chemotherapy, presence of
LVI and complete surgical staging were not signicantly associated
with differences in OS (Supplementary Table 1). For women with CS,
the Cox multivariable regression analysis revealed that lesser stage
(P b 0.0001) and use of adjuvant chemotherapy (P = 0.0148) were

P-value
0.0074
0.0047

b0.0001

b0.0001
b0.0001
b0.0001
b0.0001
b0.0001
b0.0001
0.2350

predictors of improvement in OS as was treatment center (0.0256)

(Supplementary Table 2).
Table 5 reports the potential impact of surgical staging. Stage breakdown for the entire cohort (n = 1260) is presented in addition to those
within the cohort that underwent a degree of surgical staging (n =
1013). Incomplete surgical staging may have led to an underestimation
of advanced disease. In women who did not undergo surgical staging
40.1% were stages 3 or 4 whereas in those who underwent surgical staging 49.6% of patients were stage 3 or 4.
As part of the analyses, the impact of adjuvant treatment on the various stages within histotypes was performed. One group of particular
interest was the stage 1 A group that had undergone comprehensive
surgical staging including para-aortic lymphadenectomy and
omentectomy (n = 88: 56 ESC, 21 EC3, 11 CS). The recurrence rates
were as follows: 17.8% for women with ESC, 0% for women with EC3
and 21.4% for women with CS. In women with stage 1 A ESC the use
of adjuvant chemotherapy resulted in a statistical reduction in recurrence of 8.7% versus 26.3%, P = 0.031.

4. Discussion
Table 2
A multivariate Cox regression analysis of variables associated with overall survival (OS) in
the entire dataset (n = 1260).
Parameter

Final histology (reference

= HGE)

Centre (reference = 4)

Final stage (reference = II)

Complete staging
Adjuvant chemotherapy
Adjuvant radiation
LVI positive
Age at diagnosis

Level

P-value

Hazard
ratio

Carcinosarcoma b0.0001 2.609

Clear cell
2.053
Other
1.638
Serous
1.629
1
0.1519 1.451
2
1.356
3
1.274
5
1.599
6
1.095
7
1.022
IA
b0.0001 0.343
IB
0.729
IIIA or IIIB
2.123
IIIC1 or IIIC2
2.304
IV
4.105
Yes
b0.0001 0.513
Yes
0.0164 0.709
Yes
0.0012 0.683
Yes
0.0002 1.556
b0.0001 1.025

95% CI
Lower Upper
1.898
1.349
1.014
1.207
1.027
1.005
0.925
0.946
0.722
0.674
0.226
0.483
1.364
1.492
2.640
0.367
0.536
0.543
1.229
1.014

3.587
3.125
2.646
2.197
2.050
1.829
1.754
2.701
1.660
1.550
0.519
1.101
3.306
3.559
6.384
0.717
0.939
0.860
1.971
1.035

High-risk histotypes of endometrial cancer are less common, and

until recently have not been studied independently from low-risk tumors in clinical trials. Consequently, there is less data to guide management, limited to case series and institutional experiences. The current
study, under the umbrella of the GOC (Society of Gynecologic Oncology
of Canada) represents a comprehensive assessment of the management
of high-risk endometrial cancers from 7 independent academic cancer
centers across Canada (n = 1260). With close to a 40% mortality rate
for the entire study cohort, the dataset conrms the high-risk nature
of these cases. Patient age, surgical stage and histotype were associated
with differences in overall survival in this cohort. Multivariate modeling
revealed that when all histotypes are combined, complete surgical staging, adjuvant chemotherapy and adjuvant radiation are associated with
improved overall survival. The results of the current study highlight 3
areas that warrant further discussion: 1) Complete surgical staging in
this cohort was more likely to identify advanced disease, may impact
outcomes and should be considered for all women with high-risk
histotypes, 2) The relative impact of adjuvant therapy appears to be
histotype dependent, 3) There exists a wide range of clinical practice
in the management of these cancers.
In women that underwent complete surgical staging 49.6% were
stage 3 or 4 compared to 40.1% in women who did not undergo surgical

Please cite this article as: M.Q. Bernardini, et al., Treatment related outcomes in high-risk endometrial carcinoma: Canadian high risk endometrial
cancer consortium (CHREC), Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.02.002

M.Q. Bernardini et al. / Gynecologic Oncology xxx (2016) xxxxxx

Fig. 1. A: Overall survival (OS) by histotype (complete data), (n = 1260) b: overall survival (OS) for surgically staged, stages I and II, (n = 464).

staging, suggesting incomplete surgical staging likely underestimates

the presence of advanced disease in these high-risk types. In addition,
when the entire cohort was examined, the use of surgical staging was

associated with an improvement in OS. Furthermore, the benet of adjuvant treatment among histotypes appeared to be different based on
whether women underwent surgical staging or not. For example, in a

Table 3a
A multivariate Cox regression model of variables associated with OS in women with EC3: nal stage I/II (n = 277).
Parameter

Level

P-value

Hazard ratio

Centre (reference = 4, n = 89)

1 (n = 39)
2 (n = 50)
3 (n = 46)
5 (n = 21)
6 (n = 17)
7 (n = 15)
Yes (n = 202)
Yes (n = 39)
Yes (n = 148)
Yes (n = 109)

0.0295

1.404
2.267
0.309
0.448
3.903
1.464
0.590
3.590
0.365
4.082
1.027

Complete staging (ref = no, n = 66)

Adjuvant chemotherapy (ref = no, n = 222)
Adjuvant radiation (ref = no, n = 116)
LVI positive (ref = no, n = 165)
Age at Dx

0.1653
0.0120
0.0079
0.0003
0.0753

95% CI
Lower

Upper

0.500
0.924
0.058
0.047
1.376
0.301
0.280
1.324
0.174
1.913
0.997

3.944
5.561
1.660
4.237
11.069
7.115
1.243
9.735
0.768
8.711
1.058

Please cite this article as: M.Q. Bernardini, et al., Treatment related outcomes in high-risk endometrial carcinoma: Canadian high risk endometrial
cancer consortium (CHREC), Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.02.002

M.Q. Bernardini et al. / Gynecologic Oncology xxx (2016) xxxxxx

Table 3b
A multivariate Cox regression model of variables associated with OS in women with EC3: nal stage I/II excluding women who did not undergo surgical staging (n = 202).
Parameter

Centre (reference = 4, n = 54)

Adjuvant chemotherapy (ref = no, n = 163)

Adjuvant radiation (ref = no, n = 90)
LVI positive (ref = no, n = 120)
Age at Dx

Level

1 (n = 37)
2 (n = 36)
3 (n = 29)
5 (n = 21)
6 (n = 12)
7 (n = 13)
Yes (n = 35)
Yes (n = 111)
Yes (n = 80)

separate analysis of women with stage 1B disease (data not shown),

women with EC3 or ESC who underwent surgical staging had no survival benet to the use of adjuvant radiation therapy, however in unstaged patients adjuvant radiation did confer an overall survival advantage for both EC3 and ESC patients (P = 0.02 and 0.04 respectively).
There has long been debate about the diagnostic and therapeutic
role of complete surgical staging in endometrial cancer. Part of this controversy stems from the grouping of all endometrial cancers together
when perhaps the rationale for complete staging for high-risk tumors
needs to be considered distinctly from low-risk disease. Low-risk cancers have a low likelihood of metastases and an excellent prognosis [2,
17]. Strategies like the assessment of sentinel lymph nodes have become popular and may provide further insight [18, 19]. In contrast
high-risk cancers are felt to require more intervention including extensive surgical staging and adjuvant therapy, even in cases with early
stage disease [9, 2023]. Some have argued that given the high likelihood that adjuvant treatment will be prescribed there is no justication
for complete staging and its associated morbidity. In this study we have
not collected data on surgical morbidity of lymphadenectomy (i.e.
lymphedema) and thus cannot comment on validity of this argument;
however the data conrms the utility of surgical staging and as we try
and tailor treatment in these high-risk histotypes accurate staging
data will likely be important.
Only 24.3% of women in the entire cohort underwent a para-aortic
lymphadenectomy as part of their management. This could be considered a criticism of the current data set but it represents the reality of
what procedures were performed for these patients across Canada and
may not in fact deviate from practice in other geographic areas. Isolated
positive para-aortic lymph nodes in endometrial cancer have been reported in the literature to be between 1.2 and 2% [24, 25]. Most of this
literature refers to studies that contained predominantly low grade cancers and it is likely to be higher in high-risk histotypes. Mattes et al. report a positive PA rate of up to 16.9% for early clinical stage serous and

P-value

0.1091

0.0693
0.0598
0.0029
0.2981

Hazard ratio

1.368
2.298
0.221
0.574
4.815
1.674
2.945
0.420
4.195
1.020

95% CI
Lower

Upper

0.408
0.670
0.022
0.055
1.252
0.307
0.918
0.170
1.634
0.983

4.590
7.877
2.178
6.018
18.515
9.127
9.443
1.037
10.773
1.058

clear cell cancers of the endometrium but they do not mention the isolated PA rate in the manuscript. The positive isolated PA rate in the current study was 5.6% (13/230).
The association of adjuvant radiation or chemotherapy and OS was
examined in this study and varied by histotype. The use of adjuvant radiation alone or in combination with chemotherapy was associated in
an improvement in overall survival in women with early stage EC3
and CCC but not in women with early stage ESC or CS. The use of adjuvant chemotherapy alone or in combination with radiation therapy
was associated with an improvement in overall survival in women
with ESC and CS. There was no survival advantage shown for the use
of adjuvant chemotherapy in CCC. The results of our current series
would indicate that chemotherapy is more likely to play a benecial
role in women with ESC and CS while radiation is more likely to play a
role in women with EC3 and CCC especially if complete surgical staging
is not performed.
Several studies have shown the potential benet of using chemotherapy in the serous cancer population including the benecial use in
women with stage 1 and 2 ESC [26, 27]. Data is more limited with carcinosarcoma. Vandenput et al. identied a 7 month difference in recurrence free survival with use of adjuvant chemotherapy but the study
included only 18 patients with carcinosarcoma [23]. Two further studies, one from the Mayo clinic and another from North Carolina have
identied an improvement in recurrence free survival and in the Mayo
series, disease specic survival, with the use of adjuvant, platinum
based chemotherapy in women with carcinosarcoma [28, 29].
Data on the most effective adjuvant treatment strategy for clear cell
cancers of the endometrium is very limited. Studies reporting these
cancers embed the cases with other histotypes and no meaningful
data can be obtained [19, 30]. Data from clear cell cancers of the
ovary are also limited however appear to favor the use of adjuvant radiation with questionable value to the use of adjuvant chemotherapy
[31, 32].

Table 4a
A multivariate Cox regression model of variables associated with OS in women with ESC: nal stage I/II (n = 238).
Parameter

Level

Centre (reference = 4, n = 89)

1 (n = 21)
2 (n = 47)
3 (n = 29)
5 (n = 20)
6 (n = 14)
7 (n = 18)
Yes (n = 160)
Yes (n = 125)
Yes (n = 120)
Yes (n = 78)

Complete staging (ref = no, n = 78)

Adjuvant chemotherapy (ref = no, n = 84)
Adjuvant radiation (ref = no, n = 104)
LVI positive (ref = no, n = 158)
Age at Dx

P-value

0.5791

0.2639
0.0623
0.8883
0.0002
b0.0001

Hazard ratio

1.306
0.537
1.091
0.384
1.371
1.592
0.681
0.511
1.051
3.343
1.090

95% CI
Lower

Upper

0.452
0.200
0.233
0.048
0.552
0.568
0.347
0.252
0.525
1.755
1.049

3.776
1.437
5.111
3.063
3.402
4.467
1.336
1.015
2.106
6.367
1.133

Please cite this article as: M.Q. Bernardini, et al., Treatment related outcomes in high-risk endometrial carcinoma: Canadian high risk endometrial
cancer consortium (CHREC), Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.02.002

M.Q. Bernardini et al. / Gynecologic Oncology xxx (2016) xxxxxx

Table 4b
A multivariate Cox regression model of variables associated with OS in women with ESC: nal stage I/II excluding women who did not undergo surgical staging (n = 160).
Parameter

Level

Centre (reference = 4, n = 43)

Adjuvant chemotherapy (ref = no, n = 54)

Adjuvant radiation (ref = no, n = 65)
LVI positive (ref = no, n = 105)
Age at Dx

P-value

1 (n = 19)
2 (n = 39
3 (n = 19)
5 (n = 20)
6 (n = 4)
7 (n = 16)
Yes (n = 87)
Yes (n = 84)
Yes (n = 55)

0.2386

0.0366
0.8033
0.0029
0.0064

The current study revealed statistically signicant variations in the

use of adjuvant chemotherapy, adjuvant radiation, and extent of surgical staging across cancer centers in Canada. These variations were identied in the series as a whole as well as within the various histotypes,
thus, although there is likely discrepancy in histologic classication
among the centers [33] there also exist differences in treatment strategies that appear to be center dependent. Outcomes also varied by treatment center, with differences in OS for women with EC3 and CS. There
was no difference in OS for women with CCC or ESC despite variations
in practice. We were unable to nd specic variations in practice to account for the differences in OS from one center to another.
Recently completed GOG 249 examined the difference between pelvic radiotherapy and chemotherapy with vaginal brachytherapy in
women with stage 1 and 2 high risk disease. The STATEC trial will examine the value of surgical staging in clinical stage 1 disease for high-risk
types of endometrial cancer. In both studies the inclusion criteria are
broad and include the various high-risk histologic types EC3, ESC, and
CCC. The EORTC 55102 study examining adjuvant chemotherapy versus
observation in surgically staged stage 1 and 2 disease will stratify
endometrioid from non-endometrioid cases but it too has included all
high-risk types in the inclusion criteria. These broad inclusion criteria
use the premise that all high-risk histotypes of endometrial cancer are
similar in nature and part of inclusion criteria for these studies. Data
from the current study questions this premise and combining the various histotypes together is likely to muddy the water in dening the
optimal treatment strategy for a given high risk histotype of endometrial cancer.
This study has veried that wide variations in practice exist in the
management of high-risk histologic types of endometrial cancer. It has
also conrmed the aggressive nature of these cancers and the importance of adjuvant treatment. This variation in clinical practice and outcomes is unlikely to be unique to these seven participating centers
across Canada. We know, through our international collaborations,
that many of the same challenges are faced in other cancer centers.
Through more reliable categorization of tumors, and future trials ideally

Table 5
A comparison of stage distribution between the entire dataset and women who
underwent surgical staging.
All patients (n =
1260)

IA
IB
II
IIIA or IIIB
IIIC1 or II
IV
Missing

Patients with surgical

staging (n = 1013)

423
189
131
156
184
158
19

34.09
15.23
10.56
12.57
14.83
12.73

288
132
86
156
184
158
9

28.69
13.15
8.57
15.54
18.33
15.74

Hazard ratio

1.100
0.415
1.206
0.466
3.213
2.394
0.229
1.147
5.459
1.080

95% CI
Lower

Upper

0.300
0.105
0.230
0.054
0.634
0.648
0.058
0.389
1.789
1.022

4.030
1.648
6.339
4.034
16.290
8.845
0.913
3.386
16.663
1.141

stratied according to histotype or molecular subtype of endometrial

carcinomas we hope to advance our understanding of this disease.
This may in turn enable us to develop consensus guidelines that can
be agreed and acted upon, ultimately improving improve outcomes
for women with endometrial carcinoma.
Conict of interest
The authors declare that there are no conicts of interest.
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.ygyno.2016.02.002.
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Please cite this article as: M.Q. Bernardini, et al., Treatment related outcomes in high-risk endometrial carcinoma: Canadian high risk endometrial
cancer consortium (CHREC), Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.02.002