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cancers
Review
Recurrent Endometrial Cancer: Local and Systemic
Treatment Options
Heidi Rütten 1, *, Cornelia Verhoef 1, Willem Jan van Weelden 2, Anke Smits 2, Joëlle Dhanis 3,
Nelleke Ottevanger 4and Johanna M. A. Pijnenborg 2
Citation: Rütten, H.; Verhoef, C.; van
Weelden, W.J.; Smits, A.; Dhanis, J.;
Ottevanger, N.; Pijnenborg, J.M.A.
Recurrent Endometrial Cancer: Local
and Systemic Treatment Options.
Cancers 2021,13, 6275. https://
doi.org/10.3390/cancers13246275
Academic Editors: Miguel Abal,
Laura Muinelo-Romay and
Dionyssios Katsaròs
Received: 30 September 2021
Accepted: 8 December 2021
Published: 14 December 2021
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Attribution (CC BY) license (https://
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4.0/).
1Department of Radiation Oncology, Radboudumc, 6525 GA Nijmegen, The Netherlands;
Lia.Verhoef@radboudumc.nl
2Department of Obstetrics & Gynaecology, Radboudumc, 6525 GA Nijmegen, The Netherlands;
willemjan.vanweelden@radboudumc.nl (W.J.v.W.); Anke.Smits@radboudumc.nl (A.S.);
Hanny.MA.Pijnenborg@radboudumc.nl (J.M.A.P.)
3Faculty of Medical Sciences, Radboud University, Houtlaan 4, 6525 XZ Nijmegen, The Netherlands;
j.dhanis@ru.student.nl
4Department of Medical Oncology, Radboudumc, 6525 GA Nijmegen, The Netherlands;
Nelleke.Ottevanger@radboudumc.nl
*Correspondence: heidi.rutten@radboudumc.nl
Simple Summary:
In this review, we discuss the different treatment strategies in recurrent endome-
trial cancer. The incidence of endometrial cancer is rising. The available treatment options increase
with the development of novel radiotherapy techniques and new systemic therapies. Dependent
on the site of recurrence and previous therapy, the treatment of recurrent endometrial cancer can
be curative or palliative. Newly emerging medical treatments, such as immunotherapy, might be
of benefit in selected patients. Moreover, combinations of different treatments can lead to a better
outcome. Recent insights on oligometastatic disease lead us to expect that ablative or radical local
treatment for distant metastasis will be of benefit in selected patients. Due to the complexity of the
cases, it is recommended to discuss individual cases in a multidisciplinary tumor board. Shared
decision-making principles are recommended to maximize treatment personalization.
Abstract:
The treatment of recurrent endometrial cancer is a challenge. Because of earlier treatments
and the site of locoregional recurrence, in the vaginal vault or pelvis, morbidity can be high. A total
of about 4 to 20% of the patients with endometrial cancer develop a locoregional recurrence, mostly
among patients with locally advanced disease. The treatment options are dependent on previous
treatments and the site of recurrence. Local and locoregional recurrences can be treated curatively
with surgery or (chemo)radiotherapy with acceptable toxicity and control rates. Distant recurrences
can be treated with palliative systemic therapy, i.e., first-line chemotherapy or hormonal therapy.
Based on the tumor characteristics and molecular profile, there can be a role for immunotherapy. The
evidence on targeted therapy is limited, with no approved treatment in the current guidelines. In
selected cases, there might be an indication for local treatment in oligometastatic disease. Because
of the novel techniques in radiotherapy, disease control can often be achieved at limited toxicity.
Further studies are warranted to analyze the survival outcome and toxicity of newer treatment
strategies. Patient selection is very important in deciding which treatment is of most benefit, and
better prediction models based on the patient- and tumor characteristics are necessary.
Keywords:
endometrial cancer; recurrence; treatment; surgery; radiotherapy; hormonal therapy;
systemic treatment; oligometastases
1. Introduction
Endometrial cancer (EC) is the most common gynecological cancer in the Western
world. Its incidence is rising as risk factors for endometrial cancer are more and more
Cancers 2021,13, 6275. https://doi.org/10.3390/cancers13246275 https://www.mdpi.com/journal/cancers
Cancers 2021,13, 6275 2 of 14
prevalent [
1
,
2
]. The risk factors for developing endometrial cancer include prolonged
unopposed estrogen exposure, advanced age, and obesity [
3
]. Most patients are diagnosed
in their sixth or seventh decade, and, since postmenopausal blood loss is one of the first
symptoms, most patients present with early-stage disease [4].
Endometrial cancer can be classified in different ways. Historically, two subtypes
were recognized [
5
]. Type one tumors are the most common (70% of all tumors) and are
predominantly well to moderately differentiated endometroid tumors with often high
expression of the estrogen–progesterone receptor (ER/PR), carrying a good prognosis
with surgery alone. Type two tumors are poorly differentiated endometroid carcinomas
or more aggressive subtypes, such as clear cell or serous carcinomas. Type two tumors
tend to be more advanced at diagnosis and have a poorer prognosis [
6
]. Nowadays, the
classification according to the molecular profile is upcoming with tumor types such as
POLE, MSI, and P53, where the first two predominantly have a favorable prognosis and
the latter is considered to be an aggressive subtype [7,8].
The relationship between the different histological subtypes and molecular profiles is
shown in Figure 1. As illustrated, there is quite some overlap in the historically type two
tumors and the more aggressive molecular subtypes, whereas the type one tumors tend to
have a more favorable molecular profile.
Figure 1.
Relationship between the traditional histologic classification and the molecular classification.
Each traditional histologic diagnosis is connected to the representing molecular subgroup. The
thicker the connecting line, the stronger the relationship. The figure demonstrates that each molecular
subgroup can be detected in each histologic subgroup. Yet, the NSMP is mainly reflected by grade 1
and 2 EEC (left in the figure), whereas the p53abn cancers are mainly reflected by patients with
SC (right in the figure). EEC: endometrioid endometrial cancer; CCC: clear cell carcinoma; SC:
serous cancer; NSMP: nonspecific molecular profile; MMRd: mismatch repair deficient; POLE: POLE
ultramutated; p53abn: copy number high/TP53 mutated. (Modified from [
9
] UpToDate Endometrial
cancer: Pathology and classification by Huvila J, MD, PhD, McAlpine JN, MD, FACOG, FRCPSC,
available from: URL: https://www.uptodate.com/contents/endometrial-cancer-pathology-and-
classification?source=history_widget) accessed 17 September 2021.
The primary treatment consists of the surgical removal of the uterus and adnexa with
or without lymph node dissection, or the sentinel node procedure. The rationale for nodal
staging is based on the risk factors, i.e., tumor grade, deep myometrial invasion, or, with
increasing evidence, molecular profile, but remains a subject of discussion [10,11].
The adjuvant treatment is based on the risk of locoregional recurrence or metastasis
and can be locoregional radiotherapy, chemotherapy, or a combination of both. Patients
Cancers 2021,13, 6275 3 of 14
with low-risk tumors can be treated with surgery alone, whereas patients with high-risk
tumors are eligible for adjuvant chemotherapy and/or radiotherapy. There is no real
international consensus about treating intermediate-risk tumors. The treatment strategies
can vary between surgery only, adjuvant brachytherapy or pelvic radiotherapy, and/or
chemotherapy [10,11].
Despite optimal surgical and adjuvant treatment, 7–15% of early stage (I-II) patients
present with recurrent disease [
12
–
14
]. This can be locoregional recurrence, distant metas-
tasis, or both. The risk of locoregional recurrence is low [
12
,
15
,
16
] and strongly related to
the presence of risk factors, such as LVSI, tumor grade, or molecular profile [
14
]. About
50% of the patients with a recurrence have locoregional disease, 25% present with distant
recurrence, and the remaining 25% have both [
14
]. Patients with advanced-stage disease at
diagnosis or with a more aggressive subtype have a higher probability of both locoregional
and distant recurrence [
17
]. Several studies showed a relapse-free survival of 60 to 70% after
complete debulking and adjuvant (chemo)radiation in locally advanced disease [
17
,
18
].
Most recurrences occur within three years after the primary treatment, with a median
5-year survival of 55% after pelvic recurrence and 17% after metastatic disease [12,14].
The treatment options are dependent on the site of recurrence, tumor histology, i.e.,
biomarkers, previous treatments, and the patient’s performance status and preferences.
The treatment strategies can include surgery, radiotherapy, hormonal treatment, systemic
treatment, or a combination [
19
]. In this review, we will give an overview of the local and
systemic treatment options for patients with recurrent endometrial cancer and intend to
provide insight regarding the different treatment strategies for patients with an increasingly
personalized approach in the future.
2. Surgical Treatment for Locoregional Recurrence
2.1. Vaginal Vault Recurrence
For a vaginal recurrence in previously irradiated patients, surgical resection is con-
sidered to be the first-line treatment option, followed by adjuvant local radiotherapy (i.e.,
image-guided brachytherapy) if indicated [13,20,21].
Vaginal vault recurrences in non-irradiated patients are traditionally salvaged with
radiation therapy [
13
]. However, the tumor size significantly influences the effect of
radiotherapy and, therefore, surgical resection may be considered as a viable alternative.
Wylie et al. showed that local control with radiotherapy was significantly worse for tumors
>2 cm compared to smaller tumors (54% versus 80%) [
22
]. With the use of a combination
of external beam radiotherapy (EBRT) and brachytherapy, also in larger tumors, a good
locoregional control can be achieved [
23
]. Although Haldarson et al. showed comparable
survival in patients with surgical resection and radiotherapy, in previously non-irradiated
patients, the limited number of patients warrants further research [24].
2.2. Locoregional and Abdominal Recurrence
Historically, the role of surgery for recurrent endometrial cancer has been focused on
exenterative surgery. Pelvic exenteration (anterior, posterior, or total) is performed with
curative intent and has primarily been described in highly selected patients with an isolated
pelvic adenocarcinoma recurrence after radiotherapy [
25
]. The complete resection of the
tumor is reported to be feasible in the majority of patients, with the reported complete
resection rates varying from 86% to 100% in a small case series [
25
–
27
]. However, the selec-
tion criteria are lacking, and the results are based on a small number of patients that have
been selected retrospectively over long time periods. In addition, resection is accompanied
by significant surgical-related morbidity and mortality with major complications in up to
80% of patients and mortality rates of 5% [
25
,
27
]. The five-year survival rates after pelvic
exenteration are reported to be up to 56 to 70% when complete resection has been obtained
(R0) compared to 20% or less in the presence of residual disease (R1-2) [25–27].
Over the past years, the role of surgical cytoreduction (i.e., excision of all visible
disease) for recurrent endometrial cancer has been gaining increasing interest as a surgical
Cancers 2021,13, 6275 4 of 14
alternative with less morbidity compared to exenteration. Retrospective studies have
demonstrated the feasibility and additional value of cytoreductive surgery [
28
–
32
]. Patient
selection was based upon a local multi-disciplinary team review and included endometroid
and non-endometroid tumors. Most studies included both locoregional (pelvic and nodal)
and intra-abdominal recurrences. After cytoreduction, 40–60% of the patients were treated
with systemic therapy, radiotherapy, or both [
21
,
33
,
34
]. The removal of all visible disease
was achieved in the majority of the patients, varying from 56% to 71% [
21
,
29
,
33
]. The factors
associated with complete cytoreduction were: solitary recurrence, tumor size (<6 cm), and
performance status [
30
,
32
,
33
]. Advanced age and the presence of peritonitis carcinomatosis
negatively impacted the achievement of complete cytoreduction and survival [
32
,
34
]. The
surgical morbidity rates varied from 9% to 21%, mainly grade one and two complications,
and no perioperative deaths were reported [28–30,32].
Complete resection was significantly associated with improved overall survival [
21
,
28
,
31
,
32
].
A recent multi-institutional study of 230 patients reported a significantly improved 5-year
survival of 66% in patients with no residual disease and negative resection margins com-
pared to 37% in patients with macroscopic residual disease. The site of recurrence did
not impact the survival outcomes [
31
]. In a large meta-analysis by Barlin et al., the role
of cytoreductive surgery for both advanced (n = 515) and recurrent (n = 157) endometrial
cancer patients was evaluated. Complete cytoreduction was associated with a superior
overall survival outcome, with each 10% increase in proportion with the patients under-
going complete cytoreduction showing a 9-month increase in survival. In the cases with
residual disease of 2 cm or more, the survival benefit was lost, supporting proper selection
and the aim to achieve complete debulking [35].
Whether neoadjuvant chemotherapy in a recurrent setting might be a valuable treat-
ment option prior to debulking has not been studied so far. Based on the data in the
primary setting, neoadjuvant chemotherapy in advanced-stage disease resulted in 80%
complete debulking [
36
] and, as such, could be considered in individual patients with a
good performance status.
2.3. Solitary Distant Metastasis
There are few reports on the surgical management of isolated distant recurrences.
Tangjitgamol et al. reviewed the role of the surgical resection of solitary pulmonary, hepatic,
and cerebral metastasis and deemed it feasible for individualized cases. The successful
resection of splenic metastasis has also been reported [
37
]. The favorable prognostic factors
for a prolonged survival were good performance status, long disease-free interval, and
clear margins [
38
]. However, the studies are limited and comprise mainly case reports,
warranting further research before evidence-based guidelines can be drafted.
3. Radiotherapy
3.1. Vaginal Vault Recurrence
In the PORTEC-1 trial, the locoregional recurrence was 14% in previously unirradiated
patients with 11% vaginal recurrence and 3% pelvic recurrence. In previously irradiated
patients, 4% locoregional relapse occurred, of which 2% was pelvic recurrence [
15
]. This
is in line with other published recurrence rates, such as Francis et al., who found 7%
overall recurrences with 4% only locoregional recurrences in 2691 patients with stage I-II
endometrial cancer [16].
The treatment of a vaginal recurrence usually requires a combination of external
beam radiotherapy (EBRT) with elective nodal irradiation and brachytherapy boost. In
radiation-naïve patients, this is often the treatment of choice. Local control is obtained
in 60–80% with acceptable toxicity, mostly gastrointestinal and urogenital toxicity [
13
].
The current consensus is that a cumulative dose of 80 Gy in the target volume should
be reached in order to achieve >90% local control [
23
,
39
]. MRI-guided brachytherapy
techniques are required to safely reach such doses with minimizing the dose to the organs
at risk, and, in many cases, laparoscopic guidance during applicator placement is needed
Cancers 2021,13, 6275 5 of 14
to reach adequate target coverage and avoid bowel perforation [
40
]. Isolated vaginal
vault recurrences after previous postoperative vaginal vault brachytherapy can be treated
likewise, without dose-adjustment.
3.2. Pelvic Recurrence
Local control is worse for patients with a pelvic recurrence as opposed to a vaginal
recurrence with reported 5-year local control rates between 30 and 60% [
41
,
42
]. In addition,
the overall survival is better for patients with a vaginal versus pelvic nodal recurrence,
respectively, 73% and 8–14% [41].
Patients with a pelvic recurrence can be treated with EBRT with a boost to the macro-
scopic lesions. In these cases, a combination of radiation and chemotherapy or surgery
might be beneficial as well, and this needs to be individualized [16,41].
In previously irradiated patients, the incidence of locoregional recurrence is lower, but
treatment of a recurrence is more challenging. The achievable dose will be considerably
lower in such cases and mainly depends on the tolerance of the nearby organs at risk,
particularly the bowel [
23
]. Re-irradiation has long been controversial because of the high
incidence of toxicity (fistula, bowel/bladder toxicity) [
43
]. However, with the improvement
of techniques integrating imaging during radiotherapy, this might be overcome in selected
cases. Nowadays, re-irradiation with stereotactic irradiation on a conventional linac or
MRLinac (MRL) is feasible and with acceptable toxicity [44,45].
3.3. Oligometastases
Recent developments in stereotactic radiotherapy have facilitated safe irradiation of
several malignant lesions to an ablative dose. Up to five lesions are considered ‘oligometastatic
disease’, and the SABR-COMET study has demonstrated a prolonged disease free- (DFS)
and overall survival (OS) after stereotactic radiotherapy compared to standard palliative
radiotherapy in patients with a variety of primary tumors [
46
]. Scarce retrospective data
appear to confirm these results for gynecological cancer patients [47].
3.4. MR Linac (MRL)
Stereotactic body radiotherapy (SBRT) is a method of EBRT that accurately delivers a
high dose of irradiation in one or a few treatment fractions to an extracranial target [
48
].
To safely deliver these high doses, image guidance is necessary. In the case of lung or
bone metastases, cone-beam CTs (CBCT) will be sufficient for adequate image guidance.
Hence, most modern LINACS equipped with CBCT can deliver SBRT for these disease
sites. CBCTs are not sufficient to properly visualize malignant lesions in the abdomen and
viscera, such as nodal and liver metastases.
MR guided stereotactic radiotherapy, as is performed on an MRL, is now emerging
as a treatment modality for SBRT in body sites that were recently too difficult to visualize
on CT. The MR LINACS are integrated imaging and radiation systems, which enables
visualization of the target immediately before, during, and after irradiation. The irradiation
of targets very close to sensitive organs, such as the small bowel, employment of smaller
margins, and adjustment of the treatment to the anatomy on a daily basis, are now possible.
Abdominal organs tend to move, dependent on bladder or bowel filling, and daily plan
adjustment allows the radiation oncologist to give a high dose while still sparing the organs
at risk. This feature makes MR LINAC-based SBRT very appropriate for re-irradiation of
small recurrences in previously irradiated areas, such as nodal recurrences in the abdomen.
Currently, experience is still limited, but centers worldwide are gathering evidence about
the effectiveness of MR-based SBRT [49].
In summary, the treatment of locoregional recurrence can be either with (chemo)radiotherapy
or by surgical resection and is dependent on whether or not previous pelvic radiotherapy has
been applied. In Figure 2, possible flowcharts for recurrent endometrial cancer in previ-
ously irradiated patients (Figure 2A) and in patients who did not undergo previous pelvic
radiotherapy (Figure 2B) are shown. The balance between potential toxicity and benefit
Cancers 2021,13, 6275 6 of 14
should be discussed with each individual patient. In the case of oligometastatic disease,
local treatment might be of benefit.
Figure 2.
Flow chart for possible treatment decisions in patients with recurrent endometrial cancer after initial surgical
treatment with (
A
) or without (
B
) previous adjuvant locoregional radiotherapy. EBRT: external beam radiotherapy; SBRT:
stereotactic body radiotherapy. * excluding adjuvant brachytherapy only.
4. Systemic Treatment
4.1. Chemotherapy
In the chemotherapy trials for recurrent endometrial cancer, almost all the randomized
studies also included patients with locoregionally advanced endometrial cancers, which
might result in more favorable results compared to those patients with metastatic disease.
The publication of randomized trials concerning systemic chemotherapy for metastatic
endometrial cancer started in the late previous century with doxorubicin(A), later combined
with cisplatin (P) and paclitaxel (T) [
50
–
53
]. TAP was, for a long period, the most effective
evidence-based therapy with a significantly higher response rate of 57% versus 34% for
AP (P < 0.01), and improved PFS (median, 8.3 v 5.3 months; P < 0.01), and OS (median,
15.3 v 12.3 months; P = 0.037). However, toxicity, and especially neurological toxicity, as
well as cardiac toxicity, were a major concern in this elderly population, and many centers
started to use carboplatin and paclitaxel instead, with similar results. In 2020, the long-
awaited randomized non-inferiority study GOG0209 comparing carboplatin and paclitaxel
with paclitaxel, doxorubicin, and cisplatin confirmed that carboplatin and paclitaxel is not
inferior to TAP [54].
Only a few randomized phase III and phase II chemotherapy trials have been pub-
lished since, investigating schedules for a second recurrence, albeit without startling effects.
McMeekin et al., published an early stopped, phase III trial of ixabepilone versus either
paclitaxel or doxorubicin for second-line treatment [
55
]. Docetaxel combined with plat-
inum did not seem superior to paclitaxel [
56
,
57
], and neither was vinorelbine combined
with cisplatin [
58
], nor topotecan [
59
], dactinomycin [
60
], pegylated doxorubicin [
61
,
62
],
oxaliplatin [
63
], pemetrexed [
64
], trabectedin [
65
], or gemcitabine [
66
]. A weekly schedule
with carboplatin and paclitaxel according to a phase II trial seems to have one of the more
favorable results for patients previously treated with chemotherapy with a response rate
of 39% and a median PFS of 8 months and an OS of 9 months at the cost of increased
myelodepression and neuropathy [67].
4.2. Immunotherapy
Immunotherapy with checkpoint inhibitors, both PD1 and PDL1 inhibitors, is, nowa-
days, the most promising therapy for endometrial cancer. Two drugs are currently ap-
proved by the EMA and/or FDA; pembrolizumab and dostarlimab. Dostarlimab (Jemperli)
was granted accelerated approval both by the FDA and EMA for the treatment of patients
with recurrent or advanced deficient mismatch repair (dMMR) endometrial cancer that has
progressed or following prior treatment with platinum-containing chemotherapy [
68
]. In
patients with previously treated metastatic endometrial cancer irrespective of MSI/MMR
Cancers 2021,13, 6275 7 of 14
status, a response rate of 64% in MSI-H/MMRD and 36% for MSS/pMMR was seen with the
combination of pembrolizumab and lenvatinib [
69
]. Based on this study, pembrolizumab
with lenvatinib was also approved in an accelerated manner by the FDA for patients with
previously treated metastatic endometrial cancer whose tumors were not MSI-H/dMMR.
This study was followed by KEYNOTE-775/Study 309, a randomized phase III trial for
endometrial cancer patients with tumors that are not deficient mismatch repair or MSI high
and who have recurrent disease following prior systemic therapy. For this combination of
lenvatinib and pembrolizumab, the median OS improved from 12 months to 17.4 months,
with an HR 0.68 (95% CI 0.56–0.84) (Makker (abstract SGO 2021). The marketing authoriza-
tion application is currently under review by the EMA. The results from other Checkpoint
inhibitor phase III trials with, for example, durvalumab with olaparib (NCT 04269200) and
atezolizumab with carboplatin and paclitaxel (NCT 03603184), will become available in the
future years.
4.3. Targeted Therapy
A wide range of targeted therapies have been explored for metastatic endometrial cancers.
In the early years when these drugs became available, they were used in unselected patients;
more recently, due to increased availability of genome sequencing, more studies are focused
on specific genetic alterations, such as mutations and copy number changes in the tumor. No
randomized phase III trials have been published for targeted therapies in this patient population.
Neither has any targeted drug been approved by the FDA or EMA at this moment. A large
number of randomized phase II and phase III trials have been published on angiogene-
sis inhibitors, such as bevacizumab [
70
–
72
], brivanib [
73
], nintedanib [
74
], sunitinib [
75
],
cediranib [
76
], trebananib [
77
] and lenvatinib [
78
], thalidomide [
79
], and aflibercept [
80
].
Another group of drugs of interest in endometrial cancers are the mTOR inhibitors: tem-
sirolimus [
71
,
81
–
84
], ridaforolimus [
85
–
87
], and everolimus [
88
,
89
] again without success
for registration. The newer drugs, such as PIK3CA inhibitors and AKT inhibitors, have
been tested in few phase II trials, with only one looking at a PIK3CA mutation upfront [
90
]
In addition, several EGFR inhibitors were used in phase II trials, such as gefitinib [
91
] and
erlotinib [
92
]. The MEK inhibitor selumetinib also did not pass to a phase III trial [
93
].
Selinexor, an exportin 1 inhibitor, showed interesting results in endometrial cancer, and
this is one of the rare targeted drugs proceeding to a phase III trial. It is currently being
tested as maintenance after a response to carboplatin paclitaxel (NCT03555422).
5. Hormonal Treatment
Hormonal therapy for endometrial cancer has been used since the 1950s after it became
clear that progesterone could induce the regression of endometrial hyperplasia and EC [
94
].
In the first publication by Kelley and Baker in 1961, a response rate of 29% to progestin
therapy was reported among 21 recurrent ECs. This led to widespread application of
progestin therapy in clinical practice. Initially, several investigations in patients with
advanced-stage and recurrent EC confirmed the original reported response rates, with
some studies observing a response rate as high as 56% of patients [
95
,
96
]. However, recent
studies with a more modern trial design and more stringent endpoints reported a lower
response rate ranging from 11% to 24%, although patients that did respond often had
long progression-free intervals [
97
–
99
]. Newer hormonal drugs, such as tamoxifen and
aromatase inhibitors, have shown lower response rates than progestins and are, therefore,
regarded as second-line hormonal therapies [100,101].
The response rates are significantly higher in ER/PR positive EC [
102
,
103
]. Neverthe-
less, a recent meta-analysis showed that ER/PR status was integrated in only 70 out of 1837
included cases, indicating the limited available research on ER/PR status and response to
hormonal therapy in EC. Van Weelden et al. demonstrated that the classification of ER/PR
expression into three risk groups (0–10% (high), 20–80% (intermediate), and 90–100% (low))
resulted in better prognostication in EC, suggesting tissue specific cut-off [
104
]. Multiple
studies have shown that, during cancer progression, the loss of ER/PR occurs in at least
Cancers 2021,13, 6275 8 of 14
20% of metastasis from ER/PR positive primary tumors; this underlines the relevance of
reassessing ER/PR prior to the start of the treatment of recurrent EC [105].
Yet, the presence of ER/PR is not inherently reflecting active intracellular ER sig-
naling and hormone driven tumor growth. Therefore, the ER pathway activity testing
that indicates an activated ER signaling might improve the prediction of the response to
hormonal therapy in EC. In EC, ER pathway activity scores (ERPAS) were demonstrated
to better predict the prognosis compared to ER expression [
106
]. In a recently published
paper, pretreatment biopsies of patients with recurrent (n = 51) and advanced (n = 30)
endometrial carcinoma were analyzed for ER/PR expression and integrated the ERPAS
analysis. Interestingly, all the responders, i.e., complete- and partial response (CR, PR),
had ER/PR expression >50%. Among progestin users, the response rate (RR) was 37.7%
for ER > 50%, 56.8% for PR > 50%, and 62.1% if activated ERPAS [
107
]. In a multivariable
regression analysis, including tumor grade, histology, ER/PR, and ERPAS, the ERPAS >15
was the sole marker that remained significantly associated with PFS (HR 4.525, 95%-CI
1.85–11.07, p= 0.001). A multivariable regression analysis without ERPAS showed that PR
expression was the only variable with significant association with PFS (HR 2.964, 95%-CI
1.58–5.58, p= 0.001). In those who responded to hormonal therapy, 34.3% of the patients
with PR >50% had not progressed after 2 years.
In conclusion, patients with systemic recurrent endometrial cancer can be treated with
hormonal therapy, immunotherapy, or chemotherapy. The evidence on targeted therapy is
limited. Figure 3summarizes the systemic treatment options with response rates and data
on progression-free survival and overall survival.
Figure 3.
Overview of systemic treatment options in recurrent endometrial cancer. ER: estrogen
receptor; PR: progesterone receptor; MMR-D: mismatch repair deficient; MSI: microsatellite instability;
MSS: microsatellite stable; pMMR: proficient mismatch repair; PFS: progression-free survival; OS:
overall survival. * Preferably histology on recurrent tumor ** also approved for pMMR/MSS ***
Dependent on level of expression.
6. Conclusions and Future Perspectives
The treatment of recurrent endometrial cancer is a therapeutic challenge, especially in
the previously irradiated patient or in the patient with oligometastatic disease. In the last
decade, the improved selection of patients with recurrent endometrial cancer resulted in an
improved 5-year survival rate from 25% up to 75%. The treatment modalities can be either
local (surgery and radiotherapy) or systemic (chemotherapy, targeted therapy, hormonal
therapy, or immunotherapy). In the case of systemic therapy, evidence is available for
Cancers 2021,13, 6275 9 of 14
chemotherapy, immunotherapy, and hormonal therapy. In the case of targeted therapy, so
far, no phase III trials are available, hampering specific recommendations. It is expected
that molecular profiling in endometrial cancer will be directive not only in the adjuvant
setting but also in patients with recurrent disease [
108
]. Furthermore, combinations of
local and systemic treatment might benefit selected patients. Trials with combinations of
radiotherapy and immunotherapy or combinations of different systemic treatments are on-
going, and, hopefully, more evidence will become available in the following years. To gain
better evidence regarding the different treatment strategies, further studies are warranted.
Furthermore, to better select patients, research in the field of predictive biomarkers and the
prospective analysis of outcome in large databases is necessary.
Close collaboration between the radiation oncologist, medical oncologist, pathologist,
radiologist, and gynecologic surgeon is essential to obtain the best possible outcome for
these complex patients, and discussing these patients in a multidisciplinary tumor board
with experience in treating recurrent endometrial cancer is mandatory.
Author Contributions:
Conceptualization, J.M.A.P. and H.R., Writing original draft preparation,
H.R., C.V., W.J.v.W., A.S., J.D., N.O., J.M.A.P., Writing review and editing J.M.A.P. and H.R. All
authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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