Improved Outcome of High-Grade,

Early 1-Stage Endometrioid

Endometrial Carcinoma With Adjuvant
Chemotherapy and Radiotherapy:
Comparison of 2 Treatment Strategies
Reynaers, Eline AEM MD; Jutzi, Leah MD; Ezendam, Nicole P.M. PhD; Kwon,
Janice S. MD; Pijnenborg, Johanna M.A. MD, PhD

Objective: Patients with high-grade endometrioid endometrial carcinoma have a high

risk of recurrence, even in early stage. To determine the benefit of a more aggressive
adjuvant treatment approach, different treatment strategies of 2 referral centers were
compared.

Materials and Methods: Outcome of all patients with International Federation of

Gynecology and Obstetrics IB and II high-grade endometrioid endometrial
carcinoma treated between 2008 and 2012, at the Gynecological Oncology Center
South (GOCS) were compared with patients treated at the British Columbia Cancer
Agency (BCCA). All patients underwent primary surgical treatment. Adjuvant
treatment consisted of radiotherapy dependent on final pathology (GOCS), or
adjuvant chemotherapy and pelvic radiotherapy (BCCA).

Results: A total of 116 patients were treated at the GOCS (n = 61) and BCCA (n =
55). Patient cohorts were comparable for clinicopathological factors, except for age
at diagnosis and lymphadenectomy. Radiotherapy was applied in 70.5% at the GOCS
compared with 100% at the BCCA. All BCCA patients received chemotherapy
compared with 3.3% at GOCS. The BCCA treatment strategy resulted in a significant
reduced recurrence rate when compared with GOCS, 10.9% and 36.1%, respectively.
There was no significant difference in the recurrence rate between patients with (n =
48) and without a lymphadenectomy (n = 68). Yet, numbers are relatively low.
Because most recurrences were distant 78.6% (22/28), adjuvant chemotherapy
resulted in reduced disease-related mortality.

Conclusions: Adjuvant chemotherapy and radiotherapy in early-stage high-grade

endometrioid endometrial carcinoma results in improved disease-specific and overall
survival compared to radiotherapy alone. Yet, due to the relatively low numbers,
validation of these findings is needed in large prospective trials.

1 | Endometrioid Endometrial Carcinoma

 Endometrial cancer (EC) is the most common malignancy of the female genital
tract, with an increasing incidence in western countries. Most patiens present with
early stage type 1 endometrioid type endometrial carninoma, and have a favorable
prognosis. In addition to tumor stage and histology, outcome is related to the age of
diagnosis, myometrial invasion, tumor grade, and lymph vascular space invasion
(LVSI).

Type II endometrial carninomas are characterised by a nonendometrioid

hystology, such as serous or clear cell, frequently present in advance stage, and have
worse outcome even in early stage disease. Yet patien with hight grade endometrioid
type endometrial carninoma have acomparably high risk of recurrence when
compared to type II endoometrials cancers, even in early stagedisease. For patients
with early stage serous carcinoma, adjuvant chemotherapy seems to be beneficial
with respect to disease free survival and overall survival. Whether adjuvant
chemotherapy and/or chemoradiation will improve teh outcome of early stage high
risk endometrioid type endometrial carcinoma is the question of interest in the
PROTEC III (NCT00411138) and the GOG-249 (NCT00807768) studies. Although
randomized controlled trials (RCTs) are superior to observational studies with
respect to the level of evidence, selection bias might influence result of both types of
studies. Because patient with endometrial carcinoma are often elderly women with
comorbidities, these patient s might be frequently excluded from participating in
studies that randomize conventional treatment with more aggresive treatment.
Unfortunately, neither PORTEC III nor GOG 249 incorporated an observational arm
to register potential included patient who were excluded on the basis of performance
status, or those who declined to recieve adjuvant therapy. As a result, observational
studies can still contribute important information on the outcomes of adjuvant
treatment in higt risk endometrial carcinoma.

Recently, we presented our series of high grade endometrioid type endometrial

cancer and demonstrated that adjuvant chemotherapy and radiotherapy in patient
with 2 of 3 risk factors ( deep myometrial invasion, high grade endometrioid
histology, cevical stroma invasion) resultedin an improved recurrence free survival.
Data were compared with a historical cohort that was relatively small (n=17) ,
because there was no contemporary control group. Consequently, there was a
substantial difference in the follow up between the case and control patients. These
data were in line with an Italian restrospective study demonstrating improved
outcome of patients with early stage high grade endometrial carcinoma who recieved
sequential adjuvant chemotherapy and radiotherapy.

The aim of the current study was to compare treatment protocols of 2 different
referral centers for gynecological oncology, to support the observed benefit of
adjuvant chemotherapy as part of the standard protocol for early stage, high grade
endometrioid type endometrial cancer patients.

2 | Endometrioid Endometrial Carcinoma

 MATERIALS AND METHOD

Study Design

A retrospective comparative cohort study was to performed comparing 2

different treatment strategies for early stage high grade endometrioid endometrial
cancer in 2 gynecological oncology referral centers in Canada and the Netherlands.

Inclusion Criteria

All patients diagnosed from 2005 to 2012 with high grade endometrioid type
endometrial carcinoma that at least underwent a histerectomy and bilateral salpingo-
oophorectomy were included. Additional inclusion criteria were: deep myometrial
invasion and/or cevical stromal involvement, classified as surgical stage IB or
according to the 2009 international federation of
Gynecology and Obstetrics (FIGO) staging system. If lymph node sampling was
performed, lymph nodes should be negative.

Settings

The gynecological oncology centre south (GOCS), is a collaborating

organization in registry and cooperative management of oncology in the southern
part of the netherlands. The GOCS is composed of 9 collaborating hospitals,
including 2 oncological referralcenters. The hospitals all use a web based data
registration system, to register all patients with gynecological malignancies.
According to dutch guidelines, surgical staging and lymph node dissection in clinical
stage I endometrioid type endometrial cancer is recommended only in case of clinical
suspicion of lymph node metastasis or in case of high risk histology ( eg, serous
papillary and clear cell tumors). Adjuvant therapy consists of radiotherapy either by
external beam radiation of vaginal vault brachytherapy, depending on the patients
age, myometrial invasion, LVSI, and tumor grade on final pathology. Currently,
adjuvant chemotherapy in early stage high grade endometrioid endometrial cancer is
not routinelly recommended and is administered only in clinical trial setting in the
Netherlands.
The british columbia cancer agency ( BCCA) providesa province wide,
population basedcancer control program for the residents of british columbia and the
yukon in canada. According to the BCCA endometrial cancer treatment guidelines,
hysterectomy and bilateral salpingo oophorectomy is performed routinely, and only
case of suspicious lymph nodes, as dissection or biopsy is performed. The protocol
for adjuvant therapy for FIGO stage IB/II, high grade endometrioid type endometrial
cancer was introduced in 2008 and is well defined and described in detail previously.
In summary, women with high risk early stage disease are treated with 3 or 4 cycles
of carboplatin( area under the cuve 6) and paclitaxel (175 mg/m2) chemotherapy at a

3 | Endometrioid Endometrial Carcinoma

3 week interval followed by pelvic radiotherapy and vagianl vault brachytherapy,
regardless of their nodal status.

Data Extraction

Data of patientsand tumor characteristics, primary surgical ans adjuvant

treatment were registered. Follow up visits consisted of a history and physical
examination. Routine imaging was not performed in follow up , only if symptoms or
physical findings were suggestive for reccurent disease. The last documented visit
was usedfor the of follow up. Recurence was defined as the first objective
documentation of recurrent disease by either histologyor imaging. Dataextracted
from the electronic patient record included age at diagnosis, date of diagnosis,
surgical procedure, surgical stage, tumor grade, type and number of cycles of
chemotherapy and radiation dose, and complications of treatment.

Outcome

Outcome was defined as recurrence, classified as local, regional, or distant.

Recurrences limited to the vaginal vault were defined as local metastasis, recurrences
beyond the vaginal vault but limited to the pelvic region were defined asregional
metastasis, and recurrences beyond the pelvis, the extraperitoneal cavity, and outside
the abdominal cavity were defined as distant metastasis. Outcome was compared
between the GOCS (2005-2012) and BCCA (2008-2012). Additionally, disease
related mortality (DRM) was defined in this study asthe proportion of patients dying
of endometrial cancer.

Statistical analysis

Descriptive analyses were used to describe the data, using percentages and
median with range (minimum-maximum age). Pearson X 2 and fisher exact tests were
performed to compare the differencesin recurrence and mortality between both types
of adjuvant treatment. Logistic regression was performed to measure the relationship
between the categorical dependent variables ( locoregional and distant recurrence
and mortallity) and 3 independent variables ( age of patient, surgical staging, and the
type of adjuvant treatment) . A kaplanmeier curve was constructed to present the 5
year progression free and overall survival.
Statiscal analyses were conducted using IBM SPSS statistics version 20 ( SPSS
inc., chicago, IL) P values less tahn 0,05 were considered statistically significant and
all statistical tests performed were 2 sided.

4 | Endometrioid Endometrial Carcinoma

 RESULTS

Patients and Tumor characteristic

Patients adn tomor characteristic are shown in table 1 (n= 116) the majority
(58,6%) of women were older than 60 years at the time of diagnosis. Patient cohorts
were comparable for clinicopathological factors except for age at diagnosis,

TABLE 1. Baseline and treatment Characteristics

Total GOCS BCCA P
n = 116 n = 61 n = 55
Age
Median age at diagnosis 64 (38-90) 68 (48-90) 59 (38-81)
Age>
(range) 60 8 (58.6%) 43 (70.5%) 25 (45,5%) 0.011*
FIGO stage
lB 86 (74.1 %) 48 (78.7%) 38 (69%) 0.578
II 30 (25.8%) 13 (21.3%) 17 (31%) 0.578
Surgery
Hysterectomy + BSO 63 (54.3%) 42 (68.9%) 21 (38.2%) 0.004*
Hysterectomy + BSO + LND 48 (41.4%) 16 (26.2%) 32 (58.2%) 0.002*
Other 5 (4.3%) 3 (4.9%) 2 (3.6%)
Radiotherapy
No radiotherapy 18 (15.5%) 18 (29.5%) 0
VBTonly 17 (14.7%) 15 (24.6%) 2 (3,6%)
EBRTonly 23 (19.8%) 14 (23.0%) 9 (16,4%)
VBT + EBRT 58 (50.0%) 14 (23.0%) 44 (80%)
Total RT 98 (84.5%) 43 (70.5%) 55 (100%)
Chemotherapy <0.001*
1 cycle 1 (0.9%) 0 1 (1,8%)
2 cycles 1 (0.9%) 0 1 (1,8%)
3 cycles 49 (42.2%) 0 49 (89,1%)
4 cycles 5 (4.3%) 1 (1.6%) 4 (7,3%)
Unknown 1 (0.9%) 1 (1.6%) 0
Total CT 56 (48.3%) 2 (3.3%) 55 (100%)
*Statistical significance. BSO, bilateral salpingo- <0.001*
oophorectomy; LND,lymph node dissection.
lymphadenectomy, and application of radiotherapy frequently underwent a
lymphadenectomy, and all recieved radiotherapy. The median follow up was 26 (6-
60) months for BCCA and 37 (2-125) months for GOCS.

TABLE 2. difference in recurrence of disease and disease-

related mortality after radiotherapy alone versus radiotherapy
and chemotherapy
Total GOCS BCCA P
n = 116 n = 61 n = 15
N % N % N % --
Overall recurrence 28 24,1 22 36,1 6 10,9 0.002*
Loco-regional 5 4,3 5 8,2 0 -- 0.059
Distant 22
5 | Endometrioid Endometrial Carcinoma 19,0 16 26,2 6 10.9 0.036*
OM 22 19,0 19 31,1 3 5.5 0.000*
DRM 19 16,4 16 26,2 3 5.4 0.003*
*
statistical significance.
OM, overall mortality.
Adjuvant Treatment

According to the protocol, patients treated at the BCCA significantly received

more often chemotherapy and radiotherapy. Patients treated at the GOCS received
adjuvant radiation in 70.5% of the cases (n = 43), either vaginal brachytherapy
(VBT) (n = 15), external beam radiotherapy (EBRT) (n =14), or both VBTand
EBRT (n = 14), whereas all patients treated at the BCCA received at least VBT. The
majority (80%) received both EBRT and VBT. At the BCCA 89. I% (n = 49)
completed at least 3 cycles of carboplatin (area under the curve 6) and paclitaxel
(175 rng/m"). Four women (7.3%) received 4 cycles, one of these women received
an additional cycle because she received a lower dose of radiotherapy due to prior
surgery for rectal cancer. For the remaining 3 patients, 4 cycles were given as this is
the preference in one of the 5 health authority regions in British Columbia. One
patient cancelled her chemotherapy after one cycle, and another patient had her
chemotherapy cancelled after 2 cycles due to severe facial acne from the
prepaclitaxel dexamethasone. Two (3.3%) patients at the GOCS received adjuvant
chemotherapy.

TABLE 3. impact of adjuvant chemotherapy and

radiotherapy on the patients outcome corrected for age
(>60) and surgical staging by logistic regression
OR P 95% CI
Overall recurrence 0.276 0.017* 0.096-0.795*
Loco-regional ns ns ns
Distant 0.424 0.125 0.141-1.270
OM 0.158 0.007* 0.041-0.608*
*
DRM 0.204 0.022 0.052-0.793*
*
statistical significance.
95% CI, 95% confidence interval; ns, not significant.

6 | Endometrioid Endometrial Carcinoma

FIGURE 1. Kaplan- Meier curve of the 5 year progression- free survival related to
the type of adjuvant treatment.

Outcome

There was a significant difference in recurrence rates, overall mortality, and

DRM between the 2 treatment strategies (Table 2). Patients with adjuvant
chemotherapy and radiotherapy had a recurrence rate of I 0.9% compared to 36.1
% of patients that were treated according to the PORTEC criteria and did not
receive adjuvant chemotherapy. Most recurrences were distant in both treatment
groups, including 16 (72.7%) of 22 receiving radiotherapy alone, and 6 of 6
receiving chemo therapy with radiation. After correction for age at diagnosis and
surgical staging, adjuvant chemotherapy and radiotherapy resulted in both a reduced
recurrence rate DRM (Table 3). Progression-free survival (PFS) related to the
type of adjuvant treatment is demonstrated in Figure I and illustrates the benefit of
additional chemotherapy and radiotherapy. Also, the overall survival is improved
in favor of chemotherapy and radiotherapy as demonstrated in Figure 2. There was
no significant difference in the recurrence rate between patients who underwent
lymphadenectomy (16.7%) compared with those who did not have this procedure
(29.4%, P = 0.114).

7 | Endometrioid Endometrial Carcinoma

FIGURE 2. Kaplan-Meier curve of the 5-year overall survival related to the type of
adjuvant treatment.

8 | Endometrioid Endometrial Carcinoma

 DISCUSSION

In the present study, it was demonstrated that the treatment strategy with
routine application of adjuvant chemotherapy and pelvic radiation in early stage,
high-grade endometrioid EC is superior to adjuvant radiotherapy based on final
pathology. The majority of patients planned for adjuvant chemotherapy completed at
least 3 cycles of chemotherapy and received both external beam radiotherapy and
vaginal brachytherapy. The strength of this study is the fact that all consecutive
patients treated at the referral centers were included, and hence our data reflect
everyday clinical practice. Results are in line with other published studies that report
an improved outcome in high-grade endometrioid EC with adjuvant chemotherapy
and radiotherapy. Gadducci et al!" demonstrated in a retrospective study including
patients with high-risk, early-stage endometrioid endometrial cancer (FIGO IB/I1
with myometrial invasion >50%, grades 2-3) reduced distant and/or paraaortic
recurrences in patients who received adjuvant chemotherapy and radiotherapy (n = 3
7) compared with those who did not (n = 152). None of the 29 patients who received
sequential adjuvant chemotherapy and radiotherapy developed local recurrence, and
only one had distant recurrence, which suggests that sequential adjuvant
chemotherapy and radiotherapy might be the appropriate treatment strategy in these
patients. A prospective pilot study including 68 patients with FIGO stage IA grade 3,
IB grades 2 to 3, and II EC demonstrated an equal effectiveness of adjuvant
chemotherapy when compared with radiotherapy. Yet, none of these patients received
both adjuvant treatments. Although the importance of adjuvant radiotherapy for
local control has been demonstrated in previous randomized, prospective trials, most
studies excluded patients with FIGO stage TB and high-risk histology. In a recently
published study it was demonstrated that in these high-risk early stage EC patients (n
= 51 ), adjuvant pelvic radiation was associated with improved vaginal control,
pelvic control, and overall survival. Adjuvant chemotherapy in high-risk endometrial
carcinoma has been studied in several RCTs, but most trials compared platinum
based combination chemotherapy with radiotherapy.The Cochrane systematic review
included 5 RCTs and demonstrated a significant overall survival advantage from
adjuvant chemotherapy (relative risk, 0.88; 95% confidence interval, 0.79-0.99),
with a number needed to treat for an additional beneficial outcome of 25. The authors
concluded that postoperative platinum-based chemotherapy is associated with a small
benefit in PFS and overall survival irrespective of radiotherapy treatment.

Yet, the difference in treatment related complications is significant and should be

taken into account when patients are counselled for a more aggressive treatment
approach, especially in elderly patients. As demonstrated in the published series of
the BCCA, the majority of the patients did not have toxicity that resulted in treatment
alterations. Chemotherapy related toxicity was present in 18.2%, and radiotherapy-
related toxicity in 1.9%. These data are in line with the chemotherapy reported
morbidity by Aloisa et al. Also,the percentage of late grade 3 gastrointestinal toxic

9 | Endometrioid Endometrial Carcinoma

effects related to EBRT are in line with data of the Portec-2 study. The strength of
this study is the fact that 2 treatment strategies were compared in 2 large well
organized gynecological oncology centers. Nevertheless, selection bias might be
present due to the retrospective character of the study. Moreover, there was no central
pathology review of tumor histology. The presence of LVSI was not systematically
reported, and although we did not find a relation with recurrence in the LVSI
evaluable cases in both the GOCS and the BCCA cohort, numbers are too small to
draw firm conclusions. The discrimination between high-grade endometrioid and
serous endometrial cancer may be challenging, even with additional markers.
However, we do not think that this would have influenced outcome, because
recurrence rates of early stage high-grade serous and high-grade endometrioid
endometrial carcinoma are comparable Still, this study does have some limitations.
Due to the selected tumor type and risk group, the population size is rather limited,
even in a large referral center over time. Although we did not observe a difference
in recurrence rates according to performed lymphadenectomy, due to low numbers
the data should be interpreted with caution. Historically, endometrial carcinoma was
treated with both preoperative and postoperative radiotherapies, but none of the
studies demonstrated a survival benefit from radiotherapy in endometrial carcinoma
so far. It is interesting to note that over time the application of chemotherapy in
endometrial cancer has been adopted by clinicians in patients with high-risk
endometrial cancer as shown in a recently published questionnaire among members
of the Society of Gynecologic Oncologists and supported by data that VBT alone is
not sufficient in patients with high-risk EC. Although our data support the
consideration of adjuvant chemotherapy in high-risk endometrial cancer patients,
data should be confirmed by randomized trials. Especially, because early data of the
GOG 249 study, that randomized high-interrnediate-, and high-risk patients between
pelvic EBRT and vaginal brachytherapy followed by chemotherapy (3 cycles of
carboplatin and paclitaxel) did not show a benefit with respect to PFS of adjuvant
chemotherapy over standard EBRT. Therefore, both final results of the GOG 249 as
well as the PORTEC III study are important before changing routine practice.

10 | Endometrioid Endometrial Carcinoma

 CONCLUSIONS

We have demonstrated a significant improvement of disease specific, and

overall survival with routine application ofadjuvant chemotherapy and radiotherapy
in early-stage high-grade endometrioid type EC. These data are of additional value to
the results of the ongoing randomized trials of adjuvant treatment in high-risk EC.

11 | Endometrioid Endometrial Carcinoma

 Peningkatan Hasil Karsinoma Endometrial
Endometrioid Tingkat Tinggi Stadium-1 Awal,
dengan Kemoterapi dan Radioterapi Tambahan:
Perbandingan 2 Strategi Pengobatan
Reynaers, Eline AEM MD; Jutzi, Leah MD; Ezendam, Nicole PM PhD; Kwon, Janice S.
MD; Pijnenborg, Johanna MA MD, PhD

Tujuan: Pasien dengan karsinoma endometrial endometrioid tingkat tinggi memiliki

risiko kambuh yang tinggi, bahkan pada tahap awal. Untuk mengetahui manfaat
pendekatan pengobatan tambahan yang lebih agresif, perbedaan strategi pengobatan
pada 2 pusat rujukan dibandingkan.

Bahan dan Metode: Hasilnya semua pasien dengan karsinoma endometrial

endometrioid tinggkat tinggi stadium IB dan II Federation of Gynecology and
Obstetrics yang diobati di antara 2008 dan 2012, di Gynecological Oncology Center
South (GOCS) yang dibandingkan dengan pasien yang dirawat di British Columbia
Cancer Agency (BCCA). Semua pasien menjalani pengobatan bedah primer.
Pengobatan tambahan bergantung pada radioterapi pada patologi akhir (GOCS), atau
kemoterapi dan radioterapi pelvis tambahan (BCCA).

Hasil: Sebanyak 116 pasien dirawat di GOCS (n = 61) dan BCCA (n = 55). Kohort
pasien sebanding dengan faktor klinis, kecuali usia saat didiagnosis dan adanya
limfadenektomi. Radioterapi diterapkan sebanyak 70,5% pada GOCS dan 100% pada
BCCA. Semua pasien BCCA menerima kemoterapi, sedangkan GOCS sebanyak
3,3%. Strategi pengobatan BCCA mengurangi tingkat kekambuhan yang lebih
signifikan jika dibandingkan dengan GOCS, masing-masing 10,9% dan 36,1%. Tidak
ada perbedaan yang signifikan pada tingkat kekambuhan antara pasien dengan
limfadenektomi (n = 48) dan tanpa limfadenektomi (n = 68) dengan jumlah yang
relatif rendah. Karena tingkat kekambuhan yang tinggi ialah 78,6% (22/28),
kemoterapi tambahan menghasilkan adanya penurunan angka kematian akibat
penyakit.

Kesimpulan: Kemoterapi dan radioterapi tambahan pada karsinoma endometrial

endometrioid tingkat tinggi stadium awal menghasilkan peningkatan kelangsungan
hidup secara spesifik terhadap penyakit dan keseluruhan (disease free survival dan
overall survival), dibandingkan dengan radioterapi saja. Namun, dengan angka yang
relatif rendah, validasi temuan ini sangat diperlukan dalam percobaan prospektif
yang besar.
 Kanker endometrium (EC) adalah keganasan yang paling umum terjadi pada
sistem reproduksi wanita, dengan meningkatnya insiden di negara-negara barat.
Sebagian besar pasien menderita karsinoma endometrium tipe endometrioid tingkat
tinggi stadium awal tipe 1dan memiliki prognosis yang baik. Selain stadium tumor
dan histologi, prognosis dari karsinoma berkaitan dengan usia saat didiagnosis,
adanya invasi terhadap miometrium, derajat tumor, dan invasi melalui vaskuler dan
kalenjar getah bening (lymph vascular space invasion/LVSI).

Karsinoma endometrium tipe II ditandai dengan adanya histologi

nonendometrioid, seperti sel serosa atau jernih, sering terdapat pada stadium awal,
dan memiliki prognosis yang lebih buruk, bahkan pada tahap awal penyakit.
Penderita dengan karsinoma endometrial tipe endometrioid tingkat tinggi memiliki
risiko tinggi untuk kambuh jika dibandingkan dengan kanker endoomerial tipe II,
bahkan pada stadium awal. Untuk pasien dengan karsinoma serosa tahap awal,
kemoterapi tambahan bermanfaat oleh karena berhubungan dengan kelangsungan
hidup untuk bebas penyakit (disease free survival) dan kelangsungan hidup secara
keseluruhan (overall survival). Dapatkah kemoterapi dan/atau kemoradiasi tambahan
memperbaiki prognosis karsinoma endometrium tipe endometrioid tingkat tinggi
stadium awal adalah pertanyaan dari studi PROTEC III (NCT00411138) dan GOG-
249 (NCT00807768).

Meskipun uji coba terkontrol secara acak (randomized controlled trial/RCT)

lebih baik dibandingkan dengan penelitian observasional berhubungan dengan bukti
yang lebih banyak, adanya bias seleksi dapat mempengaruhi hasil kedua jenis
penelitian. Oleh karena pasien dengan karsinoma endometrium seringkali terdapat
pada wanita lanjut usia dengan komorbiditas, pasien-pasien ini sering tidak diikutkan
dalam penelitian pengobatan konvensional secara acak dengan pengobatan yang
lebih agresif. Tetapi, PORTEC III dan GOG 249 tidak mengamati secara
observasional untuk mencari adanya kemungkinan, termasuk pasien yang dieksklusi
berdasarkan status kinerja, atau mereka yang menolak menerima terapi tambahan.
Selain itu, studi observasional dapat mengkontribusikan informasi penting tentang
hasil pengobatan tambahan terhadap karsinoma endometrium risiko tinggi.

Saat ini, kami menyajikan beberapa jenis kanker endometrium tipe

endometrioid tingkat tinggi dan menunjukkan bahwa kemoterapi dan radioterapi
tambahan pada pasien dengan 2 dari 3 faktor risiko (invasi myometrium yang dalam,
histologi endometrioid tingkat tinggi, invasi stroma kistik) meningkatkan
kelangsungan hidup yang bebas akan kekambuhan. Data yang didapatkan
dibandingkan dengan riwayat kohort yang relatif kecil (n=17) karena tidak ada
kelompok kontrol yang seimbang. Akibatnya, terdapat perbedaan yang substansial
saat dilakukan tindak lanjut kasus dan pasien kontrol. Data-data ini sesuai dengan
studi restrospektif Italia yang menunjukkan perbaikan hasil dari pasien dengan
karsinoma endometrium tingkat tinggi stadium awal yang menerima kemoterapi dan
radioterapi tambahan yang sekuensial.

Tujuan dari penelitian ini adalah untuk membandingkan protokol pengobatan

dari 2 pusat rujukan onkologi ginekologi yang berbeda untuk memperkuat manfaat
yang diamati pada kemoterapi tambahan sebagai bagian dari protokol standar pasien
kanker endometrium tipe endometrioid tingkat tinggi, stadium awal.

MATERI DAN METODE

Desain Studi

Studi kohort komparatif retrospektif dilakukan dengan membandingkan 2

strategi pengobatan yang berbeda untuk kanker endometrial endometrioid tingkat
tinggi stadium awal dalam 2 pusat rujukan onkologi ginekologi di Kanada dan
Belanda.

Kriteria Inklusi

Semua pasien yang didiagnosis dari tahun 2005 sampai 2012 dengan
karsinoma endometrium tipe endometrioid tingkat tinggi yang juga menjalani
histerektomi dan salpingo-ooforektomi bilateral. Kriteria inklusi lain ialah: invasi
miometrium yang dalam dan/atau adanya stroma serviks, yaitu pasien yang
diklasifikasikan sebagai stadium operasi IB atau II menurut sistem stadium
International Federation of Gynecology and Obstetrics (FIGO). Bila pengambilan
sampel kelenjar getah bening dilakukan, kelenjar getah bening akan negatif.

Pengaturan

The Gynecological Oncology Centre South (GOCS), adalah sebuah organisasi

gabungan registrasi dan manajemen kooperatif dari onkologi di Belanda bagian
selatan. GOCS terdiri atas 9 gabungan rumah sakit, termasuk 2 pusat rujukan
onkologi. Semua rumah sakitnya menggunakan data registrasi berbasis web, untuk
meregristasi seluruh pasien dengan keganasan ginekologi. Menurut pedoman dutch,
tahap pembedahan dan pemotongan kelenjar getah bening pada tahap klinis I tipe
endometioid kanker endometrial direkomendasikan hanya pada kasus klinik dengan
suspek metastase kelenjar getah bening atau pada kasus dengan histologi resiko
tinggi (contoh : papiler serosa dan tumor sel bening). Terapi bantuan terdiri atas
radioterapi baik melalui sinar radiasi luar dari vaginal vault brachytherapy,
tergantung pada usia pasien, invasi miometrium, LVSI, dan stase tumor pada patologi
akhir. Saat ini, terapi bantuan kemoterapi pada stase awal kanker endometrium tipe
endometrioid tingkat tinggi tidak direkomendasikan secara rutin dan diberikan hanya
pada keadaan percobaan klinis di Belanda.

The British Columbia Agency (BCCA) menyediakan program kontrol

seprovinsi berdasarkan populasi untuk penduduk British Columbia dan Yukon di
Canada. Menurut pedoman terapi kanker endometrial BCCA, histerektomi dan
salpingo oophorectomy bilateral dilakukan secara rutin, dan hanya pada kasus suspek
kelenjar getah bening, selagi pemotongan atau biopsi dilakukan. Protokol terapi
bantuan untuk FIGO stase IB/II, kanker endometrium tipe endometrioid tingkat
tinggi diperkenalkan pada tahun 2008 dan didefinisikan dengan baik serta dijelaskan
secara detail sebelumnya. Kesimpulannya, wanita dengan penyakit stase awal dengan
resiko tinggi diterapi dengan 3 atau 4 siklus kemoterapi carboplatin (daerah di
bawah kurva 6) dan paclitazel (175mg/m2) pada interval setiap 3 minggu diikuti
dengan radioterapi panggul dan vaginal vault brachytherapy, bagaimanapun status
nodulnya.

Ekstraksi Data

Data karakteristik tumor pasien, pembedahan primer dan terapi bantuan telah
diregistrasikan. Kunjungan lanjutan terdiri dari riwayat dan pemeriksaan fisik.
Pencitraan rutin tidak dilakukan pada kunjungan lanjutan, hanya bila gejala atau
pemeriksaan fisik mengarahkan pada kambuhan penyakit. Catatan kunjungan
terakhir digunakan untuk kunjungan lanjutan. Kekambuhan didefinisikan sebagai
dokumentasi objektif pertama dari penyakit kambuhan oleh histologi maupun
pencitraan. Pengambilan data dari catatan pasien termasuk diagnosis, data diagnosis,
prosedur pembedahan, tahap pembedahan, stase tumor, tipe dan jumlah siklus
kemoterapi dan dosis radiasi, serta komplikasi dari terapi.

Hasil

Hasil didefinisikan sebagai kambuhan, diklasifikasikan atas local, regional,

atau jauh. Kambuhan yang terbatas pada vaginal vault didefinisikan atas metastase
lokal, dan kambuhan di luar vaginal vault tapi terbatas pada regio panggul
didefinisikan sebagai metastase regional, dan kambuhan di luar panggul, rongga
ekstraperitoneal, dan di luar dari rongga abdominal didefinisikan sebagai metastase
jauh. Hasil dibandingkan antara GOCS (2005-2012) dan BCCA (2008-2012).
Sebagai tambahan, penyakit yang berhubungan dengan kematian (disease related
mortality: DRM) didefinisikan pada penelitian ini sebagai bagian dari kematian
pasien karena kanker endometrial.

Analisis Statistik

Analisis deskriptif digunakan untuk menjelaskan data, mengunakan persentasi

dan jarak median (usia minimum-maximum). Uji Pearson X 2 dan fisher exact
dilakukan untuk membandingkan perbedaan angka kekambuhan dan angka kematian
antara dua tipe terapi bantuan. Regresi logistic dilakukan untuk mengukur hubungan
antara variabel bergantung kategori (loco-regional dan jarak kambuhan dan
kematian) dan 3 variabel independen (usia pasien, stase pembedahan, dan tipe terapi
bantuan). Kurva Kaplan-Meier disusun untuk mempersentasikan 5 tahun bebas
kemajuan dan angka yang bertahan secara keseluruhan.
Analisis statistic dibuat menggunakan statistik IBM SPSS versi 20 (SPSS inc.,
Chicago, IL) P values kurang dari 0,05 dianggap signifikan secara statistic dan
seluruh uji statistic dillakukan 2 sisi.
 HASIL

Pasien dan Karakteristik Tumor

Pasien dan karakteristik tumor tertera di tabel 1 (n=116) mayoritas (58,6%)

dari wanita lebih dari 60 tahun pada saat diagnosis. Kohort pasien berbanding dengan
faktor patologi klinik kecuali usia saat diagnosis, lymphadenektomi, dan pengerjaan
radioterapi teratur melakukan lymphadenektomi, dan seluruh radioterapi yang
diterima. Median berikutnya 26 (6-60) bulan untuk BCCA dan 37 (2-125) bulan
untuk GOCS.

TABEL 1. Garis belakang dan Karakteristik Terapi

Total GOCS BCCA P
n = 116 n = 61 n = 55
Usia
Usia median saat diagnosis 64 (38-90) 68 (48-90) 59 (38-81)
Usia > 60
(range) 68 (58.6%) 43 (70.5%) 25(45,5%) 0.011*
Stase FIGO
lB 86 (74.1%) 48 (78.7%) 38 (69%) 0.578
II 30 (25.8%) 13 (21.3%) 17 (31%) 0.578
Pembedahan
Histerektomi + BSO 63 (54.3%) 42 (68.9%) 21 (38.2%) 0.004*
Histerektomi + BSO + LND 48 (41.4%) 16 (26.2%) 32 (58.2%) 0.002*
Lainnya 5 (4.3%) 3 (4.9%) 2 (3.6%)
Radioterapi
Tanpa radioterapi 18 (15.5%) 18 (29.5%) 0
Hanya VBT 17 (14.7%) 15 (24.6%) 2 (3,6%)
Hanya EBRT 23 (19.8%) 14 (23.0%) 9 (16,4%)
VBT + EBRT 58 (50.0%) 14 (23.0%) 44 (80%)
Total RT 98 (84.5%) 43 (70.5%) 55(100%) <0.001*
Kemoterapi
1 siklus 1 (0.9%) 0 1 (1,8%)
2 siklus 1 (0.9%) 0 1 (1,8%)
3 siklus 49 (42.2%) 0 49 (89,1%)
4 siklus 5 (4.3%) 1 (1.6%) 4 (7,3%)
Tidak diketahui 1 (0.9%) 1 (1.6%) 0
Total CT 56 (48.3%) 2 (3.3%) 55 (100%) <0.001*
*Signifikansi statistic, BSO : bilateral
salpingo-oophorectomy; LND: pembedaan
kelenjar getah benih.

TABEL 2. Perbedaan kambuhnya penyakit dan kematian terkait penyakit setelah

 radioterapi saja versus radioterapi dan kemoterapi
Total GOCS BCCA P
n = 116 n = 61 n = 15
N % N % n % --
Keseluruhan kekambuhan 28 24,1 22 36,1 6 10,9 0.002*
Loco-regional 5 4,3 5 8,2 0 -- 0.059
Jauh 22 19,0 16 26,2 6 10.9 0.036*
OM 22 19,0 19 31,1 3 5.5 0.000*
DRM 19 16,4 16 26,2 3 5.4 0.003*
*
statistical significance.
OM, keseluruhan kematian.

Pengobatan Adjuvant

Berdasarkan protokol, pasien yang diobati dengan BCCA secara signifikan

menerima kemoterapi dan radioterapi lebih sering. Pasien yang diobati dengan
GOCS menerima radiasi adjuvant sebesar 70.5% dalam kasus (n=43), baik terapi
vaginal brachytherapy (VBT) (n=15), external beam radiotherapy (EBRT) (n=14)
maupun keduanya (n=14) dimana semua pasien yang diobati dengan BCCA
setidaknya menerima VBT. Mayoritas pasien (80%) menerima EBRT dan VBT.

Pasien di BCCA, 89.1% (n=49) sudah melengkapi setidaknya 3 siklus dari

carboplatin (area dibawa kurva 6) dan paclitaxel (175 mg/m). Empat wanita (7.3%)
menerima 4 siklus, salah satu wanita tersebut menerima tambahan siklus karena ia
menerima radioterapi dengan dosis yang lebih rendah dikarenakan operasi
sebelumnya untuk kanker rektal. Untuk sisa 3 pasien lagi, diberikan 4 siklus sebagai
acuan dalam 1 dari 5 peraturan di regio British Columbia. Satu pasien membatalkan
kemoterapi setelah 1 siklus dan pasien lainnya membatalkan kemoterapi setelah 2
siklus karena munculnya jerawat parah pada wajah akibat penggunaan prepaclitaxel
dexamethasone. Dua pasien (3.3%) pada kelompok GOCS menerima kemoterapi
adjuvant.

TABLE 3. Dampak kemoterapi ajuvan dan radioterapi pada

hasil pasien yang dikoreksi untuk usia (> 60) dan stadium
bedah dengan regresi logistik
OR P 95% CI
Kesekuruhan kekambuhan 0.276 0.017* 0.096-0.795*
Loco-regional ns Ns Ns
Jauh 0.424 0.125 0.141-1.270
OM 0.158 0.007* 0.041-0.608*
DRM 0.204 0.022* 0.052-0.793*
*
statistical significance.
95% CI, 95% interval kepercayaan; ns, not significant.
FIGURE 1. Kurva Kaplan- Meier dari 5 tahun perkembangan kelangsungan hidup
bebas terkait dengan jenis pengobatan adjuvant.

Hasil

Terdapat perbedaan yang signifikan dalam tingkat kekambuhan, mortalitas

keseluruhan, dan DRM antara 2 strategi pengobatan (Tabel 2). Pasien dengan
kemoterapi dan radioterapi ajuvan memiliki tingkat kekambuhan 0,9% dibandingkan
dengan 36,1% pasien yang diobati sesuai kriteria PORTEC dan tidak menerima
kemoterapi ajuvan. Sebagian besar kekambuhan jauh pada kedua kelompok
perlakuan, termasuk 16 (72,7%) dari 22 menerima radioterapi saja, dan 6 dari 6
menerima terapi kemoterapi dengan radiasi. Setelah koreksi untuk usia saat diagnosis
dan stadium bedah, kemoterapi ajuvan dan radioterapi menghasilkan tingkat DRM
kambuhan yang menurun (Tabel 3). Progression-free survival (PFS) terkait dengan
jenis perawatan adjuvant ditunjukkan pada Gambar I dan menggambarkan manfaat
kemoterapi tambahan dan radioterapi. Selain itu, kelangsungan hidup keseluruhan
ditingkatkan dengan kemoterapi dan radioterapi seperti yang ditunjukkan pada
Gambar 2. Tidak ada perbedaan yang signifikan dalam tingkat kekambuhan antara
pasien yang menjalani limfadenektomi (16,7%) dibandingkan dengan mereka yang
tidak memiliki prosedur ini (29,4% P = 0.114).
FIGURE 2. Kurva Kaplan-Meier dari 5 tahun kelangsungan hidup secara
keseluruhan terkait dengan jenis pengobatan adjuvant.
 DISKUSI

Dalam penelitian ini, ditunjukkan bahwa strategi pengobatan dengan aplikasi

rutin kemoterapi ajuvan dan radiasi panggul pada tahap awal, kanker endometrium
endometrioid tingkat tinggi lebih unggul daripada radioterapi ajuvan berdasarkan
patologi akhir. Mayoritas pasien yang merencanakan kemoterapi ajuvan
menyelesaikan setidaknya 3 siklus kemoterapi dan menerima radioterapi balok
eksternal dan brachytherapy vagina. Kekuatan penelitian ini adalah kenyataan bahwa
semua pasien berturut-turut yang dirawat di pusat rujukan disertakan, dan karenanya
data kami mencerminkan praktik klinis setiap hari. Hasilnya sesuai dengan penelitian
lain yang dipublikasikan yang melaporkan hasil perbaikan pada kanker endometrium
endometrioid tingkat tinggi dengan kemoterapi dan radioterapi ajuvan. Gadducci
dkk! "Yang ditunjukkan dalam penelitian retrospektif termasuk pasien dengan kanker
endometrium endometrioid stadium awal yang beresiko tinggi (FIGO IB / I1 dengan
invasi miometrium> 50%, nilai 2-3) mengurangi kekambuhan jauh dan / atau
paraaortik pada pasien yang Menerima kemoterapi ajuvan dan radioterapi (n = 3 7)
dibandingkan dengan mereka yang tidak (n = 152). Tidak satupun dari 29 pasien
yang menerima kemoterapi ajuvan dan radioterapi ajuvan menunjukkan
perkembangan kekambuhan lokal, dan hanya satu yang mengalami kekambuhan
jauh, yang menunjukkan bahwa sekuensial Kemoterapi ajuvan dan radioterapi
mungkin merupakan strategi pengobatan yang tepat pada pasien ini. Sebuah studi
percontohan prospektif termasuk 68 pasien dengan tahap FIGO IA grade 3, grade IB
2 sampai 3, dan II kanker endometrium menunjukkan efektivitas yang sama dari
kemoterapi adjuvant bila dibandingkan dengan radioterapi. Tidak satu pun dari
pasien ini menerima kedua perawatan adjuvant. Meskipun pentingnya radioterapi
ajuvan untuk pengendalian lokal telah ditunjukkan pada tahap pra Secara acak,
percobaan prospektif, kebanyakan penelitian mengecualikan pasien dengan tahap
FIGO TB dan histologi berisiko tinggi. Dalam sebuah penelitian yang baru-baru ini
diterbitkan, menunjukkan bahwa dalam risiko tinggi ini, pasien kanker endometrium
tahap awal (n = 51), radiasi panggul ajuvan dikaitkan dengan peningkatan kontrol
vagina, kontrol pelvis, dan kelangsungan hidup secara keseluruhan. Kemoterapi
ajuvan pada karsinoma endometrium yang berisiko tinggi telah dipelajari di beberapa
RCT, namun sebagian besar uji coba membandingkan kemoterapi kombinasi berbasis
platinum dengan radioterapi. Tinjauan sistematis Cochrane mencakup 5 RCT dan
menunjukkan keuntungan kelangsungan hidup secara signifikan secara keseluruhan
dari kemoterapi ajuvan (risiko relatif, 0,88; 95 % Confidence interval, 0,79-0,99),
dengan jumlah yang dibutuhkan untuk mengobati hasil tambahan tambahan 25.
Penulis menyimpulkan bahwa kemoterapi berbasis platinum pasca operasi dikaitkan
dengan manfaat kecil pada PFS dan kelangsungan hidup secara keseluruhan terlepas
dari perawatan radioterapi.
 Namun, perbedaan dalam komplikasi terkait pengobatan itu penting dan harus
dipertimbangkan saat pasien diberi konseling untuk pendekatan pengobatan yang
lebih agresif, terutama pada pasien lanjut usia. Seperti yang ditunjukkan dalam
rangkaian BCCA yang diterbitkan, mayoritas pasien tidak memiliki toksisitas yang
mengakibatkan perubahan pengobatan. Toksisitas kemoterapi terkait ada pada
18,2%, dan toksisitas terkait radioterapi 1,9%. Data ini sesuai dengan kemoterapi
yang dilaporkan morbiditas oleh Aloisa dkk. Juga, persentase efek toksik
gastrointestinal kelas 3 yang terkait dengan EBRT sesuai dengan data studi Portec-2.
Kekuatan penelitian ini adalah fakta bahwa 2 strategi pengobatan yang dibandingkan
di 2 pusat onkologi ginekologi terorganisir dengan baik. Meskipun demikian, bias
seleksi mungkin ada karena sifat retrospektif penelitian ini. Selain itu, tidak ada
tinjauan patologi sentral tentang histologi tumor. Kehadiran LVSI tidak dilaporkan
secara sistematis, dan walaupun kami tidak menemukan hubungan kekambuhan pada
kasus-kasus yang dapat dievaluasi LVSI di GOCS dan kelompok BCCA, jumlahnya
terlalu kecil untuk menarik kesimpulan yang kuat. Diskriminasi antara endometrioid
tingkat tinggi dan kanker endometrium serous mungkin menantang, bahkan dengan
spidol tambahan. Namun, kami tidak berpikir bahwa ini akan mempengaruhi hasil,
karena tingkat kekambuhan tahap awal karsinoma endometri tingkat tinggi serosa
dan bermutu tinggi sebanding, studi ini memang memiliki beberapa keterbatasan.
Karena jenis tumor dan kelompok risiko yang dipilih, ukuran populasi agak terbatas,
bahkan di pusat rujukan besar sepanjang waktu. Meskipun kita tidak mengamati
perbedaan tingkat kekambuhan menurut limfadenektomi yang dilakukan, karena
jumlah yang rendah, data harus diinterpretasikan dengan hati-hati. Secara historis,
karsinoma endometrium diobati dengan radioterapi pra operasi dan postoperatif,
namun sejauh ini tidak satu pun penelitian menunjukkan manfaat bertahan hidup dari
radioterapi pada karsinoma endometrium. Menarik untuk dicatat bahwa seiring
waktu penerapan kemoterapi pada kanker endometrium telah diadopsi oleh dokter
pada pasien dengan kanker endometrium berisiko tinggi seperti yang ditunjukkan
dalam kuesioner yang baru diterbitkan di antara anggota Society of Gynecologic
Oncologists dan didukung oleh data bahwa VBT saja tidak cukup pada pasien
dengan kanker endometrium berisiko tinggi. Meskipun data kami mendukung
pertimbangan kemoterapi ajuvan pada pasien kanker endometrium berisiko tinggi,
data harus dikonfirmasi dengan uji coba secara acak. Terutama, karena data awal dari
penelitian GOG 249, bahwa pasien dengan frekuensi tinggi, interrediasi tinggi dan
berisiko tinggi antara EBRT pelvis dan brachytherapy vagina yang diikuti dengan
kemoterapi (3 siklus carboplatin dan paclitaxel) tidak menunjukkan manfaat
sehubungan dengan PFS Kemoterapi adjuvan atas standar EBRT. Oleh karena itu,
kedua hasil akhir dari GOG 249 dan juga studi PORTEC III penting sebelum
mengubah praktik rutin.
 KESIMPULAN

Kami telah menunjukkan peningkatan yang signifikan dari penyakit yang

spesifik, dan kelangsungan hidup secara keseluruhan dengan aplikasi rutin dari
kemoterapi dan radioterapi adjuvan di tahap awal kanker endometrium tipe
endometrioid. Data ini merupakan nilai tambah bagi hasil percobaan acak
pengobatan adjuvant pada kanker endometrium berisiko tinggi.
 DAFTAR PUSTAKA

1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality

worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J
Cancer. 2015; 136:E359-E386Reynaers et al
2. Morice P, Leary A, Creutzberg C, et al. Endornetrial cancer.Lancet.2016; Sep
4. pii: S0140-6736(15)00130-0.
3. Van der Putten LJ, Geels YP, Ezendam NP, et al. Lymphovascular space invasion
and the treatment of stage I endornetrioid endometrial cancer. Int J Gynecol Cancer.
2015;25:75-80.
4. Alektiar KM, McKee A, Lin 0, et al. ls there a difference in outcome between
stage I-II endometrial cancer of papillary serous/clear cell and endometrioid
FIGO Grade 3 cancer? Int J Radiat Oneal Biol Phys. 2002;54:79-85.
5. Ayeni TA, Bakkum-Gamez JN, Mariani A, et al. Comparative outcomes
assessment of uterine grade 3 endometrioid, serous, and clear cell carcinomas.
Gynecol Oneal. 2013;129:478-485.
6. Reynaers EA, Ezendam NP, Pijnenborg JM. Comparable outcome between
endometrioid and non-endometrioid tumors in patients with early-stage high-
grade endometrial cancer. J Surg Oneal. 2015;1 J.J:790-794.
7. Fader AN, Santin AD, Gehrig PA. Early stage uterine serous carcinoma:
management updates and genomic advances. Gynecol Oneal. 2013;129:244-
250.
8. Kiess AP, Damast S, Makker V, et al. Five-year outcomes of adjuvant
carboplatin/paclitaxel chemotherapy and intravaginal radiation for stage I-11
papillary serous endometrial cancer. Gynecol Oneal. 2012;127:321-325.
9. Sagae S, Susumu N, Viswanathan AN, et al. Gynecologic Cancer InterGroup
(GCIG) consensus review for uterine serous carcinoma. Int J Gynecol Cancer.
20 l 4;24(9 Suppl 3):S83-S89.
10. de Boer SM, Powell ME, Mileshkin L, et al. Toxicity and quality of life after
adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk
endometrial cancer (PORTEC-3): an open-label, multicentre, randomised, phase 3
trial. Lancet Oneal. 2016;17:1114-1126.
11. Marcus Randall, Gynecologic Oncology Group. Pelvic Radiation Therapy or Vaginal
Implant Radiation Therapy, Paclitaxel, and Carboplatin in Treating Patients With
High-Risk Stage I or Stage II Endometrial Cancer. In: ClinicalTrials.gov [Internet].
Bethesda, MD: National Library of Medicine (US); 2000 [cited 2016 dee IO].
Available at: http://clinicaltrials.gov/show/NCT00807768NLM.Identifier:
NCT00807768.
12. Robbins JR, Gayar OH, Zaki M, et al. Impact of age-adjusted Charlson comorbidity
score on outcomes for patients with early-stage endometrial cancer. Gynecol Oneal.
2013; 131 :593-597.
13. Jutzi L, Hoskins P, Lim P,et al. The importance of adjuvant chemotherapy and pelvic
radiotherapy in high-risk early stage endometrial carcinoma. Gynecol Oneal. 2013;
131 :581-585.
14. Gadducci A, Cosio S, Landoni F, et al. Adjuvant treatment and analysis of failures in
patients with high-risk FIGO Stage lb-II endometrial cancer: an Italian multicenter
retrospective study (CTF study). Gynecol Oneal. 2014; 134:29-35.
15. Creasman W. Revised FIGO staging for carcinoma of the endometrium. Int J
Gynaecol Obstet. 2009; 105: I 09.
16. Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and postoperative
radiotherapy versus surgery alone for patients with stage-I endometrial carcinoma:
multicentre randomised trial. PORTEC Study Group. Post Operative Radiation
Therapy in Endometrial Carcinoma. Lancet. 2000;355:1404-1411.
17. Nout RA, Smit VT, Putter H, et al.Vaginal brachytherapy versus pelvic external
beam radiotherapy for patients with endometrial cancer of high-intermediate risk
(PORTEC-2): an open-label, non-inferiority, randomised trial. Lancet.
2010;375:816-823.
18. Aloisi A, Plotti F, Scaletta G, et al. Chemotherapy as adjuvant treatment for
intermediate-high risk early-stage endometrial cancer: a pilot study. Int J Gynecol
Cancer.2015;25:1418-1423.
19. Lee LJ, Bu P, Feltmate C, et al. Adjuvant chemotherapy with external beam
radiation therapy for high-grade, node-positive endometrial cancer. Int J Gynecol
Cancer. 2014;24: 1441-1448.
20. Keys HM, Roberts JA, Burnetto VL, et al. A phase III trial of surgery with or without
adjunctive external pelvic radiation therapy in intermediate risk endometrial
adenocarcinoma: a Gynecologic Oncology Group Study. Gynecol Oneal.
2004;92:744-751.
21. Ly D, Soisson PA, Dodson MK, et al. Adjuvant radiation therapy is associated with
improved pelvic control and overall survival in FIGO IB endometrial carcinoma with
high grade histology. Gynecol Oneal. 2015; 138:526-531.
22. Johnson N, Bryant A, Miles T, et al. Adjuvant chemotherapy for endometrial cancer
after hysterectomy.Cochrane Database SystRev. 201l:CD003175. doi:
I0.1002/14651858.CD003175.
23. Maggi R, Lissoni A, Spina F,et al.Adjuvant chemotherapy vs radiotherapy in high-
risk endometrial carcinoma: results of a randomised trial. Br J Cancer. 2006;95:266-
271.
24. Ahmed A, Zamba G,DeGeest K, et alThe impact of surgery on survival of elderly
women with endometrial cancer in the SEER program from 1992-2002. Gynecol
Oneal. 2008;111:35-40.
25. Bourgin C, Saidani M, Poupon C, et al. Endometrial cancer in elderly women:
which disease, which surgical management? A systematic review of the literature.
Eur J Surg Oneal. 2015. pii: S0748- 7983( 15)00834-3.
26. Gatius S, Matias-Guiu X. Practical issues in the diagnosis of serous carcinoma of the
endometrium. Mod Pathol. 20l6;29(Suppl I ):S45-S58.
27. Kong A, Johnson N, Kitchener HC, et al. Adjuvant radiotherapy for stage I
endometrial cancer.Cochrane Database Syst Rev.20l2:CD0039l6.
28. Starreveld AA, Shankowsky HA, Koch M. Canadian Association of Radiologists:
treatment results in 2719 patients with carcinoma of the endometrium 1973-'l977.
Can Assoc Radio/ J. 1987;38:96-105.
29. Eldredge-Hindy HB, Eastwick G, Anne PR, et al. Adjuvant vaginal
cuffbrachytherapy for high-risk, early stage endometrial cancer. J Con temp
Brachytherapy. 20 l 4;6:262-270.
30. Pereira EB, De B, Kolev V, et al. Survey of current practice patterns in the
treatment of early-stage endometrial cancer. Int J Gynecol Cancer. 2016;26:341-
347.
31. McMeekin OS, Filiaci VL, Aghajanian C, et al. A randomized phase III trial
of pelvic radiation therapy (PXRT) versus vaginal cuff brachytherapy followed
by paclitaxel/carboplatin chemotherapy (VCB/C) in patients with high risk (HR),
early stage endometrial cancer (EC): A Gynecologic Oncology Group trial.
Gynecol Oneal. 2014; 134:438. (abstract LBA 431).