Surgical Outcomes and Patterns of Recurrence in Endometrial Cancers

Abstract

Objectives:

There were two objectives: (1) to assess the survival outcome of endometrial cancer based on surgical and adjuvant treatment and (2) to note patterns of and risk factors for recurrence in endometrial cancer.

Design:

This was a retrospective analysis of the hospital records of women diagnosed with carcinoma of the endometrium who were operated on in the Division of Gynecologic Oncology, Christian Medical College, Vellore, India, from January 2011 to December 2013.

Materials and Methods:

Electronic patient records of 152 women with endometrioid endometrial cancer were obtained and used to analyze their surgical outcomes. Information regarding survival and recurrences was obtained by various methods. Survival was assessed by Kaplan–Meir survival analysis.

Results:

The tumors were endometrioid adenocarcinomas in 94.7% of the patients. The majority of the patients were stage IA (49.3%) and stage IB (22.3%). A few patients also had occult stage II (6.6%), and 21% had advanced stage cancer. Seventy-seven (50.7%) women needed adjuvant treatment after risk stratification, with 53.6% receiving radiation only as brachytherapy (35.6%), external pelvic radiation (13.5%), or a combination of both (50.9%); 15.9% received chemotherapy; and 30.4% had radiation and chemotherapy. The 3-year survival of endometrial cancers was 94.5% and disease-free survival was 91.4%. The rate for recurrence was 8.6% and for mortality 5.5%. Recurrences were equal in distribution for local and distant metastasis. Complications of surgical treatment were minimal.

Conclusions:

Endometrial cancers tend to present as early stage cancers in the majority of cases. Appropriate risk stratification and liberal use of chemotherapy when indicated may improve survival in high-risk cases. (J GYNECOL SURG 2017:1)

Introduction

Endometrial cancer is the most common gynecologic cancer among women in developed countries and the second most common in developing countries. It has an incidence of 5.9 per 100,000 and a mortality rate of 1.7 per 100,000.¹ Approximately 80% of newly diagnosed endometrial carcinomas are endometrioid in type.² Overall, the 5-year survival rates for all grades and histologic subtypes are ∼78%–90% for stage I, 74% for stage II, ∼36%–57% for stage III, and ∼20% for stage IV.³ Survival in patients with nonendometrioid tumors, such as clear-cell or papillary-serous cancers, is as low as 40%–50%. Management of endometrial cancer has evolved from simple hysterectomy with bilateral salpingo-oophorectomy, followed by pelvic and vaginal radiation based on clinical staging. This evolution has reached an individualized approach using hysterectomy with or without node dissection as a primary therapy and using additional postoperative adjuvant treatment, depending on surgical and pathologic findings. There has been a lot of debate about the extent of surgery to be performed, especially with regard to the lymph-node dissection and adjuvant therapy postsurgery. Although there are many studies on the significance of lymph-node dissection, the number of nodes to be removed, and the extent of dissection, literature is scarce on the Indian population.

The International Federation of Gynecology and Obstetrics (FIGO) staging of endometrial cancer and other gynecologic cancers was revised in 2009.^4,5 The Gynecologic Oncology Group (GOG) 99 trial reported different survival in different risk groups based on various prognostic factors such as age, myometrial invasion, grade of tumor, and lymph-vascular space invasion.⁶ In the current authors' institution (Christian Medical College, Vellore, India; CMC) gynecologic oncology became a super-specialty since 2011. Ever since that time, there has been strict adherence to guidelines, and comprehensive cancer surgeries are being performed. This study was undertaken to assess the surgical outcomes of endometrial cancer, the patterns and risk factors of recurrence in endometrial cancer, and to determine the complications of surgical treatment in a tertiary institution such the CMC.

Materials and Methods

Patients in the analysis

Patients diagnosed with carcinoma of the endometrium, who underwent surgical staging, from January 1, 2011, to December 31, 2013, were recruited in the study after ethical clearance from the CMC's institutional review board. Data regarding baseline characteristics, disease profiles, surgical outcomes, complications, biopsy details, and adjuvant treatment details were collected from the electronic records and supplemented with patients' letters and phone interviews. All endometrial cancers, operated on in the Gynaecologic Oncology Division of the CMC were included. Patients who underwent incomplete surgery elsewhere and came to the CMC for completion procedures, and whose initial operative details were not available, were excluded.

Outcome measures

Outcome measures included the use of blood and blood products, and complications of surgery, such as infections, hemorrhage, wound breakdown, and lymphocysts. Recurrence was diagnosed based on clinical and radiologic imaging. A local recurrence was defined as any disease confirmed by histopathologic examination at the vault region. Distant recurrence was defined as disease out of the pelvis as shown clinically or on imaging.

Disease-free survival (DFS) was defined as the period during which a patient was free of local or distant disease clinically and radiologically. Overall survival was assessed over 36 months. These survival data were correlated to disease stratification, adjuvant treatment, and prognostic factors.

Staging and procedures in the analysis

At the CMC, all patients were staged according to the 2009 FIGO criteria. The protocol followed for lymphadenectomy was a slight modification of the guidelines for surgical management of endometrial cancer from the Mayo Clinic.^7,8

As the CMC did not have a facility for examining intraoperative frozen sections, a decision for assessing tumor volume was based on naked-eye examination when cutting open a specimen.

Pelvic lymph-node dissection involved opening of the retroperitoneum and removing all fibrofatty tissues along the major pelvic vessels. The distal limit of the node dissection was up to the circumflex iliac vessels over the external iliac and the obturator nerve, leaving the pelvis at the obturator fossa. The upper limit was the common iliac nodes at the bifurcation of the common iliac arteries.

Para aortic-node dissection was performed up to the level of the inferior mesenteric artery.

Completion surgery (post hysterectomy) for patients operated on elsewhere was offered if there was deep myometrial invasion, or a grade 3 tumor, or if high-risk histology and ovaries had been retained. Baseline imaging was performed, followed by a restaging laparotomy that included peritoneal washings, and pelvic and para-aortic-node dissection as indicated.

Adjuvant treatment was offered per institutional guidelines following a discussion at a multidisciplinary meeting (Appendix 1). These guidelines were formulated per the National Comprehensive Cancer Network guidelines.

Patients were followed up once every 3 months for the first 2 years, then once every 6 months for 5 years.

Statistics

The data were analyzed using SPSS software (version 19). Statistical tests performed were the χ² test, Fisher's exact test, and Kaplan-Meier survival analysis. The degree of significance was set at p < 0.05. Linear regression was used to study the determinants of survival and recurrence.

Results

During the study period, a total of 162 women were operated on for endometrial cancer. Ten women whose operative details were not available were excluded from the study. The average age was 56 (range: 30–79) and the mean body mass index was 28.7 (range: 15.9–46). The majority of the patients presented with postmenopausal bleeding (77%). Premenopausal abnormal uterine bleeding and anovulatory cycles with metropathia were the other presenting complaints. Histories of infertility were noted in ∼13.2% of the patients. Medical comorbidities were seen in 71.9% of the patients, as most of them were older (Table 1). Histories of treatment for breast cancer and treatment with tamoxifen were seen in 11 (7%) women.

Table 1.

Demographic Details

Characteristic	n	%
Age (years)	56.72 ± 9.71	Range: 30–79
Mean BMI	28.69 ± 5.6	Range: 15.9–46
Infertility—yes	20	13.2
Parity
Nulli	29	19.1
Multi	123	80.9
Perimenopausal AUB	25	16.4
Postmenopausal bleeding	117	77.0
Others	10	6.6
Family history of gynecologic malignancies	9	5.9
Medical comorbidities	108	71.9
Other malignancies (breast, ovary)	15	9.9
Mean CA-125 IU/mL (baseline)	45.62 ± 114.2	—
Mean endometrial thickness mm (TVS)	21.57 ± 11.6	Range: (4–45 mm)

BMI, body mass index; AUB, abnormal uterine bleeding; IU, international units; TVS, transvaginal ultrasound.

In this series, the preoperative histology was endometrioid in 94.7%, and most were grade 1 tumors (72.2%). Postoperative biopsies revealed endometrioid histology in 88.8% and grade 1 differentiation in 57.9%.

Most of the women underwent complete surgical staging as indicated by the institutional protocol. A few of them (15 [9.9%]) had undergone simple hysterectomy as they had had early stage (< IA) disease. Thirteen of them had undergone other procedures, which included completion surgeries (10) and radical hysterectomies (3) (Table 2).

Table 2.

Operative Details

Surgical details	n	%
Surgery
TAH & BSO	15	9.8
TAH, BSO & PLND	94	61.8
TAH, BSO, PLND & PAND	26	17.1
LAVH & BSO	2	1.3
VH	2	1.3
Other	13	8.5
Anesthesia
General	41	27
Epidural	111	73
Incision
Transverse	27	17.8
Midline	122	80.3
Vaginal	3	2.0

TAH, total abdominal hysterectomy; BSO, bilateral salpingo-oophorectomy; PLND, pelvic lymph-node dissection; PAND, para-aortic node dissection; LAVH, laparoscopic vaginal hysterectomy; VH, vaginal hysterectomy.

Pelvic lymphadenectomy, as indicated by the CMC institutional protocol, was performed in 126 of the 152 patients, with a mean count of 13 nodes. Sixteen (13%) of these patients had pelvic-node metastatic disease. Thirty-two patients underwent para-aortic node dissection, with an average node count of 10 with metastasis in 8 (28%). Omentectomy was performed in 29 (19%) of the patients when indicated. In some patients with serious comorbidities, laparoscopic hysterectomy or vaginal hysterectomy was performed. More than 80% of the series patients underwent surgical staging by a midline incision under general anesthesia and epidural anesthesia (73.3%).

Considering the fact that majority of the patients underwent surgical staging by laparotomy involving a longer operating time and large incisions, as well as the prevalence of a high incidence of diabetes, the complication rate in this series was ∼28% (43/152 patients; Table 3).

Table 3.

Complications and Other Postoperative Problems

Complication/problem	n = 43	%
Wound breakdown	5	3
Use of blood & blood products	4	3
Sepsis & fever in postoperative period	2	1
Urinary-tract infection	4	3
Vessel injury	4	3
Pulmonary edema/embolism	3	2
Postoperative ileus/intestinal obstruction	6	4
DVT	2	1
Incisional hernia	2	1
Miscellaneous	4	3
Admission to ICU/HDU (2–7 days)	7	5

DVT, deep vein thrombosis; ICU, intensive care unit, HDU, high-dependency unit.

Approximately two-thirds of the tumors were >2 cm (67.1%) and predominantly endometrioid (88.2%). In a few patients, the tumors were high grade (12.5%). The nonendometrioid tumors were 11.8% comprising serous (4), clear-cell (1) and mixed (3) type tumors. Lymph-vascular space invasion (LSVI) was seen in 41 (27.0%) patients, with deep myometrial invasion in 56 (36.8%) of them (Table 4).

Table 4.

Postoperative Biopsy Details

Tumor characteristics	N = 152	%
Tumor size
<2 cm	50	32.9
>2 cm	102	67.1
Biopsy
Endometrioid	135	88.8
Nonendometrioid	17	11.2
Grade
G1	88	57.9
G2	45	29.6
G3	19	12.5
LVSI
Positive	41	27.0
Negative	98	64.5
Not mentioned	13	8.5
Myometrial invasion
<50%	91	59.9
>50%	56	36.8
Not done	5	3.3
PLND
Done	126	82.9
Not done	26	17.2
PLND—# of nodes (average)	14
Positive pelvic nodes (# of cases)	16
PAND
Done	32	21.1
Not done	119	78.3
PAND—# of nodes (average)	9
Positive para-aortic nodes (# of cases)	8
Parametrium—positive	6	3.9
Peritoneal cytology—positive	9	5.9

LVSI, lymph-vascular space invasion; PLND, pelvic lymph-node dissection; PAND, para-aortic node dissection.

The majority of the patients in this series had stage IA and stage IB (71.7%) disease. A few of these patients also had occult stage II (6.6%) disease. Approximately 21% had an advanced stage of disease beyond stage III (Table 5).

Table 5.

Stage of the Disease

Stage	n	%
IA	75	49.3
IB	34	22.4
II	10	6.6
III A	5	3.3
IIIB	3	2.0
IIIC1	11	7.2
IIIC2	6	3.9
IVA	5	3.3
IVB	3	2.0

The final histopathology of these patients was discussed at a multidisciplinary team meeting, and decisions on adjuvant treatment were made. Of the 75 (49.3%) patients with stage IA disease in this study group, 73 patients had grade 1 or 2 tumors and, hence, did not receive adjuvant treatment (Table 6). Of the remaining 77 patients who needed adjuvant treatment, 69 (90%) underwent adjuvant treatment in some form. Thirty-seven had only radiation, 11 had only chemotherapy, and 22 had a combination of both chemotherapy and radiation. Of the 59 (86%) patients who underwent radiation in some form, vaginal brachytherapy alone was administered in 21 patients, pelvic radiation in 8, and a combination of both in 30. Vaginal brachytherapy was delivered at ∼1-month postsurgery, using a vaginal mold to help deliver high dose-rate fractions of 6–8 Gy. Pelvic radiation was either by conventional or intensity-modulated radiation therapy of 50 Gy in 25 fractions. In more than half (30/59) of the patients, a combination of pelvic radiation followed by vaginal radiation was administered.

Table 6.

Adjuvant Therapy

Therapy (n)	N = 152	%
Adjuvant treatment given	69	45.4
Radiation (59)
Vaginal	21	36
Abdominal	8	14
Vaginal + abdominal	30	51
Chemotherapy (33)
Carboplatin	3	9
Cisplatin	1	3
Paclitaxel+ carboplatin	22	67
Others	7	21
Combination of chemotherapy and radiation	22	32

In some patients, when indicated, chemotherapy was offered as adjuvant therapy (33). Four cycles of a combination of paclitaxel and carboplatin were given after sutures were removed in more than two-thirds of patients who received chemotherapy. In a few situations when there was taxane sensitivity, single-agent platinum drugs were chosen.

Adjuvant treatment was assessed by risk stratification in the treatment of the endometrioid tumors (135). Eighty-three women were found to be in the low/low–intermediate risk group, 25 in the high–intermediate risk group, and 27 in the high-risk group. The adjuvant treatment of these groups is shown in Table 7. A few of these women were also offered chemotherapy in addition to the radiation, especially when they had high-risk features such as positive peritoneal cytology, LVSI, and node positivity.

Table 7.

Adjuvant Treatment for Endometrioid Endometrial Cancers (n = 76/135)

Risk group	Total numbers (n)	No treatment	Vaginal n = 19 (%)	EBRT n = 8 (%)	Vaginal + EBRT n = 33 (%)	Chemotherapy n = 16 (%)
Low/low IR	83	56	14 (73.5)	2 (25)	6 (18.1)	5 (31.25)
High IR	25	3	3 (15.8)	2 (25)	12 (36.4)	5 (31.25)
High	27	0	2 (10.5)	4 (50)	15 (45.5)	6 (37.5)

EBRT, external beam radiation therapy; IR, intermediate risk.

There were 15 recurrences (Table 8) overall with disease-free survival of 4–48 months and recurrence rates of 9.8%. Five recurrences were in the nonendometrioid group (17), whereas there were 10 (7.4%) recurrences in the endometrioid (135) tumor group (Figs. 1 –4). Eight of the 10 recurrences in the endometrioid group were stage IB where there was deep myometrial invasion. Metastasis was a combination of distant and local in 12 of the patients, whereas 3 patients had only distant recurrences. The sites of recurrences were predominantly in the para-aortic nodes (12), abdomen (3), omentum and inguinal nodes (1), and umbilical nodule (1). Eight patients succumbed to the disease over the follow-up period of 36 months, with an overall survival of 94.7% (Table 8).

FIG. 1.

Disease free survival—91.4%.

FIG. 2.

Overall survival—94.7%.

FIG. 3.

Disease-free survival in endometrioid endometrial cancer.

FIG. 4.

Overall survival in endometrioid endometrial cancer.

Table 8.

Recurrences and Deaths

Outcome	N = 152	%
Recurrence	15	9.8
Death	8	5.3

An attempt was made to examine various factors that could have possibly affected survival (Table 9). A logistic regression was computed for all of these factors. Risk factors of deep myometrial invasion, higher grade of tumor (G3), parametrium being positive, and adjuvant treatment were significant for DFS on univariate analysis. However, an adjusted analysis was not statistically significant for these factors. Similarly, for overall survival, only infertility and higher grade of tumor (G3) were significant on univariate, and no factors were significant after adjusting for each other on multivariate analysis.

Table 9.

Risk Factor Analysis

	Disease-free survival		Overall survival
Risk factor	OR (95% CI)	p-Value	OR (95% CI)	p-Value
Age	0.96 (0.90–1.01)	0.122	0.97 (0.90–1.04)	0.397
Infertility
Yes	3.42(0.94–12.39)	0.061	4.48 (0.98–20.46)	0.053
No(R)	1		1
LVSI
Yes	3.19(0.92–11.12)	0.069	1.21 (0.21–6.85)	0.833
No(R)	1		1
Myometrial invasion
Yes	0.24 (0.06–0.97)	0.044	0.60 (0.12–3.09)	0.544
No(R)	1		1
Grade
G1(R)	1		1
G2	2.05 (0.49–8.6)	0.327	3.07 (0.49–19.09)	0.229
G3	7.50 (1.70–31.38)	0.006	8.06 (1.25–52.16)	0.028
Tumor size in cm
≤2(R)	1	0.075	1	0.627
>2	6.53 (0.83–51.75)		0.667 (0.13–3.43)
Parametrium positivity
Yes	13.40 (2.39–75.17)	0.003	0.256 (0.026–2.49)	0.240
No(R)	1		1
Adjuvant treatment
Yes	16.84 (2.13–133.22)	0.007	1.44 (0.33–6.29)	0.622
No(R)	1

(R) in Table 9 denotes the least risk.

OR, odds ratio; CI: confidence interval, LVSI, lymph-vascular space invasion.

Discussion

Endometrial cancer is one of three commonly occurring gynecologic malignancies. On average these cancers comprise ∼30%–40% of gynecologic cancers that are operated at the CMC. The retrospective analysis of surgical outcomes from this tertiary hospital emphasizes the importance of comprehensive surgical staging and adherence to protocols based on which treatments need to be carried out to result in better outcomes. Endometrial cancer is a disease that occurs primarily in postmenopausal women, and the prognosis worsens with advancing age, as the nature of disease changes in that age group. The role of estrogen in the development of most endometrial cancers has been established clearly. Any factor that increases exposure to unopposed estrogen increases the risk for endometrial cancer. With the rise in the rates of the obesity epidemic, an increasing number of younger girls tend to develop anovulatory cycles, leading to longer durations and higher incidences of estrogen exposure. In the study group of 152 patients, there were ∼10 women under age 40. Most of these women had histories of anovulation and infertility, and the number of affected patients is increasing. Patients having tamoxifen prophylaxis for carcinoma of the breast need adequate surveillance. Histories of treatment for breast cancer and treatment with tamoxifen were seen in 11 (7%) of the study women.

Preoperative evaluation for the grade, size of tumor, and extent of disease is important in guiding surgeons to decide the extent of surgery. Ultrasound examination was performed routinely for all of the study patients, per the CMC institutional protocol. The surgeries were all performed by the surgeons in the CMC's Gynaecologic Oncology Division, who had adequate training in comprehensive surgery and lymphadenectomy.

Surgery for endometrial cancer has undergone significant advances. Many studies have proven that the minimally invasive route of surgery, whether laparoscopic or robotic, has a favorable outcome with regard to survival, lymph nodes, and fewer complications. The only drawbacks of minimally invasive surgeries are the costs involved and the operating times.⁹ A Cochrane meta-analysis recently concluded that there is evidence to support the role of laparoscopy for the management of early endometrial cancer. For presumed early stage primary endometrioid adenocarcinoma of the endometrium, laparoscopy was associated with similar overall and DFS. Laparoscopy was associated with reduced operative morbidity and hospital stay. There was no significant difference in severe postoperative morbidity between the two modalities.¹⁰ In countries like ours, where gynecologic oncology as a specialty is in its early phase of development, comprehensive open surgery with appropriate and adequate lymphadenectomy, when indicated, is the need of the current time.

In this group of study, patients' open surgery was performed in >95% of the cases. Pelvic and para-aortic dissection was performed, based on per operative characteristics of the tumors.

Complications of the open procedure and lymphadenectomy were commonly occurring problems and were similar to statistics quoted by other researchers.¹¹ The most common serious complications were postoperative ileus and delayed bowel recovery. The other serious adverse events, such as vascular, bowel, and bladder injuries, occurred in smaller numbers.

Following risk stratification for adjuvant therapy enabled many of the patients to receive the appropriate adjuvant therapy as indicated. The current authors did observe, from this retrospective analysis, that some women in the low/low–intermediate risk group received adjuvant treatment mainly in settings where they had single high-risk features such as LVSI or high-grade tumors. Several studies conducted elsewhere in other populations showed that use of chemotherapy lowered the risk of distant metastasis but did not improve overall survival in the study populations.^12–14 Despite these results, chemotherapy in patients with any high-risk factors—even those that fell into the intermediate risk group—was routinely practiced in the CMC—and this stood out as a single significant protective factor for prevention of recurrences (p < 0.001) and better survival (p < 0.04). In this series, as in the abovementioned studies, the recurrences were predominantly at distant locations especially in the nodes. Even in the low intermediate–risk group whom did not receive chemotherapy, there were local as well as distant recurrences, despite receiving pelvic radiation and vaginal brachytherapy.

With the advent of newer radiation techniques resulting in better delivery of doses to tumors and unaddressed para-aortic nodes, recurrences could be reduced. Some researchers are also evaluating the possibility of chemoradiation, as is performed for patients with cervical cancer, and its role in improving overall survival. The biology of a tumor, its behavioral pattern, and the outcome may vary with race and ethnicity; thus, suggesting the concepts of genetics, unique molecular markers, and personalized medicine.

The limitations of this study were that it was a retrospective study and some follow-up details were not obtainable. The follow-up of patients and their compliance with further treatments were not satisfactory. It is probable that the results could have been different if the follow-up had been extended up to 5 years.

Conclusions

Comprehensive surgery involving pelvic lymph nodes and para-aortic node dissection where indicated, followed by adequate adjuvant therapy, can result in better survival in early stage endometrioid cancer. Open surgery, if performed by trained surgeons, could result in outcomes as good as minimally invasive surgery in settings where facilities are not available for laparoscopy or robotics. The focus should be on adequate training in surgical skills in such situations and referral to gynecologic oncology set-ups.

Footnotes

Acknowledgments

The authors acknowledge the services of Ms. Elizabeth L. Gracy, MA, the social worker in the team who helped establish contact with the patients. Thanks are also extended to the Christian Medical College for permitting this study.

This study was funded by an internal institutional grant (IRB 8726 dated 06/03/14).

Author Disclosure Statement

None of the authors has any financial interests or conflicts in connection with this article.

Appendix 1. Surgical Protocols

PROTOCOL FOR ADJUVANT THERAPY IN ENDOMETRIAL CANCER A) Type I Cancers, Completely Staged

Stage I A, G1 / G2, No risk factors	Observe
Stage I A G3, No risk factors	VBT^*
Stage I A (Inv <50%), Any grade, risk factors
Stage I B, Any grade, No risk factors
Stage I B G1/G2, Risk factors
Stage II G1/G2	VBT^* + Pelvic RT^**
Stage I B G3, Risk factors	VBT^* + Chemo + Pelvic RT^**
Stage II G3
Stage III, IV

VBT, vaginal brachytherapy

Pelvic RT, radiotherapy

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