Practice guidelines for management of uterine corpus cancer in Korea: a Korean Society of Gynecologic Oncology Consensus Statement

Clinical practice guidelines for gynecologic cancers have been developed by many organizations. Although these guidelines have much in common in terms of the practice of standard of care for uterine corpus cancer, practice guidelines that reflect the characteristics of patients and healthcare and insurance systems are needed for each country. The Korean Society of Gynecologic Oncology (KSGO) published the first edition of practice guidelines for gynecologic cancer treatment in late 2006; the second edition was released in July 2010 as an evidence-based recommendation. The Guidelines Revision Committee was established in 2015 and decided to produce the third edition of the guidelines as an

# Introduction
Uterine corpus cancer is a general term for cancer that occurs in the uterus, excluding cervical cancer. Uterine corpus cancer is histopathologically classified into endometrial cancer and uterine sarcoma; however, endometrial cancer is the most common and uterine sarcoma is rare, accounting for 2%-6% of uterine corpus cancer cases [bib_ref] The epidemiology of sarcomas of the uterus, Harlow [/bib_ref]. In Korea, although the incidence of uterine cancer is low in comparison with that in western countries [bib_ref] Estimates of the worldwide incidence of 25 major cancers in 1990, Parkin [/bib_ref] , it has been steadily increasing recently. In data from the Korea Central Cancer Registry, the incidence of endometrial cancer demonstrated the rapid increase, since 1999 (619 cases in 1999) and 2010 (1,616 cases in 2010) [bib_ref] Incidence of cervical, endometrial, and ovarian cancer in Korea, Lim [/bib_ref]. Since most of the patients are diagnosed at an early-stage, endometrial cancer has a good prognosis. However, in some patients with high risk factors for recurrence of early-stage endometrial cancer and in approximately 20% of patients diagnosed at an advanced stage, various adjuvant therapies after surgery have been suggested. Therefore, standardized practice guidelines are required in the clinical setting. Because uterine sarcoma is less responsive to several different treatments and because of the difficulty of diagnosis before surgery and the rapid progression, the prognosis is very poor. In addition, owing to its relatively low incidence, it has been difficult to develop effective practice guidelines through various clinical trials.
The purpose of these practice guidelines is to establish standard policies on clinical issues related to the diagnosis and treatment of uterine corpus cancer on the basis of the research results published to date and the consensus of experts.

# Materials and methods
The Korean Society of Gynecologic Oncology (KSGO) has revised the previously published practice guidelines for management of gynecologic cancer. The first edition of the practice guidelines for gynecologic cancer treatment was published in late 2006 and the second was released in July 2010 as an evidence-based recommendation. In 2015, the Guidelines Revision Committee, which was established within the KSGO, decided to produce the third edition of the guidelines. In doing so, they: 1) considered the rapidly advancing developments in precision medicines and analyzed and applied the results of up-to-date clinical trials, including target therapies; 2) accepted and included the recently revised World Health Organization histological classification; and 3) applied, as evidence, the data obtained from a number of Korean studies of gynecologic cancer surgery.
These guidelines were designed according to the principles of evidence-based medicine, which is the international standard method for building clinical practice guidelines. These guidelines went through a process of: 1) selecting key questions; 2) searching for evidence; 3) evaluating the level of evidence and determining the grade of recommendation; 4) deduction of the agreements; and 5) review and approval. Key questions were selected through discussion among the members of the uterine corpus cancer team after analysis of previous recommendations, consensus for revision, and confirmation of the recent significant reports. Data and literature published before 2015 in Korea and overseas were searched using Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, and EMBASE, and then a meta-analysis and systematic literature review were conducted. The collected evidence was evaluated for quality using Cochrane methodology for randomized controlled trials, the Newcastle-Ottawa Scale for nonrandom studies, and the quality assessment of studies of diagnostic accuracy included in systematic reviews (QUADAS-2) for diagnosis research. The level of evidence was divided into four categories using the methodology suggested by the grade group based on the research design, consistency among the research results, immediacy of the research subject and intervention, possibility of publishing bias, and accuracy of the research results . The grade of recommendation was decided by the methodology suggested by the grade group based on the level of evidence, considering the application subject, hazard and benefit, social and individual cost of the intervention, and patients' preference. The grades of recommendation were divided into strong recommendation and weak recommendation. The draft form and grades of recommendation were established through consultation that included all members of the revision committee. Guidelines development process in accordance with evidence-based medicine was summarized in Supplementary 1.
After debates in a public hearing with all members of the KSGO and invited representatives of related academies, a draft version of the guidelines was evaluated and supplemented. For an internal and external review, the 

## Clinical considerations and recommendations

## Endometrial carcinoma

## 1) screening and diagnosis
Most patients with endometrial cancer represent symptoms from the initial stage of the disease; common clinical profiles are vaginal bleeding in postmenopausal women and excessive menstrual bleeding or irregular spotting in premenopausal women. If endometrial cancer is suspected, it is necessary to identify the risk factors of infertility, ovulation status, the presence of obesity or diabetes, the use of estrogen or tamoxifen, and genetic factors and to conduct fundamental tests, followed by endometrial biopsy, to confirm the diagnosis. Endometrial curettage (dilatation and curettage) is a standardized test, but an endometrial sampling method has recently been reported with equivalent accuracy [bib_ref] The accuracy of endometrial sampling in the diagnosis of patients with endometrial..., Dijkhuizen [/bib_ref] [bib_ref] The evaluation of abnormal uterine bleeding, Hatasaka [/bib_ref]. Ultrasonography is commonly used because of the advantage of noninvasiveness. If clinically indicated, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) scans can be performed for preoperative clinical staging and planning for treatment. Although the tumor marker cancer antigen 125 (CA-125) has been reported to reflect the myometrial invasion and lymph node metastasis [bib_ref] Can a preoperative CA 125 level be a criterion for full pelvic..., Hsieh [/bib_ref] [bib_ref] Use of preoperative serum CA-125 levels for prediction of lymph node metastasis..., Chung [/bib_ref] , it has not yet been established as a standard diagnostic tool.

## 2) primary treatment
(1) Primary treatment for early endometrial cancer The standard surgical treatment for early-stage (stage I and II) endometrial cancer is total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) with or without lymphadenectomy. Peritoneal cytology should be considered for its prognostic value, although it is no longer a precondition for surgical staging. Definitive radiation therapy (RT) can be performed primarily for patients not suitable for standard surgical treatment due to medical problems.
Lymphadenectomy is an essential in the comprehensive surgical staging procedure for endometrial cancer. However, in early-stage endometrial cancer, the importance of lymphadenectomy is unclear because the survival benefit is still debated [bib_ref] Adenocarcinoma of the endometrium: survival comparisons of patients with and without pelvic..., Kilgore [/bib_ref] [bib_ref] Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a..., Astec Study Groupkitchener [/bib_ref] [bib_ref] Role of wide/radical hysterectomy and pelvic lymph node dissection in endometrial cancer..., Mariani [/bib_ref]. Indeed, in recently published studies, there were no differences in survival among patients with endometrial cancer who underwent lymphadenectomy and those who did not [bib_ref] Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a..., Astec Study Groupkitchener [/bib_ref] [bib_ref] Role of wide/radical hysterectomy and pelvic lymph node dissection in endometrial cancer..., Mariani [/bib_ref]. In contrast, a number of studies, including a large-scale retrospective cohort study published in 2010, reported therapeutic benefits of pelvic lymph node dissection (LND) and aortic lymphadenectomy [bib_ref] Adenocarcinoma of the endometrium: survival comparisons of patients with and without pelvic..., Kilgore [/bib_ref] [bib_ref] Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a..., Astec Study Groupkitchener [/bib_ref] [bib_ref] Role of wide/radical hysterectomy and pelvic lymph node dissection in endometrial cancer..., Mariani [/bib_ref]. According to a recent studies from Korea, a preoperative prediction model for lymph node metastasis was established from CA-125 levels and preoperative MRI findings including myometrial invasion, extension beyond the corpus, and enlarged lymph nodes [bib_ref] Preoperative identification of a low-risk group for lymph node metastasis in endometrial..., Kang [/bib_ref] [bib_ref] Prediction of lymph node metastasis in patients with apparent early endometrial cancer, Son [/bib_ref]. In addition, the volume index and myometrial invasion on preoperative MRI were indicated as predictive factors for identifying lymph node metastasis in endometrial cancer [bib_ref] Clinical significance of tumor volume in endometrial cancer: a Japan-Korea cooperative study, Todo [/bib_ref]. Therefore, we recommend a lymphadenectomy is an important section of the comprehensive surgical staging of endometrial cancer. However, pelvic lymphadenectomy may be omitted in patients who are predicted to have a very low risk of lymph node metastasis and, in some cases, who show a low-grade tumor of the endometrioid histologic type that is confined to the endometrium or invading only the superficial myometrium. An open laparotomy was the traditional way in surgical staging for endometrial cancer.
In recent randomized controlled trials comparing laparoscopic surgery and open surgery, good results of laparoscopic surgery have been reported in endometrial cancer [bib_ref] Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive..., Walker [/bib_ref] [bib_ref] Comparison of laparoscopy and laparotomy for management of endometrial carcinoma: a prospective..., Lu [/bib_ref] [bib_ref] Total laparoscopic hysterectomy versus abdominal hysterectomy with lymphadenectomy for early-stage endometrial cancer:..., Malzoni [/bib_ref] [bib_ref] Laparoscopic surgery vs laparotomy for early stage endometrial cancer: long-term data of..., Zullo [/bib_ref] [bib_ref] Laparoscopy versus laparotomy in endometrial cancer: first analysis of survival of a..., Tozzi [/bib_ref]. The results of laparoscopy or laparotomy for surgical staging were analyzed in the Gynecologic Oncology Group (GOG) LAP2 study which allocated 2,616 women with randomly 2:1 fashion [bib_ref] Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive..., Walker [/bib_ref]. The rate of moderate-to-severe postoperative adverse events was lower in laparoscopy than in laparotomy (14% vs. 21%; p<0.001) and intraoperative complications were similar. Although the operative time was longer in laparoscopic surgery, the length of hospital stay was significantly shorter in the laparoscopy group; especially the incidence of more than 2 days hospitalization was significantly less compared with laparotomy (52% vs. 94%; p<0.001). The 5-year overall survival (OS) rate was almost the same in both groups at 89.8%. In five randomized controlled trials [bib_ref] Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive..., Walker [/bib_ref] [bib_ref] Comparison of laparoscopy and laparotomy for management of endometrial carcinoma: a prospective..., Lu [/bib_ref] [bib_ref] Total laparoscopic hysterectomy versus abdominal hysterectomy with lymphadenectomy for early-stage endometrial cancer:..., Malzoni [/bib_ref] [bib_ref] Laparoscopic surgery vs laparotomy for early stage endometrial cancer: long-term data of..., Zullo [/bib_ref] [bib_ref] Laparoscopy versus laparotomy in endometrial cancer: first analysis of survival of a..., Tozzi [/bib_ref] , the 5-year OS rate was not different between laparoscopy and laparotomy. In the meta-analysis of 5-year OS from these five randomized trials, a survival difference was not shown according to the surgical approaches (risk ratio [RR], 1.00; 95% confidence interval [CI], 0.83-1.21). In a review article, laparoscopy was evaluated as a reasonable method to surgically treat patients with early-stage uterine cancer [bib_ref] Surgical treatment for apparent early stage endometrial cancer, Sonoda [/bib_ref].

## Recommendation:
Laparoscopic staging surgery is recommended for the surgical staging of early-stage endometrial cancer. Level of evidence: A (high). Strength of recommendation: 1 (strong). Consensus: 88.9% (16) yes, 11.1% (2) abstain (18 voters).
KQ 02. Does ovarian preservation affect survival in patients with early-stage endometrial cancer?
BSO has been routinely performed with hysterectomy in the surgical management of patients with endometrial cancer. This practice is performed because it is possible that the ovaries may have occult metastatic lesions, and that estrogen produced by the ovaries might increase the recurrence rate. Endometrial cancer has been rapidly increasing recently, especially in young women. In premenopausal endometrial cancer patients who want to keep the ovarian function, ovarian preservation can be considered at the time of hysterectomy. In a retrospective Korean study, investigators examined 176 premenopausal women with stage I-II endometrial cancer who did not undergo BSO, comparing them to 319 premenopausal women who underwent BSO [bib_ref] Outcomes of ovarian preservation in a cohort of premenopausal women with early-stage..., Lee [/bib_ref]. There was no difference in recurrence-free survival (p=0.742) or OS (p=0.462). The 5-year OS was 94.5% for those who had ovarian preservation compared with 97.8% for patients who underwent BSO. In addition, the 10-year OS was 94.5% for those who had ovarian preservation compared with 91.3% for patients who underwent BSO. The ovarian preservation for women 45 years of age with stage I endometrial cancer was safe and did not increase cancer-related mortality from Surveillance, Epidemiology, and End Results (SEER) database [bib_ref] Safety of ovarian preservation in premenopausal women with endometrial cancer, Wright [/bib_ref]. Our meta-analysis of three studies [bib_ref] Outcomes of ovarian preservation in a cohort of premenopausal women with early-stage..., Lee [/bib_ref] [bib_ref] Safety of ovarian preservation in premenopausal women with endometrial cancer, Wright [/bib_ref] [bib_ref] Safety of ovarian preservation in young patients with early-stage endometrial cancer: a..., Sun [/bib_ref] , including the results of another retrospective study, did not show a survival difference between ovarian preservation and BSO in earlystage endometrial cancer (hazard ratio [HR], 0.83; 95% CI, 0.47-1.47).
Recommendation: Ovarian preservation is recommended at the time of hysterectomy for young women with early-stage endometrial cancer that is confined to the uterus without evidence of extrauterine spread. Level of evidence: C (low). Strength of recommendation: 2 (weak). Consensus: 100% yes (20 voters).
KQ 03. Is progestin therapy for fertility-sparing treatment effective for young women with earlystage endometrial cancer?
Although hysterectomy is a highly effective and definitive management, it also causes a permanent loss of fertility in young women of childbearing age. Conservative management of endometrial cancer consists of a medical treatment based on oral progestins instead of hysterectomy. Patients who are considering fertility-sparing treatment should be precisely evaluated to detect advanced or high-risk disease before deciding on treatment. The most commonly used progestins are medroxyprogesterone acetate (MPA) and megestrol acetate [bib_ref] Fertility-sparing therapy in young women with endometrial cancer: 2010 update, Erkanli [/bib_ref]. A Korean study revealed that fertility-sparing management using oral progestins was highly effective and safe in 148 patients (age 40 years) with stage IA, grade 1, endometrioid adenocarcinoma [bib_ref] Long-term oncologic outcomes after fertilitysparing management using oral progestin for young women..., Park [/bib_ref]. The 5-year recurrence-free survival was 68% (95% CI, 58.5-76.9); however, 33 patients (22.3%) did not achieve a complete response and underwent definitive surgery. In a phase II prospective study, the medical treatment with oral MPA for 26 weeks was performed for 28 women less than 40 years of age who had either presumed stage IA endometrial cancer or endometrial intraepithelial neoplasia [bib_ref] Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial..., Ushijima [/bib_ref]. Although the complete response rate was 67% and 12 pregnancies and 7 deliveries were achieved after MPA therapy, 47% of those who accomplished a complete response subsequently experienced a recurrence during the 3-year follow-up period. The recurrence rate after a complete response was similar at 50.0% in a recent retrospective study in 37 patients with grade 1 endometrioid endometrial carcinoma at presumed stage IA who underwent fertility-sparing treatment of megestrol acetate (160 mg/day) .
Patients considering fertility-sparing treatment should be carefully counseled considering that data on cancer progression and pregnancy outcomes are limited. Investigators should explain the option of surgical management, including hysterectomy after the completion of childbearing or if conservative treatments are judged to be ineffective or lesion progression occurs through the entire consultation. MPA, megestrol acetate, or an intrauterine system including levonorgestrel can be considered in progestin-based therapy [bib_ref] Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia..., Gunderson [/bib_ref] [bib_ref] Management of endometrial precancers, Trimble [/bib_ref]. Although there are various methods and durations of treatment, a repeat endometrial biopsy should be performed every 3-6 months during progestin therapy and surgery, including hysterectomy, should be recommended if patients do not respond to conservative treatment 6-9 months later. (2) Primary treatment for advanced endometrial cancer Comprehensive staging, including TAH, BSO, pelvic/para-aortic lymphadenectomy, peritoneal cytology, and debulking surgery, followed by adjuvant therapy, should be performed in advanced endometrial cancer. If deemed optimal and cytoreductive surgery is not possible, RT could be selected as an initial management, followed by surgery or chemotherapy.

## Recommendation
(3) Primary treatment for papillary serous adenocarcinoma/clear cell carcinoma/ carcinosarcoma Patients with uterine papillary serous, clear cell carcinoma or carcinosarcoma have a worse prognosis than those with endometrioid-type carcinoma and have a tendency to show advanced disease at diagnosis. If suspected, comprehensive staging and cytoreduction is necessary, regardless of intrauterine disease state. The standardized surgery should be performed, including TAH, BSO, pelvic/para-aortic lymphadenectomy, peritoneal cytology, omentectomy, peritoneal biopsy, and cytoreductive surgery [bib_ref] The role of cytoreductive surgery in the management of stage IV uterine..., Bristow [/bib_ref].

## 3) adjuvant treatment (1) adjuvant treatment for early endometrial cancer
The adjuvant treatment in patients with early-stage endometrial cancer is considered according to the presence of clinicopathologic factors associated with the risk of recurrence. However, it is difficult to decide the appropriate adjuvant therapy for patients with early-stage endometrial cancer because other complicated decision processes, in addition to considering FIGO stage, are necessary for individual patients, including identifying: 1) those who are comprehensively staged including appropriate nodal evaluation; and 2) those who have risk factors for recurrence, including age, tumor size, lymphovascular space invasion, and expansion to the lower corpus. Although the value of adjuvant RT in early-stage endometrial cancer remains unclear, general recommendations can be made for adjuvant treatment. In patients with stage IA/grade 1 endometrial cancer without risk factors, no adjuvant treatment is recommended. In patients with stage IA/grade 2-3 endometrial cancer without risk factors or stage IA/grade 1 endometrial cancer with risk factors, no adjuvant treatment or adjuvant vaginal brachytherapy is possible. In patients with stage IA/grade 2-3 endometrial cancer with risk factors, no adjuvant treatment or adjuvant brachytherapy and/or pelvic RT is possible. In patients with stage IB/grade 1-2 endometrial cancer without risk factors, no adjuvant treatment or adjuvant brachytherapy is possible. In patients with stage IB/grade 1-2 endometrial cancer with risk factors, no adjuvant treatment or adjuvant brachytherapy and/or pelvic RT is possible, and in patients with stage IB/grade 3 endometrial cancer without risk factors, adjuvant brachytherapy and/or pelvic RT is recommended and no adjuvant treatment is an option. [bib_ref] Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial..., Creutzberg [/bib_ref] [bib_ref] Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC..., Astec/En.5 Study [/bib_ref]. In the PORTEC-2 study, there was no difference in relapse rates and the improvement of quality of life with brachytherapy instead of pelvic RT in patients with endometrial cancer with a high risk and moderate risk factors [bib_ref] Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer..., Nout [/bib_ref] [bib_ref] Quality of life after pelvic radiotherapy or vaginal brachytherapy for endometrial cancer:..., Nout [/bib_ref]. However, in Korea, institutions that can perform vaginal brachytherapy are relatively limited [bib_ref] Current status of brachytherapy in Korea: a national survey of radiation oncologists, Kim [/bib_ref]. Therefore, in the revised practice guidelines (V3.0, KSGO 2016 edition; KSGO), a largescale retrospective cohort study and other randomized controlled trials, which clearly divided surgical methods and RT in patients with stage IB, grade 3 endometrial cancer with risk factors, were selected and analyzed [bib_ref] Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC..., Astec/En.5 Study [/bib_ref] [bib_ref] Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer..., Nout [/bib_ref] [bib_ref] Quality of life after pelvic radiotherapy or vaginal brachytherapy for endometrial cancer:..., Nout [/bib_ref] [bib_ref] Current status of brachytherapy in Korea: a national survey of radiation oncologists, Kim [/bib_ref] [bib_ref] The influence of radiation modality and lymph node dissection on survival in..., Chino [/bib_ref] [bib_ref] Role of adjuvant radiotherapy (RT) in intermediate risk (IB G2-3-IC) endometrial carcinoma..., Soderini [/bib_ref] [bib_ref] Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical..., Aalders [/bib_ref]. The large-scale retrospective cohort study was performed through the SEER dataset for stage I endometrial cancer treated with comprehensive staging; subjects were stratified into low-, intermediate-, and high-risk cohorts using modifications of the GOG 99 and PORTEC trial criteria [bib_ref] The influence of radiation modality and lymph node dissection on survival in..., Chino [/bib_ref]. In patients with high-risk disease who underwent LND, RT was associated with increased 5-year survival, without significant differences between the radiation modalities (78.9% in brachytherapy only, 69.9% in WPRT only, 71.4% in both brachytherapy and WPRT vs. 63.5% in no RT; p<0.001); if LND was not performed, brachytherapy alone was inferior to WPRT (p=0.01). Two randomized trials reported improved 5-year disease-free survival in high-risk patients with early-stage endometrial cancer who underwent LND [bib_ref] Role of adjuvant radiotherapy (RT) in intermediate risk (IB G2-3-IC) endometrial carcinoma..., Soderini [/bib_ref] [bib_ref] Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical..., Aalders [/bib_ref].
[formula] Recommendation [/formula]

## Practice guidelines for uterine corpus cancer in korea
Advanced endometrial cancer is defined according to its presentation as vaginal or pelvic invasion, lymph node metastasis, intra-abdominal metastasis, and distant inoperable metastasis. These different patient populations are considered as one group, therefore, it is difficult to select optimal adjuvant treatment strategies. Although optimal cytoreductive surgery is related to good therapeutic results, patients with local or distant metastatic endometrial cancer have an increased risk of pelvic recurrence and distant metastases that causes the unfavorable outcomes [bib_ref] Cytoreductive surgery for advanced or recurrent endometrial cancer: a metaanalysis, Barlin [/bib_ref]. Adjuvant pelvic RT with or without external beam RT in advanced endometrial cancer has been proven to reduce pelvic recurrence; however, the limits of radiation field results in a long-term survival failure [bib_ref] Node-positive adenocarcinoma of the endometrium: outcome and patterns of recurrence with and..., Klopp [/bib_ref]. Chemotherapy reduces the risk of recurrence in the treatment of advanced endometrial cancer. Therefore, chemotherapy combined with RT may improve outcomes compared with single-modality treatment. Several studies have investigated the efficacy of combining chemotherapy with RT, although randomized trials are rare, and the treatment strategies from retrospective cohort studies were heterogeneous.
In the Gynecologic Oncology Group at the Mario Negri Institute (MaNGO) study, sequential chemotherapy and RT were associated with a 12% reduction in the risk for relapse and 5% reduction in the risk for death compared with radiotherapy alone, but the difference was not statistically significant (HR for progression-free survival [PFS], 0.61; 95% CI, 0.33-1.12) (HR for OS, 0.74; 95% CI, 0.36-1.52) [bib_ref] Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies, Hogberg [/bib_ref]. These results agree with those in several prospective and retrospective studies [bib_ref] Node-positive adenocarcinoma of the endometrium: outcome and patterns of recurrence with and..., Klopp [/bib_ref] [bib_ref] Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies, Hogberg [/bib_ref] [bib_ref] Use of adjuvant therapy in patients with FIGO stage III endometrial carcinoma:..., Marchetti [/bib_ref] [bib_ref] Concomitant postoperative radiation and chemotherapy following surgery was associated with improved overall..., Nakayama [/bib_ref] [bib_ref] Combined chemotherapy and radiation improves survival for node-positive endometrial cancer, Lee [/bib_ref]. In a retrospective analysis of 356 patients with stage III and IV endometrial cancer, combined adjuvant chemotherapy and RT was associated with improved PFS and OS compared with either modality alone [bib_ref] The role of multimodality adjuvant chemotherapy and radiation in women with advanced..., Secord [/bib_ref]. The recently completed GOG 258 trial for stage III-IV endometrial cancer may show whether the combination of external beam RT and chemotherapy has benefits reducing the recurrence or death compared with chemotherapy alone.

## Recommendation:
Combined chemotherapy and radiotherapy in a concurrent or sequential approach is recommended for patients with advanced-stage endometrial cancers after surgery. Level of evidence: C (low). Strength of recommendation: 2 (weak). Consensus: 66.7% (12) yes, 33.3% (6) abstain (18 voters).

## (3) adjuvant treatment for papillary serous adenocarcinoma/clear cell carcinoma/ carcinosarcoma
If the lesion is limited to the endometrium, no adjuvant treatment or chemotherapy or pelvic RT is possible. In patients with myometrial invasion or a more advanced stage, adjuvant chemotherapy and/or pelvic RT is recommended. Whole abdomen RT is not recommended because of the toxicity and risk of complications [bib_ref] Outcome after combined modality treatment for uterine papillary serous carcinoma: a study..., Goldberg [/bib_ref] [bib_ref] The effect of adjuvant chemotherapy versus whole abdominopelvic radiation on the survival..., Hamilton [/bib_ref] [bib_ref] Outcomes in surgical stage I uterine papillary serous carcinoma, Havrilesky [/bib_ref].

## 4) follow-up
The recommended surveillance schedule after primary and adjuvant treatment of endometrial cancer is a follow-up visit every 3-6 months for 2 years, then every 6 months for 3 years, and annually thereafter. Radiologic evaluation, such as chest radiography, ultrasonography, or CT, MRI, or PET/CT, should be used to detect recurrent disease selectively only when considered necessary. There is a lack of evidence for the use of CA-125 for routine surveillance, although there are some reports that it is helps in the follow-up of endometrial cancer [bib_ref] Serial CA 125 levels during chemotherapy for metastatic or recurrent endometrial cancer, Fanning [/bib_ref]. It is very important to educate the patient about the possible symptoms of suspected treatable recurrent disease.

## 5) treatment for metastasis and recurrence
Endometrial cancer recurrence often occurs locally in the pelvis, most commonly in the vagina. If the relapsed lesion is limited to the pelvis with no evidence of distant metastasis in radiologic evaluation, the choice of treatment strategy depends on whether or not the RT was performed on the recurrent site. In patients who did not have RT previously, RT is preferentially recommended for recurrent endometrial cancer with or without surgery. In solitary metastasis of endometrial cancer, surgical removal of the relapsed lesion with or without radiotherapy is considered. The majority of patients with disseminated metastatic disease need systemic palliative therapy. Hormonal therapy or chemotherapy can be considered preferentially; however, if there is no response to these two treatments, the best supportive care is necessary, and clinical studies are encouraged. To date, the most studied chemotherapeutic agents in endometrial cancer are doxorubicin and cisplatin. The response rate of these agents used as monotherapy has been reported as 24%-48% for doxorubicin and 21%-25% for cisplatin [bib_ref] Randomized phase II studies of cisplatin and a combination of cyclophosphamide-doxorubicin-cisplatin (CAP)..., Edmonson [/bib_ref] [bib_ref] Comparison of adriamycin with cyclophosphamide in patients with advanced endometrial cancer, Horton [/bib_ref] [bib_ref] A randomized comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the..., Thigpen [/bib_ref] [bib_ref] Phase II trial of cisplatin as first-line chemotherapy in patients with advanced..., Thigpen [/bib_ref] [bib_ref] Phase III trial of doxorubicin with or without cisplatin in advanced endometrial..., Thigpen [/bib_ref] [bib_ref] Second-line chemotherapy for recurrent carcinoma of the ovary, Thigpen [/bib_ref]. Carboplatin has been reported to exhibit similar response rates of 17%-33% [bib_ref] Treatment of advanced or recurrent endometrial carcinoma with single-agent carboplatin, Burke [/bib_ref] [bib_ref] Carboplatin therapy in advanced endometrial cancer, Green [/bib_ref] [bib_ref] Phase II evaluation of carboplatin in advanced endometrial carcinoma, Long [/bib_ref]. Other drugs, paclitaxel, cyclophosphamide and topotecan, also showed a similar response rate of approximately 20% [bib_ref] Comparison of adriamycin with cyclophosphamide in patients with advanced endometrial cancer, Horton [/bib_ref] [bib_ref] A randomized comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the..., Thigpen [/bib_ref] [bib_ref] Phase II trial of cisplatin as first-line chemotherapy in patients with advanced..., Thigpen [/bib_ref] [bib_ref] Phase III trial of doxorubicin with or without cisplatin in advanced endometrial..., Thigpen [/bib_ref] [bib_ref] Second-line chemotherapy for recurrent carcinoma of the ovary, Thigpen [/bib_ref] [bib_ref] Treatment of advanced or recurrent endometrial carcinoma with single-agent carboplatin, Burke [/bib_ref] [bib_ref] Carboplatin therapy in advanced endometrial cancer, Green [/bib_ref] [bib_ref] Phase II evaluation of carboplatin in advanced endometrial carcinoma, Long [/bib_ref] [bib_ref] A phase II trial of paclitaxel in patients with advanced or recurrent..., Ball [/bib_ref] [bib_ref] Activity of paclitaxel as second-line chemotherapy in endometrial carcinoma: a Gynecologic Oncology..., Lincoln [/bib_ref] [bib_ref] Phase II study of paclitaxel as salvage treatment in advanced endometrial cancer, Lissoni [/bib_ref] [bib_ref] Treatment options for endometrial cancer: experience with topotecan, Holloway [/bib_ref]. A combination therapy of cisplatin and doxorubicin has been used widely, showing a response rate of 30%-40% [bib_ref] A randomized comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the..., Thigpen [/bib_ref] [bib_ref] Phase II trial of cisplatin as first-line chemotherapy in patients with advanced..., Thigpen [/bib_ref] [bib_ref] Phase III trial of doxorubicin with or without cisplatin in advanced endometrial..., Thigpen [/bib_ref] [bib_ref] Second-line chemotherapy for recurrent carcinoma of the ovary, Thigpen [/bib_ref] [bib_ref] Treatment of advanced or recurrent endometrial carcinoma with single-agent carboplatin, Burke [/bib_ref] [bib_ref] Carboplatin therapy in advanced endometrial cancer, Green [/bib_ref] [bib_ref] Phase II evaluation of carboplatin in advanced endometrial carcinoma, Long [/bib_ref] [bib_ref] A phase II trial of paclitaxel in patients with advanced or recurrent..., Ball [/bib_ref] [bib_ref] Activity of paclitaxel as second-line chemotherapy in endometrial carcinoma: a Gynecologic Oncology..., Lincoln [/bib_ref] [bib_ref] Phase II study of paclitaxel as salvage treatment in advanced endometrial cancer, Lissoni [/bib_ref] [bib_ref] Treatment options for endometrial cancer: experience with topotecan, Holloway [/bib_ref] [bib_ref] Chemotherapy of metastatic endometrial cancer, Muss [/bib_ref] [bib_ref] Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a..., Van Wijk [/bib_ref]. Two randomized studies reported that the combination of cisplatin and doxorubicin produced a survival benefit comparable with doxorubicin alone in terms of response rate (42%-43% vs. 17%-25%), but with no benefit in terms of OS [bib_ref] Phase III trial of doxorubicin with or without cisplatin in advanced endometrial..., Thigpen [/bib_ref] [bib_ref] Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a..., Van Wijk [/bib_ref]. In another GOG trial, the addition of paclitaxel to cisplatin and doxorubicin (TAP regimen) significantly improved the response rate, PFS, and OS compared with cisplatin and doxorubicin (AP regimen) [bib_ref] Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus..., Fleming [/bib_ref]. The objective response (57% vs. 34%; p<0.01), PFS (median, 8.3 vs. 5.3 months; p<0.01), and OS (median, 15.3 vs. 12.3 months; p<0.04) were higher with the TAP compared with the AP regimen. Treatment was hematologically well tolerated in the TAP-treated group; however, toxicity, especially peripheral neuropathy, was significantly higher compared with the AP group. TAP has not been chosen as a standard of care by clinicians because of serious toxicity.
The combination of paclitaxel and carboplatin has been approved as a standard regimen because of fewer side effects [bib_ref] Activity of paclitaxel as second-line chemotherapy in endometrial carcinoma: a Gynecologic Oncology..., Lincoln [/bib_ref] [bib_ref] Phase II study of paclitaxel as salvage treatment in advanced endometrial cancer, Lissoni [/bib_ref] [bib_ref] Treatment options for endometrial cancer: experience with topotecan, Holloway [/bib_ref] [bib_ref] Chemotherapy of metastatic endometrial cancer, Muss [/bib_ref]. A phase II study of the Southwest Oncology Group (SWOG) reported a response rate of 40% (95% CI, 26%-56%), a median OS of 14 months (95% CI, 12-17 months), and tolerable toxicity with a regimen of paclitaxel (175 mg/ m 2 ) and carboplatin (AUC 6) [bib_ref] Paclitaxel and carboplatin with amifostine in advanced, recurrent, or refractory endometrial adenocarcinoma:..., Scudder [/bib_ref]. Recently, a randomized phase III noninferiority trial (GOG 209), has reported preliminary results of comparing the combination of paclitaxel (160 mg/m 2 ), cisplatin (60 mg/m 2 ) and doxorubicin (50 mg/m 2 ) (TAP) with paclitaxel (175 mg/m 2 ) and carboplatin (AUC 6) (TC) in 1,305 patients with metastatic or recurrent endometrial cancer [bib_ref] Randomized phase III noninferiority trial of first line chemotherapy for metastatic or..., Miller [/bib_ref]. There were no differences in response rate (51.3% vs. 51.2%) or PFS (median, 13.5 vs. 13.3 months). The median OS for TC (36.5 months) was not significantly inferior to that of TAP (40.3 months). TC had a more favorable toxicity profile than TAP in this trial. Sensory neuropathy occurred in significantly more patients treated with TAP (26% vs. 19%; p<0.01). Other toxic events (grade 3) that occurred more often with TAP were neutropenia, thrombocytopenia, nausea, vomiting, diarrhea, and stomatitis. In addition, 17.6% of patients in the TAP arm discontinued treatment because of toxicity compared with 11.9% in the TC arm.

## Recommendation:
The combination of paclitaxel and carboplatin is recommended in patients with advanced and recurrent endometrial cancer. This is supported by the preliminary results of a randomized trial showing similar efficacy and less toxicity compared with cisplatin/doxorubicin/paclitaxel. Level of evidence: C (low). Strength of recommendation: 1 (strong). Consensus: 100% yes (19 voters).
The combination of paclitaxel and carboplatin was adopted for papillary serous adenocarcinoma [bib_ref] The combination paclitaxel, carboplatin and megestrol acetate is effective in women with..., Eltabbakh [/bib_ref] [bib_ref] Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial..., Hoskins [/bib_ref]. In patients with carcinosarcoma, the combination of ifosfamide and cisplatin has been the first choice of regimen [bib_ref] Phase II trial of ifosfamide and mesna in mixed mesodermal tumors of..., Sutton [/bib_ref] [bib_ref] Phase II trial of cisplatin as first-line chemotherapy in patients with advanced..., Thigpen [/bib_ref] [bib_ref] Phase II trial of cisplatin in the treatment of patients with advanced..., Thigpen [/bib_ref] [bib_ref] A gynecologic oncology group randomized phase III trial of whole abdominal irradiation..., Wolfson [/bib_ref] , although there is no benefit regarding OS [bib_ref] A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma..., Sutton [/bib_ref]. Paclitaxel alone showed a response rate of 18% in the GOG study [bib_ref] Paclitaxel in the treatment of carcinosarcoma of the uterus: a Gynecologic Oncology..., Curtin [/bib_ref]. Finally, the combination of paclitaxel and ifosfamide was associated with higher OS compared with ifosfamide alone [bib_ref] Phase III trial of ifosfamide with or without paclitaxel in advanced uterine..., Homesley [/bib_ref].
(2) Hormonal therapy Hormonal therapy is a progestin treatment, including megestrol acetate and MPA. The response rate of hormonal therapy was 15%-25% in recurrent, metastatic endometrial cancer, and there was no correlation between the hormonal dosage and response rate. In a GOG study, the response rate in a group receiving low-dose MPA (200 mg) was 25% and that in the group receiving highdose MPA (1,000 mg) was 15%. In addition, the median PFS was similar in the two groups (2-3 months) [bib_ref] Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma:..., Thigpen [/bib_ref]. Moore et al. [bib_ref] Systemic treatment of advanced and recurrent endometrial carcinoma: current status and future..., Moore [/bib_ref] reported a 22% response rate in metastatic endometrial cancer using tamoxifen. Goserelin and danazol are also known to have some effect [bib_ref] Goserelin acetate as treatment for recurrent endometrial carcinoma: a Gynecologic Oncology Group..., Asbury [/bib_ref] [bib_ref] Phase II trial of danazol in advanced, recurrent, or persistent endometrial cancer:..., Covens [/bib_ref].

## Uterine sarcomas

## 1) screening and diagnosis
Uterine sarcomas are rare malignancies of the uterus, including endometrial stromal sarcoma (ESS), leiomyosarcoma (LMS), and undifferentiated uterine sarcoma (UUS) [bib_ref] Systemic treatment of advanced and recurrent endometrial carcinoma: current status and future..., Moore [/bib_ref]. Clinical symptoms of uterine sarcoma are similar to those of uterine fibroids, with uterine bleeding and lower abdominal pain or a palpable mass being typical. A history of previous radiation is a well-known risk factor. If there is a history of pelvic RT, irradiation can increase the risk of developing uterine sarcoma, which can occur 10-20 years after the irradiation, up to 5.4 times [bib_ref] Second maligancies of the irradiated area in patients treated for uterine cervix..., Czesnin [/bib_ref]. Because uterine sarcoma is, in most cases, diagnosed after hysterectomy or myomectomy, pathologic review of a specimen and imaging (CT, MRI, and/ or PET) are required to determine if the sarcoma is confined to the uterus or if extrauterine disease is present. In patients with suspected uterine sarcoma based on clinical symptoms and history, basic tests such as whole blood examination, chemical examination, chest radiography, electrocardiography, and urinalysis can be performed preoperatively. Although an endometrial biopsy may be performed to confirm the pathologic result, this is not useful for most cases of uterine sarcoma because the lesions are only in the uterine muscle layer. CT, MRI, and/or PET scans can be obtained to assist in preoperative diagnosis and staging, but they are not included in the basic tests for diagnostic purposes.
2) Primary treatment KQ 07. Does power morcellation affect survival in patients with uterine sarcoma?
The standard surgical treatment for uterine sarcoma is TAH with (or without) BSO. Uterine sarcoma should be removed en bloc to improve outcomes; morcellation is contraindicated. In these practice guidelines, three retrospective cohort studies were analyzed to evaluate the impact of power morcellation [bib_ref] Retrospective cohort study evaluating the impact of intraperitoneal morcellation on outcomes of..., George [/bib_ref] [bib_ref] The impact of tumor morcellation during surgery on the prognosis of patients..., Park [/bib_ref] [bib_ref] Uterine leiomyosarcoma: does the primary surgical procedure matter?, Perri [/bib_ref]. They compared 5-year OS between a morcellation group and a no-morcellation group with uterine LMS and found a significant difference in 5-year OS rates (37.5%-57.9% vs. 61.9%-83.9%, respectively). In a meta-analysis of survival from these three nonrandomized studies, a survival difference was detected according to the use of power morcellation (HR, 1.66; 95% CI, 1.08-2.53).

## Recommendation:
In patients suspected to have uterine sarcoma, power morcellation should be avoided through laparoscopic surgery because power morcellation has been found to decrease the survival of patients with uterine sarcoma. Level of evidence: D (very low). Strength of recommendation: 1 (strong).

## Consensus: 100% yes (22 voters).
Therefore, if the uterine sarcoma is diagnosed after hysterectomy and especially when the uterus is fragmented by morcellation, or the cervix or ovaries remain, additional surgery should be considered after a pathologic review and imaging work-up for detecting extrauterine disease. If the uterine sarcoma is diagnosed through biopsy or myomectomy, additional surgery should be determined considering the disease extension and operability through an imaging work-up; then, the standard surgical treatment is TAH with (or without) BSO and resection of metastatic lesions. In patients with suspected uterine sarcoma based on clinical symptoms and history, preoperative evaluation is important and standard surgical treatment is TAH with (or without) BSO and resection of metastatic lesions. Ovarian preservation can be considered when hysterectomy is performed for early-stage uterine sarcoma. Additional surgery should be individualized based on the patient's condition and operative findings. Extrauterine lesions should be removed if possible, but lymphadenectomy is not recommended because uterine sarcomas tend to spread by hematogenous metastasis [bib_ref] Clinical management of uterine sarcomas, Amant [/bib_ref] [bib_ref] Does radiotherapy or lymphadenectomy improve survival in endometrial stromal sarcoma?, Barney [/bib_ref] [bib_ref] Lymphadenectomy and ovarian preservation in low-grade endometrial stromal sarcoma, Shah [/bib_ref] [bib_ref] Lymphadenectomy in uterine lowgrade endometrial stromal sarcoma: an analysis of 19 cases..., Signorelli [/bib_ref]. For medically inoperable patients, pelvic RT with (or without) brachytherapy and/or chemotherapy is performed and hormonal therapy can be considered.

## 3) adjuvant treatment
Uterine sarcomas have a high recurrence rate and often show distant metastasis. Therefore, postoperative adjuvant treatment is often required, but the effects of adjuvant treatment are controversial. In patients with stage I, low-grade ESS, no adjuvant treatment is recommended. In patients with stage I LMS and UUS, chemotherapy with (or without) RT is recommended, and no adjuvant treatment can be considered [bib_ref] Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy..., Reed [/bib_ref] [bib_ref] The role of adjuvant radiation in uterine sarcomas, Sampath [/bib_ref] [bib_ref] Pelvic radiation improves local control after hysterectomy for uterine leiomyosarcoma: a 20-year..., Mahdavi [/bib_ref]. In patients with stage II-IVA sarcoma, hormonal therapy with (or without) pelvic RT is recommended for ESS [bib_ref] Clinical management of uterine sarcomas, Amant [/bib_ref] [bib_ref] Does radiotherapy or lymphadenectomy improve survival in endometrial stromal sarcoma?, Barney [/bib_ref] [bib_ref] Lymphadenectomy and ovarian preservation in low-grade endometrial stromal sarcoma, Shah [/bib_ref] [bib_ref] Lymphadenectomy in uterine lowgrade endometrial stromal sarcoma: an analysis of 19 cases..., Signorelli [/bib_ref] [bib_ref] Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy..., Reed [/bib_ref] [bib_ref] The role of adjuvant radiation in uterine sarcomas, Sampath [/bib_ref] [bib_ref] Pelvic radiation improves local control after hysterectomy for uterine leiomyosarcoma: a 20-year..., Mahdavi [/bib_ref] [bib_ref] The treatment of uterine sarcomas, Reichardt [/bib_ref] [bib_ref] Hormonal therapy in gynecological sarcomas, Thanopoulou [/bib_ref] , and chemotherapy and/or pelvic RT can be considered for LMS and UUS [bib_ref] Does adjuvant chemotherapy improve survival for women with early-stage uterine leiomyosarcoma?, Ricci [/bib_ref] [bib_ref] Adjuvant therapy for highgrade, uterus-limited leiomyosarcoma: results of a phase 2 trial..., Hensley [/bib_ref]. In patients with stage IVB ESS, hormonal therapy is considered, and in some cases, palliative RT can be added. Chemotherapy with (or without) palliative RT is recommended in patients with stage IVB LMS and UUS. The regimens for hormonal therapy used for ESS are MPA, megestrol acetate, tamoxifen, and gonadotropin-releasing hormone analogs. Practice guidelines for uterine corpus cancer in Korea of previous RT. If patients did not receive previous radiotherapy, surgery with (or without) radiotherapy or pelvic RT with brachytherapy is recommended. If the local recurrence is limited to the vagina, confirmed through surgery, pelvic RT with (or without) brachytherapy can be considered postoperatively. If the recurrence is in the pelvis outside of the vagina, confirmed through surgery, pelvic RT is recommended. If recurrence is confirmed to be outside of the pelvis, chemotherapy is recommended, and in patients with ESS, hormonal therapy can be recommended [bib_ref] Metastatic uterine leiomyosarcomas: a single-institution experience, Bernstein-Molho [/bib_ref] [bib_ref] Efficacy and safety of pharmacological interventions in second-or later-line treatment of patients..., Sharma [/bib_ref] [bib_ref] Stereotactic body radiotherapy for pulmonary metastases from soft-tissue sarcomas: excellent local lesion..., Dhakal [/bib_ref].

## 4) treatment for metastasis and recurrence
(2) Management for distant metastatic uterine sarcoma If a solitary metastatic lesion is removable, surgical resection is performed and postoperative chemotherapy or hormonal therapy or RT can be considered. For medically or surgically inoperable patients, chemotherapy with (or without) palliative RT or hormonal therapy is recommended. When identified with disseminated metastasis, hormonal therapy or supportive care is recommended for patients with ESS and chemotherapy with (or without) palliative RT or supportive care is recommended for other uterine sarcomas.
(3) Systemic treatment for advanced, recurrent uterine sarcoma Most patients with advanced or recurrent uterine sarcoma require chemotherapy. Unfortunately, no combined or single agent has shown a survival advantage in several clinical trials [bib_ref] Uterine sarcomas in Norway 1956-1992: incidence, survival and mortality, Nordal [/bib_ref]. For LMS, doxorubicin has been approved as the most effective single therapy, and ifosfamide has been reported to have a similar efficacy [bib_ref] A randomized study of adriamycin with and without dimethyl triazenoimidazole carboxamide in..., Omura [/bib_ref] [bib_ref] Phase II trial of ifosfamide and mesna in leiomyosarcoma of the uterus:..., Sutton [/bib_ref]. Combination therapy with doxorubicin and ifosfamide has often been used. In recent years, a high response rate has been reported in several studies that evaluated the efficacy of gemcitabine/docetaxel combination therapy for uterine LMS [bib_ref] Fixed-dose rate gemcitabine plus docetaxel as second-line therapy for metastatic uterine leiomyosarcoma:..., Hensley [/bib_ref] [bib_ref] Fixed-dose rate gemcitabine plus docetaxel as first-line therapy for metastatic uterine leiomyosarcoma:..., Hensley [/bib_ref] [bib_ref] Adjuvant gemcitabine plus docetaxel for completely resected stages I-IV high grade uterine..., Hensley [/bib_ref].
KQ 08. Does pazopanib therapy improve survival in recurrent uterine LMS?

## Summary of recommendation and conclusions
The following recommendations and conclusions are based on four levels of evidence (A, high; B, moderate; C, low; D, very low) and two strengths of recommendation (1, strong; 2, weak).

## Endometrial carcinoma
- Lymphadenectomy is recommended as an integral part in the surgical staging of endometrial cancer. However, pelvic lymphadenectomy may be omitted in patients who are predicted to have a very low risk of lymph node metastasis and, in some cases, show low-grade tumor with endometrioid histologic type confined to the endometrium or invaded to the superficial myometrium (2A).
- Para-aortic lymphadenectomy is recommended if deep myometrial invasion is considered or high-grade lesions including serous or clear cell carcinoma are identified (2A).
- Laparoscopic staging surgery is recommended for the surgical staging of early-stage endometrial cancer (1A).
- Ovarian preservation is recommended at the time of hysterectomy for young women with early-stage endometrial cancer that is confined to the uterus without evidence of extrauterine spread (2C).
- Fertility-sparing treatment through progestin-based therapy is recommended in earlystage endometrial cancer if the tumor is grade 1 endometrioid adenocarcinoma and limited to the endometrium if the patient strongly desires pregnancy (1D).
- Cervical biopsy before surgery is recommended to determine whether infiltration is present, if it is clinically suspected. In patients with uterine cervical invasion confirmed by cervical biopsy, a radical hysterectomy, BSO, pelvic/para-aortic lymphadenectomy, and pelvic and abdominal wash cytology are recommended. Preoperative RT followed by hysterectomy, BSO, and pelvic and para-aortic LND can be considered (1D).
- In patients with stage IA/grade 1 endometrial cancer with risk factors, no adjuvant treatment or adjuvant brachytherapy is possible. In patients with stage IA/grade 2-3 endometrial cancer with risk factors, no adjuvant treatment or adjuvant brachytherapy and/or pelvic RT is possible (1A).
- In patients with stage IB/grade 1-2 endometrial cancer without risk factors, no adjuvant treatment or adjuvant brachytherapy is possible (1A).
- Pelvic RT and/or vaginal brachytherapy with (or without) chemotherapy is recommended as the adjuvant treatment in patients with stage IB, grade 3 endometrial cancers with risk factors after surgery (2D).
- In early-stage grade 3 endometrial cancer with positive peritoneal cytology, no adjuvant treatment or adjuvant brachytherapy or pelvic RT and/or brachytherapy and/or chemotherapy is possible (2C).
- Combined chemotherapy and radiotherapy in a concurrent or sequential approach is recommended for patients with advanced-stage endometrial cancers after surgery (2C).
- If the lesion of papillary serous adenocarcinoma/clear cell carcinoma/carcinosarcoma is limited to the endometrium, no adjuvant treatment or chemotherapy or pelvic RT is possible. In patients with myometrial invasion or a more advanced-stage carcinoma, adjuvant chemotherapy and/or pelvic RT is recommended (1C).
- The combination of paclitaxel and carboplatin is recommended in patients with advanced and recurrent endometrial cancer. This is supported by the preliminary results of a randomized trial showing similar efficacy and less toxicity compared with cisplatin/ doxorubicin/paclitaxel (1C).
- In patients with carcinosarcoma, the combination of ifosfamide and cisplatin has been the first choice of regimen, but the combination of paclitaxel and ifosfamide is recommended to improve OS (2B).

## Uterine sarcomas
- In patients suspected to have uterine sarcoma, power morcellation should be avoided through laparoscopic surgery because power morcellation has been found to decrease the survival of patients with uterine sarcoma (1D).
- In patients with stage I, low-grade ESS, no adjuvant treatment is recommended. In patients with stage I LMS and UUS, chemotherapy with (or without) RT is recommended, and no adjuvant treatment can be considered (1C).
- In patients with stage II-IVA, hormonal therapy with (or without) pelvic RT is recommended for ESS, and chemotherapy and/or pelvic RT can be considered for LMS and UUS (1C).
- For LMS, doxorubicin has been approved as the most effective single therapy, and combination therapy with doxorubicin and ifosfamide has often been used. In recent years, gemcitabine/docetaxel combination therapy is recommended in uterine LMS because of the high response rate (1C).
- In patients with metastatic and recurrent LMS that previously failed to respond to standard chemotherapy, pazopanib is recommended as monotherapy (1D).
[fig] 1: Management for locally recurred uterine sarcoma Management for locally recurred uterine sarcoma is determined by the presence or absence 12/22 http://ejgo.org https://doi.org/10.3802/jgo.2017.28.e12 [/fig]