Endometrial cancer is the fourth most common cancer in women in North America and the most common cancer of the female genital tract. It accounts for 50% of all new gynecologic cancers and 7% of all cancers in women, with an annual incidence of 23.3 per 100,000 women in developed countries. 1 In Alberta, there were 529 cases of cancer of the uterus and 87 deaths in 2012. 2 The majority (75-85%) of cases are in women over the age of 50 years, with 95% of cases in women over the age of 45 years. 1 The peak incidence is at the age of 55-65 years. 3 Over 80% of cases are early stage. There are several histological types of endometrial cancer. These include (1) endometrioid and variants, such as ciliated cell carcinoma, secretory adenocarcinoma, villoglandular, and carcinoma with squamous and mucinous differentiation, accounting for 75-80% (endometrioid carcinomas are graded based on the extent of solid non-squamous component into grade 1-3) (2) mixed accounting for 10% (3) uterine serous, accounting for <10%; (4) dedifferentiated and undifferentiated carcinoma (1%), ( 5) clear cell, accounting for 4%; (6) squamous cell, accounting for <1%. 4,5 Staging of endometrial cancer is based on the Federation Internationale de Gynecologie et d'Obstetrique (FIGO). 6,7 A detailed description of this staging system can be found in the Appendix A.#
The reasons for the staging system are summarized as follows: 8 - Stage IA cannot always be reliably distinguished - Stage IA and IB are poorly defined pathologically and may not differ prognostically (5-year survival for endometrioid carcinomas: 90%) - Stage IIIA alone is heterogeneous; positive cytology is rare but with small effect 9 (5-year survival: 85%); adnexae/uterine serosa is more significant (5-year survival: 63.4%) - Stage IIIB vaginal metastasis/parametria have a poor prognosis but are rare (5-year survival: 38.8%) - Stage IIIC (5-year survival: 51.1%) - Stage IIIC1 pelvic nodes significant (5-year survival: 70%) - Stage IIIC2 para-aortic nodes significantly worse (5-year survival: 30%); grossly positive nodes, capsule involvement and desmoplasia are associated with a worse prognosis - Stage IV (5-year survival: 20-26%)

# GUIDELINE QUESTIONS
- Is chemotherapy following surgery in women diagnosed with endometrial cancer, at various stages and grades and in certain histotypes more effective than surgery alone in preventing recurrence and/or improving progression free survival?
- Is radiation therapy following surgery in women diagnosed with endometrial cancer, at various stages and grades and in certain histotypes more effective than surgery alone in preventing recurrence and/or improving progression free survival?
- Is hormone therapy following surgery in women diagnosed with endometrial cancer, at various stages and grades and in certain histotypes more effective than surgery alone in preventing recurrence and/or improving progression free survival?
CLINICAL PRACTICE GUIDELINE GYNE-002 Version 5

# DEVELOPMENT AND REVISION HISTORY
This guideline was reviewed and endorsed by the Alberta Provincial Gynecologic Oncology Tumour Team. Members of the Alberta Provincial Gynecologic Oncology Tumour Team include gynecologic oncologists, radiation oncologists, medical oncologists, pathologists, nurses, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Gynecologic Oncology Tumour Team and a Knowledge Management Specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in September, 2009. This guideline was revised in December 2009, August 2011, April 2012, October 2013, and November 2015.

# SEARCH STRATEGY
Entries to the Medline, EMBASE, and Cochrane databases and clinical practice guideline databases were searched for evidence relevant to this topic. Search terms originally included: endometrial OR endometrium AND cancer OR carcinoma OR adenocarcinoma OR carcinosarcoma AND (1) chemotherapy OR carboplatin OR Taxol; or (2) brachytherapy OR radiotherapy OR radiation; or (3) progestagens OR megestrol OR Megace OR hormone; or (4) oophorectomy OR lymphadenectomy OR hysterectomy OR surgery. The literature was reviewed prior to each update, using the search terms: endometrial OR endometrium AND cancer OR carcinoma OR adenocarcinoma OR carcinosarcoma. A total of 46, 13, and 11 studies were included in the 2011, 2012, and 2013 reviews, respectively. The 2015 update focused on imaging, sentinel lymph node mapping and screening for Lynch syndrome and retrieved a total of 33 studies were included from a search of the Medline database. Following a review of the evidence by the Alberta Gynecologic Oncology Team, relevant literature was added to the discussion section.
In addition, the National Guidelines Clearinghouse database was searched and other guideline developers for existing guidelines. The following guidelines were reviewed and information included where relevant: the National Comprehensive Cancer Network (NCCN) guidelines, 10 the European Society for Medical Oncology (ESMO) guidelines, 11 the BC Cancer Agency (BCCA) guidelines, 12 Cancer Care Ontario (CCO) Program in Evidence-Based Care guidelines, 13,14 the Society of Gynecologic Oncology of Canada Society of Obstetricians and Gynaecologists of Canada and Society of Canadian Colposcopy (SOG-GOC-SCC), 15 the Society of Gynecologic Oncology (SGO), 16,17 the American College of Radiology, 18 and the Mallorca group. 19

# TARGET POPULATION
The recommendations outlined in this guideline apply to women with endometrial cancer, including uterine carcinosarcoma. This guideline does not cover leiomyosarcoma and endometrial stromal sarcoma, which should be staged as uterine sarcomas. For recommendations on the management of uterine sarcomas, please refer to the Alberta Health Services guideline, Uterine Sarcoma.
CLINICAL PRACTICE GUIDELINE GYNE-002 Version 5
The following recommendations were considered when developing the recommendations: NCCN, ESMO, BCCA, and CCO, as per FIGO Staging (2010).

# I. Lynch Syndrome Screening
Lynch syndrome screening is recommended for all patients with newly diagnosed endometrial carcinoma.

# II. Surgery
All patients should be referred to a gynecologic oncologist for comprehensive continuing care as they are trained to decide and provide appropriate individualized treatment. Additionally, a full staging procedure with minimally invasive surgery can be offered with evidence to suggest that high volume centers have better long-term outcomes. 17 A pathology review should be performed by a pathologist with experience in gynecologic pathology. Preoperative imaging is not recommended for all patients. However, imaging may be considered if clinically indicated, for example, patients suspected to have extrauterine disease.
As the majority of patients are diagnosed with grade 1 endometrioid carcinomas and have an early stage, the standard treatment is a hysterectomy with bilateral salpingo-oophorectomy with or without lymph node dissection. Para-aortic lymphadenectomy is recommended for those patients with high risk histologies, such as grade 3 endometrioid carcinomas. Many patients with endometrioid carcinoma are upstaged based on final histology 20,21 and therefore consideration may also be given to para-aortic lymphadenectomy for patients with grade 2 endometrioid carcinomas.
Endometrial serous, clear cell carcinomas, and carcinosarcomas of the uterus require a comprehensive staging procedure which includes a hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node dissection, and an omentectomy. 14 Consideration should be given to an appendectomy in endometrial serous and clear cell carcinomas.
For clinically obvious cervix involvement consideration can be given to a radical hysterectomy, bilateral salpingo-oophorectomy with lymphadenectomy, OR preoperative radiotherapy followed by a simple CLINICAL PRACTICE GUIDELINE GYNE-002 Version 5
hysterectomy with bilateral salpingo-oophorectomy. For medically unfit patients, where surgery is not an option, treatment may include radiotherapy alone or with hormonal therapy and/or chemotherapy.
There is insufficient evidence to recommend routine sentinel lymph node biopsy for patients with endometrial cancer.

# III. Adjuvant Treatment for Completely Surgically Staged Endometrioid Carcinoma (as per FIGO, 2010)

# Stage IA
The majority (70%) of Stage 1A patients will present with a grade 1 or 2 tumours, while about 30% will present with a grade 3 tumour. Treatment can vary, depending on the presence of adverse risk factors. These include positive lymphovascular invasion, tumour size, and age > 65 years.
- Grade 1: observe/no adjuvant treatment - Grade 2: observe/no adjuvant treatment or vaginal vault brachytherapy can be considered if patient has LVSI or based on patient age - Grade 3: vaginal brachytherapy if adverse risk factors are present (30% of stage 1A grade 3 patients)

# Stage IB
Approximately 30% of all patients with endometrial cancer will present with a stage IB.
- Grade 1/2: vaginal vault brachytherapy can be offered - Grade 3: vaginal vault brachytherapy +/-whole pelvic radiation therapy (consideration of chemotherapy to be discussed in a multidisciplinary setting)

# Stage II
Approximately 10% of all patients with endometrial cancer will present with a stage II tumour. For clinically obvious cervix involvement, consider a radical hysterectomy, bilateral salpingo-oophorectomy with lymphadenectomy, OR preoperative radiotherapy followed by a simple hysterectomy with bilateral salpingo-oophorectomy. In the case of stage II disease where pre-operative radiotherapy is given, intracavitary radiotherapy is usually given in addition to EBRT. Recommended Chemotherapy Six cycles of carboplatin (AUC 5) with paclitaxel at 175 mg/m 2. In the case of hypersensitivity to paclitaxel, docetaxel at 75 mg/m 2 should be considered.

# V. Adjuvant Treatment for Incompletely Surgically Staged Patients
A CT scan of the chest, abdomen and pelvis is recommended.
Consider reoperating for surgical staging.

# Stage IB
- Grades 1/2: Options include o If radiologic imaging is negative, treat with vaginal brachytherapy +/-pelvic radiotherapy o If radiologic imaging is positive, surgically restage and then treat as for completely surgically staged patients (as above)
- Grade 3: Options include o If radiologic imaging is negative, treat with pelvic radiotherapy and vaginal brachytherapy +/-paraaortic radiotherapy. For Grade 3 tumours, chemotherapy may be added. o If radiologic imaging is positive, consider surgical restaging; treat with pelvic radiotherapy +/-vaginal brachytherapy.

# Stage II
Options include - If radiologic imaging is negative, treat with pelvic radiotherapy and vaginal brachytherapy +/-para-aortic radiotherapy. For Grade 3 tumours, chemotherapy may be added. - If radiologic imaging is positive, treat with pelvic radiotherapy +/-vaginal brachytherapy +/chemotherapy.

# VI. Therapy for Relapsed Patients
The recurrence rate for endometrial cancer is approximately 20%. The majority (70%) of recurrences will be confined to the pelvis (endometrioid type more common), while the remaining (30%) will be extrapelvic recurrences (high risk histotypes more common).
- Consider enrolment in a clinical trial if available
- For pelvic recurrences, if no prior radiotherapy has been given to site of recurrence, then treat with external beam radiotherapy plus brachytherapy or surgical exploration of the pelvis plus resection, with post-operative radiation therapy (PORT)
- For extrapelvic recurrences, treat with chemotherapy +/-hormone therapy +/-radiotherapy; if prior radiotherapy has been given to the site of recurrence, one of the following can be considered: o Surgical exploration of the pelvis plus resection, with or without PORT o Hormone therapy o Chemotherapy CLINICAL PRACTICE GUIDELINE GYNE-002 Version 5
- For isolated metastases, consider resection with or without radiotherapy. If the tumor is unresectable or if there is further recurrence, then treat as disseminated metastases (see below).
- For disseminated metastases, if asymptomatic or low grade, treat with hormone therapy then chemotherapy. If symptomatic or Grade 2/3, or large volume, then treat with chemotherapy and/or palliative radiotherapy.

# VII. Follow Up and Surveillance
The following suggestions for follow-up of women without evidence of disease after primary potentially curative treatment for any stage of endometrial cancer have been modified from the ACOG 22 and CCO 23 follow-up guidelines.
- A general examination, including complete history, speculum, and a pelvic-rectal examination, could be performed as follows: o Low-risk patients (i.e., stage IA or IB, grade 1 or 2): every 6 months during years 1 through 3, then once yearly during years 4 and 5. o High-risk patients (i.e., stage IA or IB, grade 3, or stage II or higher): every 4 months during years 1 through 3, then every 6 months during years 4 and 5.
- Patients who are symptomatic should undergo appropriate investigations to rule out recurrence, as many local recurrences are potentially curable with additional therapy.
Treatment of endometrial carcinoma should be managed by a gynecologist oncologist and is based on staging and histological type. It is recognized that the reproducibility of histological type for high-risk histologies is limited among pathologists. 24,25 Review by a pathologist with subspecialty interest in gynecological pathology is recommended. The use of immunohistochemical markers such as p53 to support endometrial serous and Napsin A to support clear cell carcinoma may be indicated in appropriate cases. It is also important to note that many patients are upstaged after final histology. Retrospective analyses have found between 13% to 30% of patients are upstaged from preoperative biopsy. 20,21 The SGO recommends that gynecologic oncologists be involved in the complete care of patients with endometrial carcinoma as their expertise allows for comprehensive and cost-effective care. 17 In particular,

# CLINICAL PRACTICE GUIDELINE GYNE-002 Version 5
the SGO highlights that gynecologic oncologist "involvement enhances the preoperative and intraoperative decision process, allowing for completion of any necessary procedure (comprehensive staging or debulking), and facilitates the decision regarding the need for additional therapy." 17 There is conflicting evidence on the usefulness of imaging for all patients. The American College of Radiation (2014) states that cross-sectional imaging is a complementary tool to surgical evaluation and can play a role in pretreatment assessment. 18 The Canadian SOG-GOC-SCC guideline recommends that CT and MRI scans not be routinely used, except in specific clinical cases for high-grade tumours or if there is a clinical suspicion of extrauterine disease. 16 The NCCN also recommends limited use of pretreatment imaging. 26 In addition to the accuracy of imaging the cost must also be considered. There is limited research specifically investigating the utility of CT scans for endometrial cancer. Basnal and colleagues 27 examined 250 abdominal-pelvis CT scans of patients with adenocarcinomas of the uterus in the United States and found that CT imaging altered management in 4% of cases. Imaging was significantly more likely to alter management in those patients with high-risk histologies such as endometrial serous and clear cell tumors (11%) and sarcomas (13%). They reported a cost of $17,622 to alter management of one patient.
In early stage carcinoma, post-operative radiotherapy has been shown to reduce vaginal and pelvic recurrences, but not distant metastases, thereby yielding no differences in 15-year survival between radiotherapy and observation alone; 28 however, patients with poorly differentiated tumours that infiltrate more than half the myometrial thickness were found to benefit from additional radiotherapy. 29 In fact, subsequent studies have also shown benefit, in terms of recurrence and survival outcomes, from radiotherapy among early stage high risk patients.  However, a recent meta-analysis of data from the ASTEC and EN.5 trials comparing adjuvant radiotherapy with observation alone in early stage intermediate and high risk patients confirmed no benefit of radiotherapy in terms of overall survival (hazard ratio 1.04; 95% CI 0.84-1.29). 33 In the absence of data to clearly show an advantage of post-operative radiotherapy over chemotherapy in patients with high-risk disease, 34 efforts have shifted towards a combined modality approach, combining chemotherapy with radiotherapy. The PORTEC-3 trial was designed to compare concurrent radiation and adjuvant chemotherapy with pelvic radiation alone in high risk and advanced stage endometrial carcinoma. Results of this study are awaited.
A combination of carboplatin with paclitaxel is the recommended protocol for systemic therapy in endometrial cancer. This is based on results showing better efficacy and less toxicity compared to other regimens, including cisplatin/doxorubicin, cisplatin/doxorubicin/paclitaxel, ifosamide/paclitaxel, carboplatin, carboplatin/paclitaxel, cisplatin alone, doxorubicin alone, paclitaxel alone, cisplatin/ifosamide (for carcinosarcoma), and ifosamide alone (for carcinosarcoma).  Hoskins et al. 43 had initially shown that a combination of carboplatin with paclitaxel was effective and less toxic than other combination chemotherapy regimes in advanced and recurrent endometrial cancers. Subsequently, a meta-analysis by Humber et al. 44 in 2007 concluded that combination chemotherapy was superior to single agent chemotherapy, with the addition of anthracyclines and taxanes to cisplatin giving the best response. Many studies since then have shown the superiority of carboplatin with paclitaxel, both in response and toxicity profile.  Results from GOG 209 a randomized phase III trial of doxorubicin/cisplatin/paclitaxel and G-CSF vs. carboplatin/paclitaxel in patients with stage III and IV or recurrent endometrial cancer are awaited.
Martin-Hirsch et al. 51 carried out a meta-analysis of six randomized control trials (4,350 patients) and concluded that progestins alone were not efficacious in the adjuvant setting. Subsequent studies have also failed to demonstrate efficacy with adjuvant hormone therapy alone.  Furthermore, combination CLINICAL PRACTICE GUIDELINE GYNE-002 Version 5
therapy (e.g. megestrol and tamoxifen) has not shown better results than megestrol alone: response rate of 19% versus 20% and median survival time of 8.6 versus 12.0 months, respectively. 55
There is growing evidence to suggest that carcinosarcomas (malignant mixed mesodermal tumours or MMMT) arise through a transdifferentiation of a uterine carcinoma into a sarcoma. Hence, in the 2010 FIGO staging, they are now staged with endometrial carcinoma. 7,8 They are rare tumours that account for 1% of female genital cancers and 3% of uterine cancers. Carcinosarcomas are highly aggressive tumours, with a 5-year survival rate of about 20% overall; between five and ten percent have a history of pelvic radiotherapy with a risk of 0.17 per 1000 women on long term tamoxifen. The recurrence rate for patients with stage I and II disease is 50% with metastasis to the pelvic and para-aortic lymph nodes and omentum being the most common. 56,57 National guidance supports a treatment approach consisting of surgery (i.e. surgical staging, total hysterectomy plus bilateral salpingo-oophorectomy with pelvic and para-aortic lymphadenectomy, cytology, omenectomy, and maximal tumour debulking for the advanced carcinosarcomas) and adjuvant therapy. 10 Lymph node involvement will be found in 14-38% of carcinosarcoma patients undergoing lymphadenectomy and lymphadenectomy has been shown to provide significant survival benefit. 57 Depending on the stage of disease, adjuvant therapy may include chemotherapy and/or whole abdominopelvic radiotherapy with or without brachytherapy. 10,58 The majority of evidence for the role of radiotherapy is from non-randomized controlled trials (RCTs). However, there have been two RCTs: EORTC 55874 and GOG 150. EORTC 55874 compared post-operative radiation and observation alone in 'high grade' sarcomas. Pelvic radiotherapy (51 Gy in 28 fractions over 5 weeks) improved local control (61 vs. 47%) but provided no survival benefit. There was, however, an increased rate of distant first relapse. 59 GOG 150 compared whole abdominal radiotherapy with cisplatin/ifosfamide chemotherapy in stage I-IV optimally debulked patients. Vaginal recurrences were more frequent in the chemotherapy arm, while abdominal recurrences were more common in the radiotherapy arm. Having adjusted for stage, cell type, and age, the death rate was 30% lower for the chemotherapy arm. 60 Chemotherapy drugs have included single agent cisplatin, carboplatin, ifosfamide, doxorubicin, and paclitaxel. 10 Combination therapy has included treatment with cisplatin and ifosfamide with or without doxorubicin, and carboplatin and paclitaxel. 10 As yet there is no convincing evidence that adjuvant chemotherapy can improve progression free survival (PFS) and overall survival (OS) in patients with early stage disease.
Ifosamide combination therapy has demonstrated efficacy both with cisplatin (54% overall response rate; 52% overall survival rate at 84 months) 61,62 and with paclitaxel (45% response rate overall) 63 in patients with advanced, persistent, or recurrent uterine carcinosarcoma. Other regimens that have shown promising results include: carboplatin and paclitaxel alone or alternated with carboplatin and doxorubicin (overall response rate 62-67%; median progression-free survival 5.5-12.0 months)  Hoskins et al. reported a 60% response rate using a combination of carboplatin and paclitaxel. 47 Median PFS was 16 months with a median 12 month PFS for recurrences. Importantly, the decrease in toxicity and convenience of administration was superior to the combination of cisplatin and ifosfamide. Other regimens that have demonstrated limited efficacy in carcinosarcoma include gemcitabine and paclitaxel, imatinib mesylate, sorafenib, docetaxel alone, topotecan, and paclitaxel alone.

# Sentinel lymph nodes CLINICAL PRACTICE GUIDELINE GYNE-002 Version 5
There is a lack of evidence for the evaluation of sentinel lymph nodes. A meta-analysis conducted by Ansari et al. 73 combined results from 51 studies and found a pooled detection rate of 77.8% and pooled sensitivity of 89%. They note that sentinel lymph node mapping appears feasible for patients with endometrial cancer, but will not consider this procedure safe until larger studies evaluating the false negative rates and factors influencing sensitivity are conducted. Another meta-analysis performed by Kang et al. 74 found a similar detection rate of 78% and sensitivity of 93% in 26 studies, however, they caution the interpretation of the results because of significant small study effects.

# Lynch syndrome screening
Lynch syndrome is an inherited cancer syndrome caused by autosomal dominant mutations in genes encoding DNA mismatch repair (MMR) proteins. Women with Lynch syndrome are at risk of endometrial, colorectal, and other Lynch syndrome-associated cancers. 75 Their first-degree relatives (parents, siblings, and children) are at a 50% risk of also having Lynch syndrome. 75 Identifying individuals with Lynch syndrome allows for increased screening and earlier detection of cancer. Universal screening of endometrial tumours for Lynch syndrome via IHC and/or MSI analysis has been recommended by the SGO. 17 Screening has also been shown to be cost-effective. 76,77 However, there is no evidence to recommend IHC and/or MSI analysis over each other or both. 75

# GLOSSARY OF ABBREVIATIONS
- Present the guideline at the local and provincial tumour team meetings and weekly rounds.
- Post the guideline on the Alberta Health Services website.
- Send an electronic notification of the new guideline to all members of CancerControl Alberta.
A formal review of the guideline will be conducted at the Annual Provincial Meeting in 2017. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.