Japan Society of Gynecologic Oncology 2018 guidelines for treatment of uterine body neoplasms



# Introduction
Endometrial cancer is a major gynecologic malignancy that has the highest rate among patients with gynecologic malignant tumors in Japan. The age-adjusted prevalence of endometrial cancer in 2014 was 16.0 per 100,000 females, and this has increased about fourfold in the past 30 years . However, the age-adjusted mortality rate in 2017 was 2.0, which is lower than the rates for cervical and ovarian cancers .
The 1st edition of the Guidelines for Treatment of Uterine Body Cancer was published by the Japan Society of Gynecological Oncology (JSGO) in 2006, and was revised in the 2nd edition in 2009 . In the second revision, 3 chapters on treatment of mesenchymal tumors such as leiomyosarcoma and treatment of serous carcinoma and clear cell carcinoma were added . In the 3rd edition in 2013, treatments for trophoblastic disease were added, and the target disease was expanded . The current 4th revision does not have major changes from the 3rd version. The new version includes nine chapters with the following contents, and 9 algorithms.
Chapter 1: Overview of the guidelines, recommendation process, and conflict of interest. Chapter 2: Initial treatment for endometrial cancer; hysterectomy and clinical significance of pelvic lymph node dissection and paraaortic lymph node dissection; minimally invasive surgery (MIS) based on endoscopic (laparoscopic and robot-assisted) surgery and sentinel lymph node biopsy; and optimal treatment for endometrial cancer found after hysterectomy or after inadequate staging surgery. Chapter 3: Postoperative adjuvant treatment for endometrial cancer; and superiority of chemotherapy over radiation therapy based on the actual clinical situation in Japan. Chapter 4: Post-treatment surveillance for endometrial cancer; and hormone replacement therapy. Chapter 5: Treatment for advanced or recurrent endometrial cancer; adjuvant chemotherapy is often used for a case with recurrence risk, and many patients are not chemo-naive at the time of recurrence. Chapter 6: Fertility-sparing treatment; treatment for atypical endometrial hyperplasia (AEH) and endometrioid carcinoma G1, followed by infertility treatment and treatment for recurrent cases. Chapter 7: Treatment for uterine carcinosarcoma and uterine sarcoma; initial treatment and treatment for recurrent cases. Chapter 8: Treatment for trophoblastic disease (added in 3rd edition); choriocarcinoma, invasive mole, persistent trophoblastic disease, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). Chapter 9: Document collections, including literature search terms.
Most treatment for uterine body neoplasms including endometrial cancer (excluding trophoblastic diseases) involves surgical therapy, including total hysterectomy as initial treatment. Methods of hysterectomy and the need for pelvic/paraaortic lymphadenectomy will mainly be discussed. Chemotherapy or radiotherapy is added as needed in cases with a high risk of postoperative recurrence. This also affects the choice of treatment for recurrent cancer. Hormone therapy is used for recurrence or in fertility preservation therapy. Immunotherapy has yet to be included in the guidelines. Chemotherapy is the main treatment for unresectable advanced uterine cancers and trophoblastic diseases.

## Chapter 1: overview of the guidelines

## How to use the guidelines
We describe one criterion for selecting a better treatment method for uterine body neoplasms in Japan, and show evidence for the suggested approach. This does not limit treatment to that described in the Guidelines. The aims of the guidelines are as follows:
1) To define appropriate treatment for endometrial cancer, carcinosarcoma/sarcoma, and trophoblastic disease. 2) Reduce disparities in treatment approaches among institutions.
3) Improve the safety of these treatments and the prognosis of patients. 4) Reduce physical, psychological and economic burdens on patients by using appropriate treatment. 5) Improve mutual understanding between medical staff and patients.

## Intended audience
These Guidelines are intended for practicing physicians engaged in treatment of patients with endometrial cancer, carcinosarcoma/sarcoma, and trophoblastic diseases.

## Diseases addressed by these guidelines
Diseases addressed by the guidelines include AEH, endometrial cancer, uterine carcinosarcoma, uterine sarcoma, and trophoblastic tumor, and recurrence of these diseases. There are fewer randomized controlled trials of treatment of uterine body tumor compared to lung, breast, and colorectal cancers. Some items cannot be defined in the guidelines at the evidence level. 2) Some evidence in Europe and the United States is unacceptable in Japan due to differences in background, while some treatment that is common in Japan differs from that in Europe and the United States. In such cases, the content is prioritized using the current consensus in Japan. 3) Therapy is often difficult to administer under the Japanese medical care insurance system.

## Notes on using these guidelines
In this regard, the guidelines follow the Committee on Clinical Practice Guidelines for Use of Anticancer Agents of the Japan Society of Clinical Oncology (JSCO).

## Literature retrieval
In this revision, we asked the Japan Medical Library Association (JMLA) to prepare literature search terms for a systematic database search. The specific literature retrieval method was as follows.
1) The Formulation Committee selected an article using keywords related to the clinical question (CQ), and the JMLA then prepared relevant search terms and conducted a comprehensive literature search. If a large number of articles were found, the keywords were changed and more were added after review by the Formulation Committee and the JMLA. The Formulation Committee examined the retrieved articles and finally identified about 20 important articles. 2) Articles in PubMed, the Japan Medical Abstract Society, and the Cochrane Library from January 2011 to December 2016 were covered in the search. Articles published before 2011 that were cited in previous editions of the guidelines and are needed for recommendations are used as references. Articles published after January 2017 were examined separately and some were used as references.

## Procedure for creation of the guidelines
To create these guidelines, the Guidelines Formulation Committee and Evaluation Committee were independently established within the Committee for Treatment Guidelines for Uterine Body Neoplasms that was established by the Guidelines Committee of the JSGO. The Chair of the Guidelines Committee was concurrently Chair of the Committee for Treatment Guidelines for Uterine Cancer and Chair of the Guidelines Formulation Committee. Revision of the Guidelines took place from October 2016 to June 2018, after 5 meetings of the Guidelines Formulation Committee, a consensus meeting, and a period for public comment.

## Evidence levels and recommendation grades
1) Collected evidence was evaluated for quality using the criteria of the JSCO and its Committee of Clinical Practice Guidelines for the Use of Anticancer Agents. However, some contents were modified in line with these guidelines . 2) Strengths of recommendations in our guidelines were also determined using the recommendation criteria of the JSCO and its Committee of Clinical Practice Guidelines for the Use of Anticancer Agents. These were modified with reference to the Guide 2007 Minds Practice Guidelines . 3) We referred to the Guide 2014 Minds Practice Guidelines to determine recommendation grades. Judgment of recommendation grades was made based on agreement of the Guidelines Committee, based on the evidence level, effect, concerns with the reference study, implementation of the treatment regimen, and coverage by insurance in Japan. 4) If it was difficult to reach a decision, the recommendation grade was decided by a vote.

# Disclosure of information

## Responsibility for treatment
The JSGO bears responsibility for the content and descriptions of these guidelines. However, the final decision to use the guidelines should be made by the individual user. Thus, the responsibility for the treatment outcomes is directly attributed to the person in charge.

## Revision
1) These guidelines are continuously being revised by the Committee for Treatment Guidelines for Uterine Body Neoplasms based on medical advances and changes. 2) Evidence that is newly accumulated after preparation of these guidelines is saved in a database. 3) Information on clinical problems occurring with use of these guidelines is being collected.

## 4) revisions are considered by the guidelines formulation committee and evaluation
Committee based on new evidence and information. Opinions from academic societies, groups and JSGO members are also widely sought. 5) After these processes, the Committee for Treatment Guidelines for Uterine Cancer will develop a revised version with the approval of the JSGO.

# Funding
Preparation of these guidelines was funded by the JSGO only. No assistance was provided by other organizations or companies.

## Conflicts of interest
1) The Board of the Society Conflict of Interest Committee confirmed the absence of any conflicts of interest. Thirteen members (4 in the Guidelines Formulation Committee and 9 in the Guidelines Evaluation Committee) had conflicts of interest due to work or social activity with a company, but none of these conflicts of interest conditions were judged to have exceeded the acceptable range.
2) The contents of these Guidelines are based on the consensus of the Guideline Committee and thus are unaffected by any interest associated with specific groups or products.

## Summary of recommendations
Each chapter comprises CQs, recommendations, background, objectives, explanations, and references. This article summarizes the guidelines in a question-and-answer format.
Recommendations from each chapter are listed below, under their respective chapter titles.

## Algorithms
The guidelines contain the following 9 algorithms: 1) Initial treatment for endometrial cancer considered to be stage I or II preoperatively .
2) Initial treatment for the patients who are confirmed to be endometrial cancer after hysterectomy and for cases with an intermediate or high risk of postoperative recurrence despite a presumed low risk preoperatively . 3) Initial treatment for endometrial cancer considered to be stage III or IV preoperatively . 4) Postoperative adjuvant treatment for endometrial cancer . 5) Treatment of recurrent endometrial cancer . 6) Fertility-sparing therapy for AEH and endometrioid carcinoma (corresponding to G1) . 7) Treatment for uterine carcinosarcoma . 8) Treatment for uterine sarcoma . 9) Treatment for choriocarcinoma CQ09. Is intraoperative frozen-section diagnosis useful to determine the optimal operative method?