Published online Nov 27, 2023.
https://doi.org/10.3802/jgo.2024.35.e15
Japan Society of Gynecologic Oncology 2022 guidelines for uterine cervical neoplasm treatment
Abstract
The Japan Society of Gynecologic Oncology (JSGO) Guidelines 2022 for the Treatment of Uterine Cervical Cancer are revised from the 2017 guideline. This guideline aimed to provide standard care for cervical cancer, indicate appropriate current treatment methods for cervical cancer, minimize variances in treatment methods among institutions, improve disease prognosis and treatment safety, reduce the economic and psychosomatic burden of patients by promoting the performance of appropriate treatment, and enhance mutual understanding between patients and healthcare professionals. The guidelines were prepared through the consensus of the JSGO Guideline Committee, based on a careful review of evidence gathered through the literature searches and the medical health insurance system and actual clinical practice situations in Japan. The guidelines comprise seven chapters and 5 algorithms. The main features of the 2022 revision are as follows: 1) added discussed points at the final consensus meeting; 2) revised the treatment methods based on the International Federation of Gynecology and Obstetrics 2018 staging system; 3) examined minimally invasive surgery based on Laparoscopic Approach to Cervical Cancer trial; 4) added clinical question (CQ) for treatments of rare histological types, gastric type, and small-cell neuroendocrine carcinoma; 5) added CQ for intensity-modulated radiation therapy; 6) added CQ for cancer genomic profiling test; and 7) added CQ for cancer survivorship. Each recommendation is accompanied by a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here, we present the English version of the JSGO Guidelines 2022 for the Treatment of Uterine Cervical Cancer.
INTRODUCTION
Cervical cancer is declining in developed countries due to the spread of human papillomavirus (HPV) vaccines [1]. Unfortunately, the spread of HPV vaccines has been delayed in Japan, and the number of patients has not decreased. Many cases of invasive cervical cancer are still diagnosed [2]. In Japan, 10,879 new cases of cervical cancer and 2,887 deaths occurred in 2020 across all ages [3].
The first edition of the Guidelines for Treatment of Uterine Cervical Cancer was published by the Japan Society of Gynecological Oncology (JSGO) in 2007 and was revised in the second edition in 2011 [4]. The second revision incorporated many opinions from radiation oncologists [5]. The third edition in 2017 defined cervical intraepithelial neoplasia (CIN) 3 and adenocarcinoma in situ (AIS) as precancerous lesions and added minimally invasive surgery, fertility-sparing surgery, sentinel lymph nodes navigation surgery, and hormone replacement therapy after treatment [6]. The current fourth revision has had major changes since the International Federation of Gynecology and Obstetrics (FIGO) staging system was revised from FIGO 2008 to FIGO 2018. The new version includes 7 chapters with the following contents and 5 algorithms.
Chapter 1: Overview of the guidelines, recommendation process, and conflict of interest.
Chapter 2: Primary treatment for cervical precancerous lesions and stage IA cervical cancer.
Chapter 3: The initial treatments for stage IB–IV cervical cancer.
Chapter 4: The adjuvant therapy.
Chapter 5: The treatment of residual lesions and recurrent cervical cancer.
Chapter 6: Follow-up after primary treatment.
Chapter 7: The treatment of cervical cancer with pregnancy.
Consensus for each recommendation was achieved by voting of the committee and external evaluation board.
CHAPTER 1. OVERVIEW OF THE GUIDELINES, RECOMMENDATION PROCESS, AND CONFLICT OF INTEREST
1. How to use the guidelines
We describe one criterion for selecting a better treatment method for uterine cervical neoplasms in Japan and show evidence for the suggested approach. This does not limit treatment to that described in the guidelines. The guidelines aim to:
1) Define appropriate treatment for uterine cervical neoplasm
2) Reduce disparities in treatment approaches among institutions
3) Improve treatment safety and patient prognosis
4) Reduce physical, psychological, and economic burdens on patients using appropriate treatment
5) Improve mutual understanding between medical staff and patients
2. Intended audience
These guidelines are meant for healthcare professionals, such as doctors, nurses, and pharmacists, who treat patients with uterine cervical neoplasm. Furthermore, these guidelines aim to assist individuals including patients and their families in comprehending uterine cervical neoplasm.
3. Diseases addressed by these guidelines
Diseases addressed by the guidelines include CIN3, AIS, primary uterine cervical cancer, and their recurrence.
4. Notes on using these guidelines
Therapy is often difficult to administer under the Japanese medical care insurance system. Thus, the guidelines follow the Committee on Clinical Practice Guidelines for Use of Anticancer Agents of the Japan Society of Clinical Oncology (JSCO).
5. Committee members
The making and evaluating of the guidelines’ draft involved gynecologic oncologists, medical oncologists, radiologists, pathologists, and palliative care physicians. Furthermore, pharmacists, nurses, patients, and general (male and female) participants have cooperated from the beginning of setting clinical questions (CQs) as a third party. Those external committee members were informed of the contents and revision points of the final version of these guidelines by the chairman and vice chairman and participated in voting for consensus. The patient group Katoreanomori participated as an evaluating committee.
6. Literature retrieval
This revision requested 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 CQ, and then the JMLA prepared relevant search terms and conducted a comprehensive literature search. The keywords were changed, and more were added after review by the Formulation Committee and the JMLA if a large number of articles were found. The Formulation Committee examined the retrieved articles and finally identified approximately 20 important articles.
2) Articles in PubMed, the Japan Medical Abstract Society, and the Cochrane Library were covered in the search from January 2016 to December 2020. Articles published before 2014 that were cited in previous guideline editions and are needed for recommendations are used as references. Articles published after January 2021 were separately examined and some were used as references.
3) Literature search items are published on the web (https://jsgo.or.jp/guideline/keigan2022.html).
7. Level of evidence and grade of recommendations
1) We referred to the 2017 Minds Practice Guidelines to determine evidence levels of recommendation grades [7]. Outcomes were set for each CQ. The body of evidence was assessed considering study designs, bias risk, and indirectness of the studies selected for each outcome (Table S1).
2) Levels of evidence in these guidelines are determined based on the factors prescribing a body of evidence that differ from the previous “Levels of evidence,” which were based on study design, such as “randomized phase III.” Level of evidence might be “B (moderate),” not “A (strong),” depending on the quality of the clinical trial although evidence arises from a randomized phase III trial.
3) The Formulation Committee evaluated recommendation grades considering not only evidence levels, balance between benefits and harms, and patient values and preferences but also the community standards and insurance coverage in Japan (Table S2).
4) Systematic reviews and meta-analyses have been performed for each outcome of the three CQs (CQ03, CQ08, and CQ13). A qualitative systematic review in which logic and certainty are inferred from the context was performed for the CQ unable to perform quantitative evaluation (meta-analysis).
5) Recommendations, levels of evidence, and grades of recommendation were determined in the seventh Formulation Committee. Consensus was achieved by voting.
6) The recommendation was reviewed and revised as “grades of recommendation,” “levels of evidence,” or recommendation itself when the consensus did not reach 75%. Then, we voted again.
7) Opinions and points of discussion for the revoted recommendations or the recommendations with consensus lower than the criteria followed the recommendations. Discussion points at voting are described in revoted CQs.
8) The external committee voted on the recommendations in CQ07–14, CQ20, CQ31–36 and those that achieved the criteria of consensus in the Formulation Committee. Thus, the consensus in these CQs show the sum of votes by both the core and external committee members.
8. Procedure for guideline creation
The Guidelines Formulation Committee and Evaluation Committee were independently established within the Committee for Treatment Guidelines for Cervical Cancer established by the Guidelines Committee of the JSGO to create these guidelines. The Chair of the Guidelines Committee was concurrently the Chair of the Committee for Treatment Guidelines for Cervical Cancer and the Chair of the Guidelines Formulation Committee. Guideline revisions took place from August 2020 to May 2022, after seven meetings of the Guidelines Formulation Committee, a consensus meeting, and a period for public comment.
9. Tips for activation of use and disclosure of information
1) Algorithms were created to boost usefulness for the audience.
2) These guidelines are published as a pamphlet and are shown on the homepages of JSGO, JSCO, and Minds to facilitate widespread use.
3) The results of systematic reviews and meta-analyses in CQ13 have been published in internationally cited journals.
10. 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.
11. Monitoring and revision
1) These guidelines are continuously being revised by the Committee for Treatment Guidelines for Cervical Cancer based on medical advances and changes.
2) Evidence that is newly accumulated after the preparation of these guidelines is saved in a database.
3) Information on clinical problems occurring with the use of these guidelines is being collected.
4) The next version, as a pamphlet, will be published in 2027.
5) Revisions are considered by the Guidelines Formulation Committee and Evaluation Committee based on new evidence and information before publishing the next pamphlet depending on necessity. Opinions from academic societies, groups, and JSGO members are also widely sought.
6) The Committee for Treatment Guidelines for Cervical Cancer will develop a revised version with JSGO approval after these processes.
12. Funding
The preparation of these guidelines was funded only by the JSGO. No assistance was provided by other organizations or companies.
13. Conflicts of interest
1) The Board of the Society Conflict of Interest Committee confirmed the absence of any conflicts of interest. A total of 24 members (12 in the Guidelines Formulation Committee and 12 in the Guidelines Evaluation Committee) in 2019 and 22 members (10 in the Guidelines Formulation Committee and 12 in the Guidelines Evaluation Committee) in 2020 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.
14. 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 under their respective chapter titles below.
15. Algorithms
The guidelines contain the following 5 algorithms:
1) Primary treatment for cervical precancerous lesions (CIN3 and AIS) and stage IA cervical cancer (Fig. 1).
2) Primary treatment for stages IB–II cervical cancer (Fig. 2).
3) Adjuvant therapy for stages IB–II cervical cancer (Fig. 3).
4) Primary treatment for stages III–IV cervical cancer (Fig. 4).
5) Therapy for relapsed cervical cancer (Fig. 5).
Fig. 1
a)The cone biopsy should aim for a diagnosis or a diagnosis and treatment. The patient should be treated as if they have positive margins if cervical curettage is positive. b)The flow chart is based on a diagnosis with the resected specimen of the cone biopsy. However, if cone biopsy is difficult because of cervical atrophy, such as in older patients, the omission of cone biopsy may be suggested. However, preoperatively, it is necessary to carefully review the cytology, colposcopy, and biopsy tissue findings; this allows for a hysterectomy suitable for the estimated lesion. c)A lesion should be diagnosed as more than CIN3 (squamous lesions) or AIS (glandular lesions) in the case of a positive stump. d)This is suggested when the patient strongly wishes to preserve her fertility. Careful inspection is required to preserve fertility. e)Operative procedures should be individualized according to the histopathological findings of the cone biopsy specimens, namely the extent of invasion and the presence or absence of lymphovascular space invasion. f)Radiation therapy is also an option when surgical treatment is difficult because patients are elderly or with medical complications.
Flow chart 1: primary treatment for cervical precancerous lesions (CIN3 and adenocarcinoma in situ) and IA cervical cancer. The flow of the treatment is based on a cone biopsy diagnosis.
AIS, adenocarcinoma in situ; CIN, cervical intraepithelial neoplasia; CQ, clinical question.
Fig. 2
a)This is suggested when the patient strongly wishes to preserve her fertility. Residual lesions are reported with negative margin, and careful inspection is required to preserve the uterus. Fertility and perinatal prognosis should also be considered. b)See the section on CQ26 when the primary treatment is radiation therapy or CCRT. c)Background and histological type should be considered, and the operator should be carefully selected.
Flow chart 2: primary treatment for stage IB–II cervical cancer.
CCRT, concurrent chemoradiotherapy; CQ, clinical question.
Fig. 3
Flow chart 3: postoperative therapy for stage IB–II cervical cancer. Many discussions and reports exist on risk assessment for postoperative recurrence. Postoperative therapy must be considered according to the individual case.
CCRT, concurrent chemoradiotherapy; CQ, clinical question.
Fig. 4
a)For stage IIIC1 (T1, 2). b)For stage IIIC2. c)Radiation therapy to regional lymph nodes is decided according to stage III. *Prophylactic irradiation to the para-aortic region is not recommended if only positive pelvic lymph nodes are present.
Flow chart 4: primary treatment for stage III–IV cervical cancer.
CCRT, concurrent chemoradiotherapy; CQ, clinical question.
Fig. 5
a)Total pelvic exenteration is indicated in a case that forms vesicovaginal fistula and rectovaginal fistula in the vagina stump center recurrence case, etc. However, careful consideration of indications is required because total pelvic exenteration is associated with a higher incidence of postoperative morbidity. b)It is necessary to pay attention to the indication. c)Surgical resection is indicated, for example, if a single or few brain metastases are resectable, and the intracranial lesion is controlled with good performance status. d)Surgical resection involves local pelvic recurrence, vaginal stump, and central cervical recurrence; however, the same caution as in a) is required.
Flow chart 5: therapy for relapsed cervical cancer.
CCRT, concurrent chemoradiotherapy; CQ, clinical question.
CHAPTER 2. PRIMARY TREATMENT FOR CERVICAL PRECANCEROUS LESIONS AND STAGE IA CERVICAL CANCER
CQ01: Are additional treatments that are recommended for CIN3/AIS diagnosed by cone biopsy?
Recommendations
|
CQ02: Are additional treatments recommended for positive cervical resection margins for CIN3/AIS?
Recommendations
|
CQ03: Is repeated cone biopsy recommended for recurrent CIN3 following conservative treatment?
Recommendations
|
Discussion points at voting: First, the consensus of recommendation 1 was <75% (63%): “1. Repeated cone biopsy is recommended, level of evidence is B, and strength of recommendation is 1 (↑↑).” A total hysterectomy is often performed when the patient does not wish to preserve fertility in practice, and there is insufficient evidence for re-cone biopsy. Therefore, “who strongly desire fertility preservation” was added to the previous recommendation 1. The revote resulted in 100% consensus.
CQ04: What treatments are recommended for stage IA1 disease?
Recommendations
|
CQ05: Is modified radical hysterectomy with pelvic lymph node dissection recommended for stage IA2 disease?
Recommendation
|
Discussion points at voting: An opinion was raised on the poor rationale about a modified radical hysterectomy for IA2 disease. A radical hysterectomy for IA2 may become the excessive treatment in the guideline preparation in the process so far although radical hysterectomy was often performed for IA2 in Japan. Conversely, no sufficient evidence proved simple hysterectomy is enough for stage IA2. Therefore, a modified radical hysterectomy is suggested in IA2. An opinion was raised that separating the recommended sentences in the presence or absence of lymphovascular space invasion is better since the previous version of the guidelines suggested omission of pelvic lymphadenectomy in the absence of lymphovascular space invasion, and the consensus did not reach 75% in the first vote (73%). Subsequent discussions suggested that the present FIGO staging system involves previous IB1, uncertainty about the pathologic diagnosis of lymphovascular space invasion and IA2, and there is insufficient evidence that the omission of lymphadenectomy does not affect prognostic. As annotated, the lymphadenectomy is suggested in the absence of vascular invasion, and the above recommendation sentence achieved the consensus of 90% by revoting. Further, the omission of lymphadenectomy for stage IA2 was agreed to be based on sentinel lymph node assessment.
CQ06: Is adjuvant radiation therapy recommended for stage IB and/or advanced disease after a simple hysterectomy?
Recommendation
|
CHAPTER 3. THE INITIAL TREATMENTS FOR STAGE IB–IV CERVICAL CANCER
CQ07: Between surgery or radiotherapy, which treatment is recommended for clinical stages IB1–2 and IIA1?
Recommendation
|
CQ08: Between surgery or radiotherapy, which treatment is recommended for clinical stages IB3 and IIA2?
Recommendation
|
CQ09: Between surgery or radiotherapy, which treatment is recommended for clinical stage IIB?
Recommendations
|
CQ10: Is neoadjuvant chemotherapy recommended for clinical stage IB–II diseases?
Recommendation
|
Discussion points at voting: The consensus in the first vote was 36%. Although there was a consensus that chemotherapy should not be recommended prior to surgery, there was an opinion that preoperative chemotherapy may be selected depending on clinicopathological factors such as tumor size and histological type, as well as social factors that require waiting time until surgery due to infection or restrictions on the surgical frame. Finally, since the evidence for recommending preoperative chemotherapy was weak, a re-voting was conducted with the above recommendation on the condition that the points should be described in this “Discussion points at voting” section, with a consensus rate of 88%.
CQ11: Is laparoscopic surgery, or robotic-assisted surgery recommended for clinical stages IB–IIA?
Recommendations
|
CQ12: Is radical trachelectomy recommended for patient who strongly desire fertility preservation?
Recommendation
|
CQ13: Is omission of pelvic lymph node dissection recommended when negative for sentinel node by the sentinel lymph node navigation surgery?
Recommendation
|
CQ14: Is ovarian preservation recommended for patients who undergo radical hysterectomy?
Recommendations
|
Discussion points at voting: The consensus for recommendation 2 was 36% when the first voting in the level of evidence B. No evidence supporting ovarian preservation was cited as an opinion, and the revoting as the level of evidence C resulted in a consensus of 100%.
CQ15: Is pelvic and/or para-aortic lymph node biopsy recommended before primary treatment?
Recommendation
|
CQ16: What treatment is recommended for clinical stages I–II with rare variants?
Recommendations
|
Discussion points at voting: The consensus for recommendation 2 was 73% when the first voting was in the strength of recommendation 2 (↑). The strength of recommendation changed to 1 (↑↑) and revoted because many review articles reported the efficacy of systemic chemotherapy, resulting in a 90% consensus.
CQ17: Is surgery recommended for clinical stages IIIA, IIIB, IIIC (T3), and IVA?
Recommendation
|
CQ18: Is CCRT recommended for clinical stages IIIA, IIIB, IIIC (T3), and IVA?
Recommendation
|
CQ19: What CCRT regimens are recommended for local advanced cervical cancer?
Recommendation
|
CQ20: Is neoadjuvant or adjuvant chemotherapy recommended for stages III and IVA?
Recommendations
|
CQ21: What treatment is recommended for stage IVB disease?
Recommendations
|
CQ22: What treatment is recommended for stage IIIC (T1 and T2) patients with lymph node metastasis confirmed by imaging or biopsy before the main treatment?
Recommendations
|
CHAPTER 4. ADJUVANT THERAPY
CQ23: What adjuvant therapy is recommended for postoperative patients?
Recommendations
|
CQ24: Is intensity-modulated radiation therapy (IMRT) recommended for adjuvant whole pelvic radiotherapy?
Recommendation
|
CQ25: Is prophylactic para-aortic irradiation recommended for stage IIIC1 disease?
Recommendations
|
CHAPTER 5. THE TREATMENT OF RESIDUAL LESIONS AND RECURRENT CERVICAL CANCER
CQ26: Is additional hysterectomy recommended for whom primary radiation therapy was performed?
Recommendation
|
CQ27: Is radiotherapy recommended for recurrence confined to the pelvis if radiotherapy has not been previously performed?
Recommendations
|
CQ28: What treatments are recommended for recurrence within the previous radiation field?
Recommendations
|
CQ29: Is combination chemotherapy recommended for recurrent disease?
Recommendations
|
Discussion points at voting: The consensus for recommendation 2 was 55% when the first voting in the strength of recommendation of 2 (↑), level of evidence B. Paclitaxel and cisplatin combination therapy rather than paclitaxel and carboplatin combination therapy was agreed to be recommended if paclitaxel and cisplatin combination therapy was available, but there was an opinion that the strength of recommendation 1 was appropriate in the setting described in recommendation 2. Revoting with the above recommendation resulted in a consensus of 100%.
CQ30: Is treatment based on a cancer genome profiling test using a next-generation sequencer recommended for patients with cancer who are expected to complete standard treatment?
Recommendations
|
CHAPTER 6. FOLLOW-UP AFTER PRIMARY TREATMENT
CQ31: Are periodic examinations recommended to detect recurrence after cervical cancer treatment?
Recommendations
|
CQ32: What points should be kept in mind regarding lifestyle guidance after cervical cancer treatment?
Recommendations
|
CQ33: Is hormone replacement therapy recommended after treatment?
Recommendation
|
CQ34: What points should be kept in mind when guiding reproductive activity after trachelectomy?
Recommendations
|
CHAPTER 7. THE TREATMENT OF CERVICAL CANCER WITH PREGNANCY
CQ35: Is cone-biopsy during pregnancy recommended for patients with CIN3, AIS, or stage IA cancer diagnosed by biopsy during pregnancy?
Recommendations
|
CQ36: Is waiting before definitive therapy for patients with stage IB1 or higher disease?
Recommendations
|
SUPPLEMENTARY MATERIALS
Certainty ratings for outcomes to determine grades of recommendationTable S1
Strength of recommendationTable S2
Classification of risk of postoperative cervical cancer recurrenceTable S3
Conflict of Interest:No potential conflict of interest relevant to this article was reported.
Author Contributions:
Writing - original draft: S.M.
Writing - review & editing: N.S., T.H., Y.W., K.Y., T.T., K.M., H.Y., N.H., Y.K., T.K., B.T., K.H., M.M.
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Kojimahara N, Nakayama T, Morizane T, Yamaguchi N, Yoshida M. In: Minds manual for guideline development 2017. Tokyo: Japan Council for Quality Health Care; 2017.
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