Clinical practice guidelines for cervical cancer: the Korean Society of Gynecologic Oncology guidelines

- ¹Department of Obstetrics and Gynecology, Daejeon St. Mary’s Hospital, The Catholic University of Korea, Daejeon, Korea.
- ²Department of Obstetrics and Gynecology, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea.
- ³Department of Obstetrics and Gynecology, Institute of Women’s Medical Life Science, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
- ⁴Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Korea.
- ⁵Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
- ⁶Department of Obstetrics and Gynecology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea.
- ⁷Department of Obstetrics and Gynecology, Keimyung University Dongsan Medical Center, Daegu, Korea.
- ⁸Department of Obstetrics and Gynecology, CHA Ilsan Medical Center, CHA University, Goyang, Korea.
- ⁹Department of Obstetrics and Gynecology, Hallym University Kangnam Sacred Heart Hospital, Seoul, Korea.
- ¹⁰Department of Obstetrics and Gynecology, Wonju Severance Christian Hospital, Yonsei University College of Medicine, Wonju, Korea.
- ¹¹Department of Obstetrics and Gynecology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea.
- ¹²Department of Obstetrics and Gynecology, Hanyang University Medical Center, Seoul, Korea.
Correspondence to Keun Ho Lee. Department of Obstetrics and Gynecology, Seoul St. Mary’s Hospital, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea. Email: hohoho@catholic.ac.kr

Received October 31, 2023; Revised December 24, 2023; Accepted December 25, 2023.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

This fifth revised version of the Korean Society of Gynecologic Oncology practice guidelines for the management of cervical cancer incorporates recent research findings and changes in treatment strategies based on version 4.0 released in 2020. Each key question was developed by focusing on recent notable insights and crucial contemporary issues in the field of cervical cancer. These questions were evaluated for their significance and impact on the current treatment and were finalized through voting by the development committee. The selected key questions were as follows: the efficacy and safety of immune checkpoint inhibitors as first- or second-line treatment for recurrent or metastatic cervical cancer; the oncologic safety of minimally invasive radical hysterectomy in early stage cervical cancer; the efficacy and safety of adjuvant systemic treatment after concurrent chemoradiotherapy in locally advanced cervical cancer; and the oncologic safety of sentinel lymph node mapping compared to pelvic lymph node dissection. The recommendations, directions, and strengths of this guideline were based on systematic reviews and meta-analyses, and were finally confirmed through public hearings and external reviews. In this study, we describe the revised practice guidelines for the management of cervical cancer.

Synopsis

The Korean Society of Gynecologic Oncology developed an updated practice guidelines for the management of cervical cancer. Each key questions were developed focusing on recent notable insights and crucial contemporary issues. The recommendations, directions and strength in this guideline were based on systematic reviews and meta-analyses.

Keywords

Chemoradiotherapy; Immune Checkpoint Inhibitors; Minimally Invasive Surgical Procedures; Practice Guideline; Sentinel Lymph Node Biopsy; Uterine Cervical Neoplasms

INTRODUCTION

The Korean Society of Gynecologic Oncology (KSGO) has issued practice guidelines to standardize cervical cancer treatment and enhance its quality in Korea, with the ultimate goal of improving the survival rates of patients with cervical cancer. While various countries and academic organizations, including those in the United States and Europe, have issued clinical guidelines, it is essential to develop treatment guidelines tailored to the Korean healthcare environment because of the differences in medical systems, healthcare quality, and national health insurance coverage among countries. These guidelines are evidence-based and created through systematic reviews of clinical trial results and the application of objective evaluation tools. It targets gynecologic oncologists at tertiary hospitals, where patients with cervical cancer mainly receive treatment, and physicians are responsible for post-treatment follow-ups.

Cervical cancer treatment guidelines have been updated approximately every 5 years since their inception in 2006. The current version, the fifth revised edition, is based on version 4.0, which was released in 2020, and incorporates recent research findings and changes in treatment strategies.

The histopathological classification in these guidelines follows the 2020 revised World Health Organization classification [1], and the staging of cervical cancer is based on the 2018 revised International Federation of Gynecology and Obstetrics staging system (Table 1) [2].

Table 1
International Federation of Gynecology and Obstetrics clinical staging for uterine cervix (2018)

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MATERIALS AND METHODS

1. The committee on guideline development

The development committee of the KSGO cervical cancer practice guidelines was organized into an operating committee, working committee, advisory committee, conflict of interest committee, and an administrative support team based on the agreement and recommendations of the KSGO and the National Cancer Center. The operating committee consisted of the current executive board members of the KSGO and chairpersons of the guideline subcommittees, overseeing the planning and support for the development of these clinical practice guidelines. The working committee was responsible for evidence collection, systematic reviews, grading of the level of evidence, and manuscript writing. Methodology experts provided consultation on methodology throughout the development process. The advisory committee included eminent professors in the field of gynecologic oncology and professors recommended by relevant societies, who evaluated the applicability of clinical practice guidelines in real-world settings, and reviewed their validity from different perspectives. The conflict of interest committee conducted investigations and assessed risks according to conflict of interest management principles.

2. Development of key questions and literature search strategy

Key questions were developed, focusing on recent notable insights and crucial contemporary issues in the field of cervical cancer. These questions were evaluated for their significance and impact on the current treatment and were finalized through voting by the development committee. Subsequently, we defined and detailed Patient/Problem, Intervention, Comparison, Outcome (PICO) for each key question (Table S1). After extracting the primary keywords of each key question for PICO, we converted these keywords into search terms for each database (MeSH, free text, and Emtree) and constructed search strings (Table S2). The databases included in the literature search were MEDLINE, Embase, Cochrane CENTRAL, KoreaMed, and KMbase, with searches limited to Korean and English literature. Animal studies and systematic reviews were excluded. We subsequently combined the search results from the various databases and removed duplicates. The identified studies were reviewed for inclusion and exclusion criteria (Data S1). For the selected literature, a quality assessment was conducted using the Cochrane risk-of-bias tool for randomized trials (RoB) (version 2.0; Data S2). Finally, meta-analyses and systematic reviews were performed on the included literature to establish evidence for deriving the direction and strength of the recommendations (Data S3, S4 and S5).

3. Derivation of recommendations

The recommendations were developed based on the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) Evidence to Decision framework. The factors considered in the recommendation formulation included benefits, harm, certainty of evidence, balance of effects, values, acceptability, feasibility, resource requirements, and equity (Data S6). The strengths of the recommendations were classified into 4 levels according to the GRADE methodology: strong for, weak/conditional for, weak/conditional against, and strong against. After drafting the initial recommendations, a consensus meeting was held, where the recommendations and their strengths were finalized through discussions and voting.

4. External review by experts

For the external review of the developed practice guidelines, an advisory committee consisting of experts from various societies related to gynecologic cancer, including the KSGO, Korean Society of Pathologists, Korean Society of Medical Oncology, Korean Society of Urogenital Radiology, Korean Society for Radiation Oncology, and Korean Society of Nuclear Medicine, conducted reviews and validity assessments. After a consensus meeting, the initial draft of the recommendations was subjected to external review by the advisory committee to gather opinions. A public hearing was organized during the 38th Annual Meeting of the KSGO in 2023 to collect as many opinions as possible. The final clinical practice guidelines were formulated after the revision process, incorporating feedback received during this phase.

CLINICAL CONSIDERATIONS AND RECOMMENDATIONS

1. KQ1. Does the addition of immune checkpoint inhibitors to primary treatment (chemotherapy +/− bevacizumab) improve the survival of patients with persistent, recurrent or metastatic cervical cancer?

Recommendation: Adding pembrolizumab to chemotherapy +/− bevacizumab is recommended for patients with persistent, recurrent or metastatic cervical cancer.

Level of evidence: High.

Strength of recommendation: Strong for.

Evidence

The literature review for this key question included one randomized phase 3 clinical trial. This study (KEYNOTE-826) involved the addition of immune checkpoint inhibitor pembrolizumab to the standard treatment [3]. In the entire group of 617 patients, the pembrolizumab group demonstrated a significant increase in progression-free survival (PFS; hazard ratio [HR]=0.65; 95% confidence interval [CI]=0.53–0.79) and overall survival (OS; HR=0.67; 95% CI=0.54–0.84) compared to the placebo group. Subgroup analysis revealed a significant improvement in both PFS (HR=0.62; 95% CI=0.50–0.77) and OS (HR=0.64; 95% CI=0.50–0.81) among patients with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 (548 patients). However, for the 69 patients with CPS <1, there was no significant difference in both PFS (HR=0.94; 95% CI=0.52–1.70) and OS (HR=1.00; 95% CI0.53–1.89).

In KEYNOTE-826, grade 3 or higher complications occurred in 81.8% and 75.1% of the patients in the pembrolizumab and placebo groups, respectively. Although there was a higher trend in the pembrolizumab group, statistical significance was not proven (odds ratio [OR]=1.46; 95% CI=0.99–2.15). Grade 3 or higher complications most commonly observed in the entire patient group were anemia and neutropenia, with hyperthyroidism being more than 10% higher in the pembrolizumab group compared to the placebo group. Treatment-related toxicity led to the discontinuation of one or more drugs in 37.5% and in 26.5% of the patients in the pembrolizumab and placebo groups, respectively. Two (0.7%) and 4 (1.3%) deaths were directly related to therapeutic agents.

Consideration

In a cost-effectiveness analysis conducted in the United States, the addition of pembrolizumab to standard chemotherapy was reported to be not cost-effective, suggesting that a reduction of approximately 55.8% in the current drug price would make it cost-effective [4]. Another study indicated that the addition of pembrolizumab to standard chemotherapy is cost-effective; however, the addition of bevacizumab along with pembrolizumab is not [5]. Considering the Korean healthcare environment and drug prices, adding pembrolizumab is expected to be cost-effective; however, no studies have investigated this thus far. Furthermore, owing to the high cost of immune checkpoint inhibitors in environments with no Korean national insurance coverage, there is a potential increase in health inequality based on socioeconomic status.

2. KQ2. Do immune checkpoint inhibitors improve the survival of patients with recurrent or metastatic cervical cancer in whom primary treatment has failed?

Recommendation: Immune checkpoint inhibitor monotherapy can be used for patients with recurrent or metastatic cervical cancer that has failed primary treatment.

Level of evidence: High.

Strength of recommendation: Weak/conditional for.

Evidence

The literature review for this key question included one randomized phase 3 clinical trial. In this study (EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9), the investigator’s choice of single-agent chemotherapy and standard treatment for recurrent or metastatic cervical cancer after the failure of first-line platinum-based chemotherapy with cemiplimab, an immune checkpoint inhibitor, was compared [6]. For the population of 608 patients, the cemiplimab group showed a significant improvement in PFS (median PFS: 2.8 vs. 2.9 months; HR=0.75; 95% CI=0.63–0.89) and OS (median OS: 11.1 vs. 8.8 months; HR=0.69; 95% CI=0.56–0.84) compared to the chemotherapy group. The objective response rate for cemiplimab was 16.4% (95% CI=12.5–21.1), with 18% (95% CI=11–28) in the PD-L1 expression ≥1% group and 11% (95% CI=4–25) in the <1% group. Grade 3 or higher complications occurred in 45.0% and 53.4% of the cemiplimab and chemotherapy groups, respectively, with no statistically significant difference between the 2 groups (OR=0.77; 95% CI=0.56–1.06). Drug discontinuation due to toxicity occurred in 8.7% and 5.2% of the patients in the cemiplimab and chemotherapy groups, respectively. Grade 3 or higher immune-related adverse events were more common in the cemiplimab group (5.3%) than in the chemotherapy group (0.7%).

Consideration

In a cost-effectiveness analysis conducted in the U.S. for the EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 study, cemiplimab treatment was reported to be cost-effective for patients with squamous cell carcinoma (SCC), adenocarcinoma, and those with CPS ≥1 [7]. Although cemiplimab received approval from the Korean Ministry of Food and Drug Safety in 2022 for cutaneous SCC, it has not been introduced in Korea. Therefore, during the consensus meeting, the recommendation strength was lowered by one level considering the current status of cemiplimab availability.

3. KQ3. Does minimally invasive radical hysterectomy result in survival outcomes similar to those of open radical hysterectomy in patients with cervical cancer?

Recommendation: Consideration should be given to not performing minimally invasive radical hysterectomy in patients with cervical cancer.

Level of evidence: Moderate.

Strength of recommendation: Weak/conditional against.

Evidence

The only randomized comparative study addressing this key question is the Laparoscopic Approach to Cervical Cancer (LACC) trial [8]. This multinational, multicenter phase 3 study engaged 33 institutions globally and enrolled 631 participants. However, due to a 10.8% patient dropout rate after randomization, this study was assessed with an uncertain risk of bias (RoB 2.0), leading to an overall moderate risk of bias and a downgraded evidence level by one tier.

In the overall population, the 4.5-year disease-free survival (DFS) rates were 86.0% and 96.5% for the minimally invasive surgery (MIS) and open surgery groups, respectively; while the 3-year OS rates were 91.2% and 97.1% for the MIS and open surgery groups, respectively. Both DFS and OS were significantly lower in the MIS than in the open surgery group (3-year DFS; HR=3.74; 95% CI=1.63–8.58; 3-year OS; HR=6.00; 95% CI=1.77–20.30).

Regarding recurrence patterns, peritoneal carcinomatosis was observed in 23% (8/35) and 9% (1/11) of patients in the MIS and open surgery groups, respectively. In the per-protocol analysis, all 9 patients with peritoneal carcinomatosis underwent MIS [9].

In the subgroup analysis, both for tumors larger and smaller than 2 cm, MIS resulted in a lower DFS compared to open surgery. Analysis based on the presence of preoperative conization showed no significant difference in DFS between MIS and open surgery in patients who underwent conization (HR=1.27; 95% CI=0.39–4.17; p=0.69) [9]. The incidence of intraoperative adverse events (grade 2 or higher) did not differ significantly between the 2 treatment groups (MIS: 12% vs. open: 10%; p=0.45). Similarly, there was no significant difference in the incidence of postoperative adverse events (grade 2 or higher) between the 2 groups (MIS: 54% vs. open: 48%; p=0.14) [10].

Consideration

The most significant reason for the decreased survival rate in minimally invasive radical hysterectomy compared to open radical hysterectomy is believed to be tumor cell spillage caused by the uterine manipulator or CO₂ gas used during the minimally invasive surgical procedure [11, 12]. Various efforts have been made to prevent tumor cell spillage during MIS, such as vaginal cuff closure and uterine extraction using a retrieval bag, uterine extraction through vaginal colpotomy [11], vaginal cuff resection using a laparoscopic stapler [13], and the no-look-no-touch technique [14] with several comparative clinical studies based on these efforts [15, 16, 17, 18]. Additionally, in the LACC trial, there was no difference in survival rates between the MIS and open surgery groups when conization was performed before radical hysterectomy (HR=1.27; 95% CI=0.39–4.17; p=0.69) and similar results have been reported in several retrospective studies [19, 20]. Therefore, for patients with minimal residual disease due to prior consultation for early stage cervical cancer, there is no evidence suggesting that minimally invasive radical hysterectomy has a lower survival rate than open radical hysterectomy. For these patients, the choice between minimally invasive and open hysterectomies should be discussed.

4. KQ4. Does adjuvant systemic therapy after chemoradiotherapy and brachytherapy improve the survival of patients with locally advanced cervical cancer?

Recommendation: Consideration should be given to not administering chemotherapy or immune checkpoint inhibitors after concurrent chemoradiotherapy (CCRT) for patients with locally advanced cervical cancer.

Level of evidence: Low.

Strength of recommendation: Weak/conditional against.

Evidence

The search results for this key question identified 5 randomized phase 3 clinical trials (Data S4) [21, 22, 23, 24, 25]. All included studies were well planned, and the analysis of outcomes was conducted according to predefined protocols, minimizing the risk of bias. However, there was heterogeneity in the reported survival rates among the studies, and statistical significance was not confirmed; hence, the evidence level was downgraded to ‘low.’

In the meta-analysis of survival outcomes for this key question, there was no significant difference in PFS between the CCRT plus adjuvant group and the CCRT group (HR=0.87; 95% CI=0.75–1.01). Similarly, OS did not differ significantly between the 2 groups (HR=0.88; 95% CI=0.72–1.08). The meta-analysis of treatment-related complications varied in the reporting format among studies. Three studies reported overall complications of grade 3 or above, and the analysis showed no significant difference between the 2 treatment groups (OR=2.17; 95% CI=0.66–7.18). When complications were analyzed separately by category, hematologic complications, such as neutropenia and thrombocytopenia, occurred more frequently in the CCRT plus adjuvant group than in the CCRT group. Non-hematologic complications were reported in only 2 studies, limiting the analysis, and no significant differences were observed between the groups.

Consideration

Three of the 5 studies included in this meta-analysis excluded patients with suspected para-aortic lymph node metastasis. Therefore, the potential for adjuvant therapy following CCRT to increase survival rates in patients at a high risk of recurrence cannot be conclusively ruled out. Some retrospective studies have reported that adjuvant chemotherapy after CCRT reduces recurrence in patients with cervical cancer and para-aortic lymph node involvement [26, 27, 28]. Additionally, it is necessary to await the results of future clinical studies on checkpoint inhibitors during and after CCRT, including the KEYNOTE-A18 trial (NCT04221945).

5. KQ5. Does sentinel lymph node mapping demonstrate similar survival outcomes to those of pelvic lymph node dissection in patients with cervical cancer undergoing radical hysterectomy?

Recommendation: Sentinel lymph node mapping can be selectively performed as part of the surgical treatment for patients with cervical cancer.

Level of evidence: Low.

Strength of recommendation: Weak/conditional for.

Evidence

The literature review for this key question included only one randomized phase 3 clinical trial, the SENTICOL-2 study [29]. In the survival analysis, there was no significant difference in the 4-year DFS (HR=1.48; 95% CI=0.44–4.98) and OS (HR=1.18; 95% CI=0.00–6,576.79) between the sentinel lymph node mapping and pelvic lymph node dissection groups. All grades of adverse lymphatic events were significantly lower in the sentinel lymph node mapping group than in the pelvic lymph node dissection group (31.4% vs. 55.4%; p=0.004) [30]. In the subgroup analysis, although there was no statistically significant difference in the occurrence of major lymphatic adverse events of grade 3 or above (1.2% vs. 5.9%; p=0.061), it was considered to be caused by the small number of patients experiencing adverse events.

Consideration

A limitation of the SENTICOL-2 study was the insufficient sample size for conducting survival analysis because the study design was set to confirm the primary outcome: morbidity related to lymph node dissection, making the sample size inadequate for performing the secondary outcome analysis, which was 3-year recurrence-free survival. The total number of recurrent cases was 18, with 11 and 7 in the sentinel and pelvic lymph node dissection groups, respectively. Due to these limitations, there was a moderate risk of bias, leading to the downgrading of the evidence level by one tier. Additionally, as there was no statistical significance observed in survival rates, the evidence level was downgraded by one tier, ultimately evaluating the evidence level as ‘low.’ Large-scale clinical studies are required to accurately assess the effect of sentinel lymph node dissection on survival. Precise insights into this matter can be gained through the results of future studies such as SENTICOL-III (NCT03386734) and SENTIX (NCT02494063).

6. KQ6. Is there a difference in accuracy between self-collected and clinician-collected samples for human papillomavirus (HPV) testing in cervical cancer screening?

Recommendation: Self-collected HPV testing is feasible for cervical cancer screening.

Level of evidence: Low.

Strength of recommendation: Weak/conditional for.

Evidence

An evaluation based on 2 meta-analyses published in 2022 was conducted [31, 32]. The evidence presented in the meta-analyses was primarily based on retrospective studies rather than radomised-controlled trials, and both studies reported Cohen’s kappa values within the range of 0.6–0.8 (substantial agreement).

Consideration

The literature search conducted for KQ6 revealed that the majority of recently published studies aimed to investigate the utility of a novel HPV testing product. Therefore, there were limitations in the analysis as the HPV testing methods were not standardized, with each study using different HPV tests. In Korea, with over 40 HPV tests available on the market, it poses challenges for analysis.

There was a survey study conducted on 732 Korean women, indicating significantly higher satisfaction with HPV test by self-sampling compared to satisfaction with clinician-collected Pap tests [33]. Although issues such as HPV test validation and cost-effectiveness require further investigation, the fact that Korean women exhibit apprehension towards clinician-collected tests suggests that self-tests could present an opportunity to broaden the scope of screening. Therefore, there is an expectation that self-tests could expand the target population for screening. In Korea, with over 40 HPV products in use and minimal research conducted on the comparative superiority among these products, the situation leads to the conditional acknowledgment of HPV tests as a screening tool. Considering these circumstances, it may be premature to recognize self-collected HPV tests as a screening tool at this moment.

DISCUSSION

1. Epidemiology

Cervical cancer had a global annual incidence of 604,000 cases in 2020, with 342,000 deaths, ranking fourth in terms of both incidence and mortality among cancers in women [34]. Recent data shows a significant decline in cervical cancer incidence and mortality rates in developed countries, which has been attributed to effective screening and prevention through the HPV vaccination. However, developing countries continue to experience high incidence and mortality rates. According to data from the Korea Central Cancer Registry, cervical cancer ranked seventh among cancers affecting Korean women in 2020, with 2,998 new cases. While the incidence of cervical cancer in Korea is gradually decreasing, it remains the third most common cancer among young women aged 15–34, with an incidence rate of 4.1 cases per 100,000 people, after thyroid and breast cancers [35].

2. Risk factors

The most important risk factor for cervical cancer is persistent high-risk HPV infection. The prevalence of chronic HPV infection is approximately 10–20% in countries with a high incidence of cervical cancer and approximately 5%–10% in low-incidence countries [36]. The HPV infection rate in South Korea varies according to researchers, but is reported to be approximately 10%–15% [37, 38, 39, 40]. HPV testing is used as a method for cervical cancer screening [41], and HPV vaccines are being used in clinical practice for cervical cancer prevention [42].

3. Diagnosis

Cervical cancer often lacks noticeable symptoms in its early stages, although it can be accompanied by increased vaginal discharge, postcoital bleeding, and occasional spotting. Cervical cancer can be screened using cytology and colposcopy, providing an accurate diagnosis through a cervical punch biopsy. Cervical conization is recommended when the depth of infiltration is difficult to assess using cervical punch biopsy or when evaluating microinvasions.

After the histopathological diagnosis of cervical cancer, routine tests such as blood tests (including complete blood count and liver and kidney function tests), urine analysis, chest radiography, and electrocardiography are performed. For staging purposes, additional tests including colposcopy, cervical punch biopsy, cervical conization, cystoscopy, sigmoidoscopy, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and PET/CT imaging are performed [43, 44, 45]. Squamous cell carcinoma-related antigen (SCC-Ag) is a useful serum tumor marker derived from squamous epithelial cells of the cervix. It is associated with tumor stage, size, depth of invasion, lymphovascular space invasion, lymph node involvement, and clinical outcomes. SCC-Ag measurements can be conducted before or during follow-up observations [46].

4. Treatment

Early stage cervical cancer

In early stage cervical cancer, the primary treatment involves surgery or radiation therapy after determining the clinical stage. For patients with stage IA1, conization or simple hysterectomy can be performed [47]. After conization, the patients are observed if there are no residual lesions on the excised surface and no lymphovascular space invasion. If lymphovascular space invasion is present or residual lesions exist on the excised surface, repeat conization, hysterectomy, or radical hysterectomy with pelvic lymph node dissection can be performed [48, 49, 50]. For IA1 cervical cancer patients who wish to conceive and have positive lymphovascular space invasion, procedures such as simple trachelectomy, conization, or radical trachelectomy are options. For stage IA2 patients, radical hysterectomy and pelvic lymph node dissection is performed. However, based on clinical judgment, pelvic radiation should also be considered. For patients with stages IA2–IB1 who wish to conceive, radical trachelectomy and pelvic lymph node dissection can be considered [51].

For patients with tumor size of 2 cm or smaller and no parametrial invasion or lymph node metastasis, less extensive procedures such as type A hysterectomy can be performed. Patients in stages IB1–2 or IIA1 undergo radical hysterectomy and pelvic lymph node dissection, with the possibility of additional para-aortic lymph node biopsy, as needed. Compared with pelvic lymph node dissection, sentinel lymph node mapping reduces complications without significantly increasing the risk of recurrence. Therefore, the procedural choice should be discussed with the patient, along with their advantages and disadvantages (KQ5; level of evidence: low; strength of recommendation: conditional for) [29, 52].

In early stage cervical cancer, radical hysterectomy can be performed not only through laparotomy but also using robotic or laparoscopic approaches, and nerve-sparing radical hysterectomy can also be performed. However, according to the LACC trial published in 2018, minimally invasive radical hysterectomy resulted in shorter disease-free and OS as compared to open radical hysterectomy. Therefore, open radical hysterectomy remains the standard treatment, and the choice of surgical method should be made after discussing the advantages and disadvantages with the patient (KQ3; level of evidence: moderate; strength of recommendation: conditional against) [8].

In cases with high-risk factors after surgery (positive surgical margins, lymph node involvement, and parametrial invasion), CCRT is administered, and if there are positive findings at the surgical margins, brachytherapy is administered [52]. If there were 2 or more moderate risk factors (large tumor size, deep stromal invasion, and lymphovascular space invasion), pelvic radiation therapy is performed. However, it is advisable to await the results of the GOG-0263 clinical trial (NCT01101451) to determine whether CCRT is more effective than pelvic radiotherapy.

Locally advanced cervical cancer

In stage IB3 and IIA2 cervical cancers, radical hysterectomy resulted in survival rates similar to those of CCRT. Therefore, radical hysterectomy or CCRT can be chosen appropriately depending on the patient’s clinical condition. After CCRT, additional or radical hysterectomy can be performed selectively based on clinical circumstances [53, 54].

To determine the treatment approach for stage IIB or higher cervical cancer (up to IVA), assessing the involvement of the para-aortic lymph nodes is important. Surgical methods such as extraperitoneal or laparoscopic lymph node dissection are recommended for accurate assessment. However, considering the specificities of each clinical institution, evaluation can also be conducted using imaging tests such as CT, MRI, or PET/CT [55]. Pelvic CCRT can be administered if the para-aortic lymph nodes are negative. If positive, CCRT can be performed for both the pelvic and para-aortic lymph nodes [56].

After primary treatment with CCRT in patients with locally advanced cervical cancer, consideration should be given to not giving chemotherapy or immune checkpoint inhibitors after CCRT based on current evidence, as it does not improve their survival (KQ4; level of evidence: low; strength of recommendation: conditional against) [21, 22, 23]. However, it is necessary to await the results of upcoming clinical studies related to immune checkpoint inhibitors during and after CCRT, including the KEYNOTE-A18 trial (NCT04221945).

Metastatic disease

In cases of stage IVB metastatic cervical cancer, systemic therapy is administered; however, depending on the patient’s condition, radiation therapy may also be considered.

Recurrent cervical cancer

1) Pelvic recurrence

If radiation therapy has not been previously administered, CCRT should be considered, and brachytherapy should be selectively performed [57]. In contrast, pelvic exenteration can be performed in patients who have received previous radiation therapy [58]. In some cases, retreatment with radiation therapy may also be considered [59, 60, 61].

2) Extrapelvic recurrence

Patients with extrapelvic, para-aortic, multiple, or unresectable recurrences should undergo systemic chemotherapy or supportive therapy. Isolated recurrence may be considered for selective treatment options, including chemotherapy, surgical resection, radiation therapy, and CCRT [62, 63].

Systemic treatment for recurrent/metastatic cervical cancer

Systemic chemotherapy is recommended for patients with advanced or recurrent cervical cancer who are not candidates for radiation therapy or pelvic exenteration. Platinum-based combination chemotherapy is recommended as the primary treatment for advanced or recurrent cervical cancer, and the addition of bevacizumab can increase survival rates when they are used in combination [64]. Furthermore, the immune checkpoint inhibitor pembrolizumab, when added to or used as maintenance therapy alongside platinum-based combination chemotherapy, has demonstrated improved PFS and OS rates in patients with cervical cancer who have a PD-L1 CPS ≥1 (KQ1; level of evidence: strong; strength of recommendation: strong for) [3].

Palliative chemotherapy can be attempted in cases of advanced or recurrent cervical cancer with failed primary treatment, although its effectiveness is limited [65]. In the case of immune checkpoint inhibitors, cemiplimab has demonstrated superior survival rates and duration of response compared to conventional single-agent chemotherapy in patients with cervical cancer who have failed first-line treatment. However, cemiplimab is not currently available in Korea. Pembrolizumab and nivolumab have been approved for use in patients with SCC or PD-L1 positive status (KQ2; level of evidence: strong; strength of recommendation: conditional for) [66, 67]. Patients with refractory cervical cancer require a comprehensive approach tailored to their individual circumstances, including palliative care, pain management, and psychological support.

5. Follow-up

The principle for patient follow-up is every 3–4 months for the first 2 years, every 6 months for the next 3 years, and annually thereafter, with adjustments based on the clinical status and circumstances. At each visit, a physical examination, including medical history review and pelvic examination, should be conducted. Although cervical cytology is recommended annually, it can be performed at each visit. Cervical cytology, laboratory tests, pelvic/abdominal/thoracic CT, MRI, PET scans, and serum tumor marker tests can be selectively performed based on clinical circumstances [68]. PET/CT is helpful in cases in which recurrence is not detected using conventional imaging, when the status of recurrence is unclear, or when confirming its extent.

SUPPLEMENTARY MATERIALS

Table S1

The PICOs for key questions

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Table S2

Search strategies

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Data S1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart

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Data S2

Risk of Bias (RoB 2.0) table

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Data S3

Meta-analyses of each key questions

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Data S4

Characteristics of the included studies

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Data S5

GRADE evidence profiles

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Data S6

Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) summary of judgements table

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Notes

Funding:This work was supported by Research fund of National Cancer Center, Republic of Korea (NCC-2112570-3).

Conflict of Interest:No potential conflict of interest relevant to this article was reported.

Author Contributions:

Conceptualization: Y.J.G., L.S.J., N.E.J., N.J.H., P.J.Y., S.J.Y., S.S.J., Y.B.S., P.S.T., L.S.H., L.K.H.
Data curation: Y.J.G., L.S.J., P.S.T.
Formal analysis: N.E.J., L.S.H.
Funding acquisition: K.Y.B.
Investigation: N.E.J., S.J.Y.
Methodology: N.J.H., L.K.H.
Project administration: Y.B.S., P.J.Y., N.J.H.
Resources: S.J.Y., S.S.J.
Supervision: S.D.H., K.Y.B.
Validation: S.S.J., P.S.T.
Visualization: P.J.Y., L.S.H.
Writing - original draft: Y.J.G., L.S.J., L.K.H.
Writing - review & editing: Y.J.G., L.S.J., N.E.J., N.J.H., P.J.Y., S.J.Y., S.S.J., Y.B.S., P.S.T., L.S.H., S.D.H., K.Y.B., L.K.H.

ACKNOWLEDGEMENTS

We thank the Korean Cancer Management Guideline Network (KCGN) for the technical support.

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