Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with endometrial cancer

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with endometrial cancer was published in 2022. It was therefore decided, by both the ESMO and the Indian Society of Medical and Paediatric Oncology (ISMPO), to convene a virtual meeting in July 2022 to adapt the ESMO 2022 guidelines to take into account the variations in the management of endometrial cancer in Asia. These guidelines represent the consensus opinion of a panel of Asian experts representing the oncological societies of China (CSCO), India (ISMPO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO). Voting was based on scientific evidence and was conducted independently of the current treatment practices and treatment access constraints in the different Asian countries, which were discussed when appropriate. The aim of this guideline manuscript is to provide guidance for the optimisation and harmonisation of the management of patients with endometrial cancer across the different regions of Asia, drawing on the evidence provided by Western and Asian trials whilst respecting the variations in clinical presentation, diagnostic practices including molecular profiling and disparities in access to therapeutic options, including drug approvals and reimbursement strategies.


INTRODUCTION
Cancer of the corpus uteri (endometrial cancer) is the most common gynaecological malignancy in high-and intermediate-income countries. 1,2 In 2020, endometrial cancer was the sixth most commonly diagnosed cancer in women, with 417 367 new cases recorded, accounting for 2.2% of the new cancers diagnosed worldwide. Approximately 40% of these new cases occurred in Asia, with China, where endometrial cancer is the third most common female malignancy, accounting for nearly half (81 964) of the cases. 3 Endometrial cancer was in turn responsible for 97 370 cancer deaths representing 1% of all cancer deaths worldwide. 4 Although endometrial cancer has a higher incidence in Western countries than in Asia, the incidence is increasing worldwide. Risk factors that are associated with sporadic endometrial cancer include obesity (high body mass index), diabetes, polycystic ovary syndrome, early age at menarche, late menopause, infertility, menopausal estrogen therapy and the use of tamoxifen, 5,6 whilst inherited endometrial cancer is linked to Lynch and Cowden syndromes. 7 A rising trend in endometrial cancer is being observed in several Asian countries. The number of new cases of endometrial cancer in 2020 was 16 413 cases in India, 4524 cases in Thailand, 4374 cases in the Philippines, 3425 cases in South Korea, 1401 cases in Malaysia and 775 cases in Singapore. 8 The increasing incidence is attributed to evolving lifestyle, younger age at menarche, late age at menopause and fewer children, especially in women living in urban areas. 9,10 Although endometrial cancer occurs most frequently in postmenopausal women, there is a higher proportion of younger women being diagnosed with endometrial cancer in China, 11,12 with w40% of patients diagnosed before their menopause compared with <25% of Western women. 13 In Hong Kong, 65% of 1165 new cases of endometrial cancer diagnosed in 2018 occurred in women aged between 45 and 64 years (www3.ha.org.hk/cancereg).
The majority of endometrial cancers are diagnosed at an early stage and the 5-year overall survival rate for patients with localised disease is high (95%), However, endometrial cancers with high-risk factors such as high-grade serous pathology and TP53 mutation have a tendency to recur. 1,14 Patients with recurrent endometrial cancer have a poor prognosis, with a 5-year overall survival of <20%, particularly in patients with metastatic disease. 15 Guidelines and recommendations for the treatment and management of patients with endometrial cancer in Asia have been published for the Asia-Pacific region, India [National Cancer Grid (NCG) guidelines for endometrial cancer (tmc.gov.in)], Japan, 16 Korea, 17 Singapore, 18 Taiwan, 19 China, Thailand, the Philippines and Indonesia, and are important for the standardisation of diagnostic and treatment approaches. These guidelines aim to optimise clinical outcomes for what is a growing health care problem in each Asian country. The European Society for Medical Oncology (ESMO) guidelines for the diagnosis, treatment and followup of patients with endometrial cancer were published in 2022, 20 and a decision was taken by ESMO and the Indian Society of Medical and Paediatric Oncology (ISMPO) that these guidelines should be adapted for the management and treatment of patients in Asian countries. An international panel of experts was selected from the ISPMO (n ¼ 6), the ESMO (n ¼ 6) and two experts representing each of the oncological societies of China (CSCO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO). One expert from Thailand (ST) was member of the Thai Gynecologic Cancer Society endorsed by TSCO. Only two of the six expert members from the ISMPO (SG and KGB) were allowed to vote on the recommendations together with the experts from each of the nine other Asian oncology societies (n ¼ 20). Among the six experts from ISMPO, three were medical oncologists and one a gynaecological oncologist, one a radiation oncologist and one a pathologist. The majority of experts from the other Asian societies were medical oncologists or gynaecological oncologists. None of the additional ISMPO members present and none of the ESMO experts were allowed to vote and were present only in an advisory role.
A modified Delphi process was used to review, accept or adapt each of the individual recommendations in the latest ESMO Clinical Practice Guidelines. 20 The 20 voting Asian experts were asked to vote YES or NO (one vote per society) on the 'acceptability' (agreement with the scientific content of the recommendation) and 'applicability' (availability, reimbursement and practical challenges) of each of the ESMO recommendations in a pre-meeting survey (see Methodology in Supplementary Material S1, available at https://doi.org/10.1016/j.esmoop.2022.100744). For recommendations, where a consensus was not reached, the Asian experts were invited to modify the wording of the recommendation(s) at the virtual 'face-to-face' meeting using further rounds of voting, if necessary, in order to determine the definitive acceptance or rejection of an adapted recommendation and discuss the applicability challenges.  21 was used to define the LoE and strength (grade) of each recommendation. Any modifications to the initial recommendations were highlighted in bold text in a summary table of the final Asian recommendations and in the main text, if applicable. A consensus was considered to have been achieved when !80% of experts voted that a recommendation was acceptable.

RESULTS
In the initial pre-meeting survey, the 20 voting Asian experts reported on the 'acceptability' and 'applicability' of the 51 recommendations for the diagnosis, treatment and followup of patients with endometrial cancer from the 2022 ESMO Clinical Practice Guidelines. 20 These recommendations were made in the five categories outlined in the text below and in Table 1.
During the pre-meeting survey there were 32 voting discrepancies in relation to scientific 'acceptability' (Supplementary Table S2

Diagnosis, pathology and molecular biologydrecommendations 1a-b
Endometrial cancer is clinically a very heterogeneous malignancy for which the assignment of histological subtype, grade, disease extension and lymphovascular space invasion (LVSI) has been highly subjective, 20,22 impacting on the accurate assessment of an individual patient's risk of recurrence and metastasis, and therefore management. Furthermore, it has reduced the ability to accurately compare different clinical studies in terms of outcome due to uncertainty over the classification of patient risk.
The traditional histopathological classification of Bokhman identified two types of endometrial cancer, type I [endometrioid, grade 1-2 (G1-2) with a favourable prognosis], w70% of cases, and type II (G3 endometrioid and non-endometrioid histologies with a poor prognosis), w30% of cases. 23 There is general agreement, however, that endometrioid tumours should now be classified according to the International Federation of Gynecology and Obstetrics (FIGO) defined criteria, 20,24 providing a two-tier grading system with G1 and G2 endometrioid tumours grouped together as low grade, and G3 tumours classified as high grade. Factors traditionally associated with a high risk of recurrent disease include histologic subtype, FIGO G3 histology, myometrial invasion !50%, LVSI, 25-27 L1 cell adhesion molecule expression, 28,29 lymph node metastases and tumour diameter >2 cm.
However, the heterogeneity of endometrial cancer is due to an array of underlying molecular alterations. The results of The Cancer Genome Atlas (TCGA) analysis 30 showed that the molecular diversity of endometrial cancer could be stratified into four distinct molecular subgroups (Supplementary Table S4, available at https://doi.org/10. 1016/j.esmoop.2022.100744). The four molecular subgroups are: (i) patients with copy number stable, ultramutated endometrial cancers characterised by pathogenic variants in the exonuclease domain of DNA polymeraseepsilon (POLE), (ii) patients with hyper-mutated endometrial cancer characterised by microsatellite instability (MSI) due to dysfunctional/deficient mismatch repair genes (dMMR), (iii) an MMR-proficient, low somatic copy number aberration (SCNA) subgroup with a low mutational burden and (iv) a high SCNA subgroup with frequent TP53 mutations. Therefore, well-established immunohistochemical (IHC) staining techniques for the detection of p53 and MMR proteins (MLH1, PMS2, MSH2, MSH6) are now recommended as standard practice for all endometrial cancer pathology specimens, regardless of histological type, together with sequencing of the exonuclease domain of POLE if available. 17 Patients presenting with either newly diagnosed or recurrent/metastatic endometrial cancer should have a biopsy to confirm histology and assess tumour molecular biology.
These molecular classes are identified across all of the histological subtypes, 31,32 and correlate with endometrial cancer prognosis. 33 Thus, molecular classification could facilitate more accurate comparison of clinical outcomes between different groups of patients. Furthermore, it could impact treatment considerations. Firstly, testing for MMR/ MSI status serves not only as a screening test for Lynch syndrome, but also identifies patients with metastatic disease who could benefit from immune checkpoint blockade agent. Secondly, the benefit of adjuvant chemotherapy is observed in patients with p53mut endometrial cancer, 34 whilst the de-escalation of therapy in patients with POLE mutated (POLEmut) endometrial cancer, which has a favourable outcome, is being investigated. Thirdly, the overexpression/gene amplification of human epidermal growth factor receptor 2 (HER2), which has been demonstrated in 20%-40% of type II non-endometrioid endometrial cancers, supports the use of HER2-targeted therapy in combination with chemotherapy. This combined treatment has also recently been shown to be an effective treatment approach for patients with advanced and recurrent serous endometrial cancer. [35][36][37][38][39] As a consequence, HER2 testing is now being proposed to guide the management of these patients. 40,41 Endometrial cancers that have not been completely molecularly classified should be designated as endometrial cancers not-otherwise-specified and use the histologybased classification system. 42 With improved tumour characterisation facilitated by more sophisticated diagnostic testing and molecular profiling, the diagnosis and management of patients with endometrial cancer is evolving towards a more objective, reproducible, personalised medicine approach. The algorithm for the diagnostic work-up of endometrial cancer proposed by ESMO 20 and adapted from Vermij et al. 2020 42 is presented in Figure 1.
The Pan-Asian panel of experts agreed with and accepted completely (100% consensus) the ESMO recommendations on diagnosis, pathology and molecular biology 'recommendations 1a-b' below and in Table 1. However, they mentioned that POLE hotspot mutation analysis was not available as part of the standard molecular evaluation in many centres in Asia. 1a. Histological type, FIGO grade, myometrial invasion and LVSI (focal/substantial) should be described for all endometrial cancer pathology specimens 20

Staging and risk assessmentdrecommendations 2a-c
The Pan-Asian panel of experts agreed with and accepted completely (100% consensus) the ESMO recommendations on diagnosis, pathology and molecular biology 'recommendations 2a-c' below and in Table 1

Management of local and locoregional diseasedrecommendations 3a-u
Surgery. Early endometrial cancer is typically treated with surgery to remove the macroscopic disease and stage the tumour for planning with regard to adjuvant therapy. Traditionally, surgery for endometrial cancer was carried out via laparotomy until the results of two large, randomised trials showed minimally invasive laparoscopic techniques to have no negative impact on either staging or clinical outcomes. 47,48 An algorithm for the surgical treatment and management of patients with stage I endometrial cancer is presented in Figure 2. Preservation of fertility in younger patients with endometrial carcinoma should be considered when appropriate 49   The comment of the Taiwanese experts with respect to inclusion of sentinel lymph node sampling as part of surgical procedure (recommendation 3a) is covered in recommendation 3e.
However, some Asian experts did not accept ESMO 'recommendations 3e and 3f' because they did not reflect real-life clinical practice in their countries with respect to sentinel lymph node excision (SLNE), which is not available in many centres in Asia.
Therefore, the original 'recommendations 3e and 3f' were modified, as per the bold text below and in Table 1. However, the consensus was that SLNE should be encouraged wherever possible, based on the evidence available from two studies, 50,51 including in patients with deeply invasive endometrioid endometrial cancer, 52 but not in patients with the more aggressive type II histology 53    Low-risk endometrial cancer. There is no indication for the use of adjuvant therapy for the treatment of patients with low-risk endometrial cancer, 56-58 due to a low risk of recurrence. Also, in the few patients in whom local recurrence does occur, it can be treated effectively with radiotherapy (RT). Combined analysis of cohorts from the PORTEC-1 and PORTEC-2 studies 59 and other studies 33,60,61 has shown the presence of a POLE mutation (POLEmut) to be a favourable indicator of prognosis, independently of other clinicopathological characteristics. As a consequence, patients with stage I-II endometrial cancer with POLEmut tumours are now classified as low risk and unlikely to benefit from adjuvant therapy. Omitting adjuvant therapy in patients with G3 POLEmut endometrial cancer may also be an option, although currently there are no robust data available.
Higher-level evidence from a prospective registry study is likely to be available shortly together with data from a cohort of the RAINBO trial (NCT05255653). The planned cohorts for the Trans PORTEC RAINBO programme of clinical trials aim to refine the adjuvant treatment of patients with endometrial cancer based on molecular profile including POLEmut status, dMMR, no specific molecular profile (NSMP) and abnormal p53 (p53abn).
The Pan-Asian panel of experts agreed with and accepted completely (100% consensus) the ESMO 'recommendation 3i' below.
3i. For patients with stage IA (G1 and G2) endometrioid (dMMR and NSMP) type endometrial cancer with no or focal LVSI, adjuvant treatment is not recommended [I, E].
However, some of the Asian experts did not accept the ESMO 'recommendations 3j, 3k and 3l', which suggest the omission of adjuvant treatment, because there are little supporting data on the safety of omitting therapy. However, in relation to 'recommendation 3k' for patients with stage I-II POLEmut disease, there is encouraging, although limited, evidence regarding the omission of adjuvant therapy. 34,43 When the POLEmut status of a tumour is unavailable, patients should be treated on the basis of the other available risk information. The current focus is on de-escalation of therapy in these patients, whenever possible. Thus, the wording of the original 'recommendations 3j, 3k and 3l' (Supplementary Table S2 The adjuvant therapy options for low-risk disease are outlined in Figure 3. Intermediate-risk endometrial cancer. The PORTEC-1 56 and Gynaecology Oncology Group (GOG)-99 57 trials demonstrated the benefit of pelvic external beam RT (EBRT) after surgery in reducing locoregional recurrence in patients with intermediate-risk endometrial cancer. However, a Norwegian trial 62 and an ASTEC study group trial 58 showed that EBRT and vaginal brachytherapy (VBT) achieve similar results. The long-term results of the PORTEC-2 study showed VBT to result in excellent vaginal control in women with high-intermediate-risk endometrial cancer, with 10-year vaginal control above 96% in both arms. Although the risk of pelvic recurrence was significantly higher in the VBT group (6% versus 1%), no differences were found in 10-year rates for distant metastasis and overall survival. There were lower toxicity rates and better health-related quality of life among women who received VBT compared with EBRT. 63 The Pan-Asian panel of experts agreed with and accepted completely (100% consensus) the ESMO 'recommendations 3m, 3n and 3o' below without change, after much discussion over the use of adjuvant RT. Adjuvant RT is not commonly used in Japan (Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2022.100744), with chemotherapy being used as an alternative based on a study by the Japanese Gynecologic Oncology Group. 64 The experts from China and Taiwan favoured EBRT AE VBT or EBRT alone, respectively, over VBT for stage II G1 endometrial cancer 'recommendation 3o'. It was mentioned by the experts that molecular profiling was not available in certain regions of Asia. In such situations, patients should be treated according to their assessed risk of recurrence.

Stage I-IVA EC: adjuvant therapy for low-and intermediate-risk patients
The Pan-Asian panel of experts agreed with and accepted completely (100% consensus) 'recommendation 3p' below without any change.
3p. Omission of adjuvant VBT can be considered (especially for patients aged <60 years) for all above stages, after patient counselling and with appropriate follow-up [III, C].
High-intermediate-risk endometrial cancer with lymph node staging (pN0). There was much discussion over the adjuvant treatment of this group of patients which includes those with stage IA and IB disease with substantial LVSI, stage IB G3 and stage II G1 disease with substantial LVSI and stage II G2-G3 (dMMR or NSMP) disease.
The Pan-Asian panel of experts agreed with and accepted completely (100% consensus) the ESMO 'recommendation 3q.1' below, with the proposal from Taiwan that chemotherapy might be considered as an alternative.
With regard to 'recommendation 3q.2', some of the experts considered that stronger evidence was needed for the benefit of the addition of chemotherapy, but accepted the recommendation without change based on the data from the PORTEC-3 trial. 65 However, it was felt that the high incidence of short-and long-term side-effects associated with the addition of chemotherapy to EBRT, whilst conferring minimal benefit, needed to be discussed with these patients.
With regard to 'recommendation 3q.3', some of the experts considered that there was insufficient evidence to use the presence or absence of LVSI to decide the type of RT (VBT versus EBRT). In Korea EBRT is used for G3 disease, except in those without LVSI. 'Recommendation 3q.3' was accepted completely by replacing 'could be recommended' with 'could be considered' as per the bold text below. 3q.3. Adjuvant VBT (instead of EBRT) could be considered to decrease vaginal recurrence, especially for those without substantial LVSI [II, B; consensus ¼ 100%].
With regard to 'recommendation 3q.4', experts from 6 of the 10 Asian countries considered that adjuvant treatment should be recommended. Thus, the consensus was that the standard treatment for most patients should include adjuvant treatment. However, in highly selected patients (stage IA G1-G2), when close follow-up (every 3 months) is possible, adjuvant treatment may be withheld in consultation with the patient.
Thus, the original 'recommendation 3q.4' was revised from: 3q.4. With close follow-up, omission of any adjuvant treatment is an option following shared decision making with the patient [IV, C], to read as the 'recommendation 3q.4' below with the new text highlighted in bold.
3q.4. Despite evidence of a benefit from adjuvant treatment, its omission is an option, when close follow-up can be ensured, following shared decision making with the patient [IV, C].
An algorithm for the treatment of these patients is presented in Figure 4.
High-intermediate-risk endometrial cancer without lymph node staging. Again, there was much discussion over the adjuvant treatment of this group of patients which includes those with stage IA and IB disease with substantial LVSI, stage IB G3 and stage II G1 disease with substantial LVSI and stage II G2-G3 (dMMR or NSMP) disease.
The Pan-Asian panel of experts agreed with and accepted completely (100% consensus) the ESMO 'recommendations 3r.1' below without change.
3r.1. Adjuvant EBRT is recommended [I, A]. With regard to 'recommendation 3r.2', experts from some Asian countries, despite the evidence from the PORTEC-1 trial 56 in patients who had undergone primary surgery (without node dissection) and the PORTEC-3 trial, 66 were of the opinion that concomitant treatment should be reserved for medically fit patients, but was the preferred option for patients with substantial LVSI. For patients with no initial lymph node dissection, carrying out a lymph node dissection is also an option, followed by tailored adjuvant treatment. 'Recommendation 3r.2' below was accepted without change with consideration to be given to the observations cited above.
With regard to 'recommendation 3r.3', five of the Asian countries did not agree with the original recommendation, and it was generally accepted that in the absence of lymph node staging, EBRT should be considered. Thus the original 'recommendation 3r. 3 This recommendation is based on evidence from a subgroup analysis of the phase III GOG-249 trial of adjuvant pelvic RT versus VBT plus paclitaxel/carboplatin in highintermediate-and high-risk early-stage endometrial cancer. 67 Radiological evaluation, if not already carried out, should be done before using this option.
An algorithm for the treatment of these patients is presented in Figure 4.
High-risk endometrial cancer. There were differences amongst the Asian experts in terms of 'acceptability' with regard to 'recommendations 3s, 3t and 3u' (see Supplementary Table S2 There was much discussion over the adjuvant treatment of this group of patients with some of the experts considering the therapy proposed in 'recommendation 3s' below too toxic for patients with endometrial cancer due to their age and comorbidities although there are supporting data from the PORTEC-3 trial 65,66 and GOG trial 68 for the benefits of combining chemotherapy with RT in this patient group. High-risk endometrial cancer patients include those with stage III-IVA cancers without residual disease regardless of histology and regardless of molecular subtype, or stage I-IVA p53abn with myometrial invasion, or non-endometrioid cancers without residual disease with myometrial invasion (see Supplementary Table S5

ESMO Open
After discussion, the Asian experts also accepted 'recommendations 3t and 3u' without change. Extended field RT can be considered along with EBRT and chemotherapy for patients with para-aortic node disease.
3t. Sequential chemotherapy and RT can be used [I, B; 3u. Chemotherapy alone is an alternative option [I, B; consensus ¼ 100%].
However, concern was expressed over the use of chemotherapy alone ('recommendation 3u'), due to the fact that the data regarding comparable efficacy were inconsistent. Certainly, data from the PORTEC-3 trial 34 showed the treatment effect to differ between the different molecular subgroups. Poor prognosis patients with p53abn endometrial cancer benefitted significantly from chemoradiotherapy (CRT) regardless of stage and histological subtype, whilst patients with POLEmut cancers achieved an excellent benefit with either RT or CRT. No benefit was observed for CRT over RT for patients with dMMR endometrial cancer, whilst a trend for benefit was observed in the NSMP subgroup. An algorithm for the treatment of these patients is presented in Figure 4.
For any patients with endometrial cancer who are medically unfit for surgery, by virtue of severe comorbidities, definitive RT is an option (see Supplementary Material S4, available at https://doi.org/10.1016/j.esmoop.2022. 100744).

Recurrent/metastatic diseasedrecommendations 4a-m
As stated previously, the outcomes in patients with recurrent and/or metastatic endometrial cancer are poor. 15 The management of these patients should, wherever possible, involve a multidisciplinary team approach, treatment in specialised centres and the development of individualised treatment plans. Algorithms for the treatment of recurrent locoregional and metastatic disease are presented in Figures 5 and 6, respectively. Several factors influence the outcomes (local control and survival) in patients with recurrent and/or metastatic disease, including its site and extent (isolated vaginal or peritoneal involvement), size (<2 cm or !2 cm), histology and relapse-free survival (RFS). Isolated vaginal recurrence, lower grade, endometrioid histology and longer RFS are associated with a better prognosis. 69,70 Additionally, prior treatment (surgery and/or RT) and patient's general condition also influence outcome.
The Asian experts expressed concern over the omission of surgery from the ESMO 'recommendation 4a', and the recommendation of only VBT, which should be considered if there is isolated vaginal recurrence. Thus, 'recommendation 4a' was revised by inclusion of the text in bold below.
4a. For patients with locoregional recurrence following primary surgery alone, the preferred primary therapy should be EBRT with or without VBT, depending on the site of recurrence [IV, A; consensus ¼ 100%].
It was discussed that surgery could be considered in selected patients in whom it is possible to achieve complete surgical resection in the absence of excessive morbidity, and that the use of VBT alone can be considered in the subgroup of patients with a small vaginal recurrence.
'Recommendations 4b-e' were accepted without change with the caveat that they may not be applicable in all cases, depending on extent of disease.
In relation to 'recommendation 4e' there is no evidence of an increased benefit for >6 cycles of chemotherapy, but it was agreed that this could be considered on an individual basis.
Some Asian experts did not agree with the original 'recommendation 4f' because hormone therapy is rarely offered as first-line systemic therapy in these patients. The experts agreed that chemotherapy is the first choice of treatment. Hormone therapy can be considered for patients with low-grade, low-volume disease who are not suitable for chemotherapy, dependent on knowledge of the hormone receptor status [estrogen receptor (ER) and progesterone receptor (PgR)] of the tumour at the time of treatment. However, the predictive value of hormone receptor expression in endometrial cancer is not as strong as it is for patients with breast cancer due to the limitations associated with a lack of standardisation of tissue processing and factors such as a well-defined cut-off limit in relation to receptor levels. 20 Furthermore, responses to hormone therapy have been reported in ER-/PgR-negative disease. 74 Thus, due to these concerns, the text of the original recommendation 'recommendation 4f' below was modified by the inclusion of the bold text.
4f. Hormone therapy could be considered as an option for front-line systemic therapy in patients with low-grade carcinomas of endometrioid histology with low-volume disease [III, A; consensus ¼ 100%].
The Asian experts accepted without change 'recommendations 4g, 4h and 4i' below, despite some discussion and the removal of the dosing details for medroxyprogesterone acetate and megestrol acetate (Supplementary Table S2   4i. There is no standard of care for second-line chemotherapy. Doxorubicin and weekly paclitaxel are considered the most active therapies [77][78][79] The Asian experts queried 'recommendation 4j', but eventually accepted it without change with the provision that for patients with a long disease-free interval after prior chemotherapy, retreatment with further platinum-based treatment can also be considered, based on a retrospective analysis, 80  Immune checkpoint blockade alone or in combination with targeted therapies has emerged as a promising intervention in patients with recurrent endometrial cancer in view of a high mutational burden (dMMR/POLEmut subtypes), tumour-infiltrating lymphocytes and programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) expression. Pembrolizumab, which targets PD-1, has been investigated in the endometrial cohorts of the KEYNOTE-158 trial in patients pre-treated with chemotherapy, and a short progression-free survival (PFS), and showed PD-1 blockade to be highly effective. 81 Data from the GARNET trial with the anti-PD-1 monoclonal antibody dostarlimab, which blocks interaction with the programmed death ligands PD-L1 and -L2, have led to the approval of dostarlimab monotherapy by the Food and Drug Administration (FDA) in the United States to treat dMMR recurrent or advanced endometrial cancer that has progressed on platinum-containing regimens 82 ( Figure 6). Agents that target PD-L1 such as avelumab 83 and durvalumab 84 have also shown promising activity in patients with dMMR endometrial cancer, as well as atezolizumab and nivolumab (anti-PD-1). 85 The phase Ib/II KEYNOTE 146 trial 86 showed encouraging response, PFS and overall survival rates with the combination of pembrolizumab and the multi-kinase inhibitor lenvatinib, and the phase III KEYNOTE-775 trial 87 demonstrated the statistically significant PFS (P < 0.0001) and overall survival (P < 0.0001) benefits of this combination compared with standard chemotherapy. As a consequence, pembrolizumab in combination with lenvatinib has been approved by the FDA for patients with advanced endometrial cancer, that is not MSI-high (MSI-H) or dMMR, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or RT. The European Medicines Agency (EMA) approved pembrolizumab in combination with lenvatinib for the treatment of advanced or recurrent endometrial cancer in patients who have disease progression on or following prior treatment with a platinum-containing regimen in any setting regardless of MMR status and who are not candidates for curative surgery or RT ( Figure 6).
However, due to the lack of availability of dostarlimab in 6 of the 10 Asian countries, the wording of the original 'recommendation 4k' was reworded from the original ESMO recommendation below, 4k. Dostarlimab has recently been approved by both the EMA and the FDA for this indication 82  Targeted therapy approaches are also being investigated in patients with endometrial cancer. Uterine serous carcinoma (USC) is an aggressive endometrial cancer subtype associated with a poor outcome. 89 One-third of USCs overexpress HER2/Neu, 35 a target for trastuzumab in breast cancer. A small randomised phase II trial for the addition of trastuzumab to paclitaxel/carboplatin compared with paclitaxel/carboplatin alone in stage III-IV or recurrent USC demonstrated a meaningful benefit for PFS [hazard ratio (HR) 0.46, P ¼ 0.005] and overall survival (HR 0.58).The benefit for stage III-IV was greater than in recurrent disease. 37 The cyclin-dependent kinase inhibitor palbociclib has shown superiority in combination with letrozole in previously treated patients with ER-positive disease in the phase II ENGOT EN3 PALEO trial, 90  There was considerable discussion amongst the Asian experts about the frequency of follow-up appointments with no evidence of a survival benefit from intensive versus minimalist follow-up, even in high-risk patients, as demonstrated by the results of the European multicentre phase III TOTEM trial. 93 Furthermore, the evidence showed that there was no need to add routine vaginal cytology, laboratory investigations or imaging to the minimalist follow-up strategies.
Thus, 'recommendation 5a' was modified very slightly as per the bold text below.
5a. For low-risk endometrial cancer, the proposed surveillance is at least every 6 months for the first 2 years and then yearly until 5 years. A physical and gynaecological examination should be performed at each follow-up [V, C; consensus ¼ 100%].
With regard to 'recommendation 5b' the experts were concerned that access to phone follow-up would be difficult in certain regions. Therefore, 'recommendation 5b' (Supplementary Table S2 The Asian experts accepted 'recommendations 5c, d and e' below without change despite concern over the frequency/timing of follow-up in 'recommendation 5c'.
5c. For the high-risk groups, physical and gynaecological examinations are recommended every 3 months for the first 3 years, and then every 6 months until 5 years [V, C]. 5d. A CT scan or PETeCT could be considered in the highrisk group, particularly if node extension was present [V, D].
5e. Regular exercise, healthy diet and weight management should be promoted with all endometrial cancer survivors [II, B].

Availability of diagnostic tests, drugs and equipment
Following the virtual face-to-face meeting hosted by ISMPO, the Pan-Asian panel of experts agreed with and accepted completely (100% consensus) the adapted ESMO guidelines listed in Table 1.
The drug and treatment availability for each of the 10 Asian countries is summarised in Supplementary There was only one area of discrepancy in terms of diagnostic tests, drugs and equipment. This was POLE hotspot mutation analysis and the lack of/limited availability of such analysis in five of the Asian countries represented at the meeting.
Thus, the recommendations detailed in Table 1 can be considered the consensus clinical practice guidelines for the treatment of patients with endometrial cancer in Asia. As mentioned previously, the acceptance of each recommendation by each of the Asian experts was based on the available scientific evidence and was independent of the approval and reimbursement status of certain procedures and drugs in the individual Asian countries. A summary of the availability of the recommended treatment modalities and recommended drugs, as of July 2022, is presented for each participating Asian country in Supplementary  Table S6, available at https://doi.org/10.1016/j.esmoop. 2022.100744, and will impact on some management strategies that can be adopted by certain Asian countries. Cancer Communications and Consultancy Ltd, Cheshire, UK is acknowledged for her contribution to the preparation of the manuscript. Mrs N. Latino, ESMO Head of Scientific Affairs, is acknowledged for her contribution in the completion of the ESMO-MCBS table.

FUNDING
All costs relating to this consensus conference were covered by the ESMO and the ISMPO from central dedicated funds. There was no external funding of the event or the manuscript production.

DISCLOSURE
DB is a board member of the Society of Gynaecologic Oncologists of the Philippines; GC has received consulting fees from BMS, Roche, Pfizer, Eli Lilly, AstaZeneca, Daichii-Sankyo, Merck, Seagen and Ellipsis, received honoraria from Pfizer, Eli Lilly and Relay and support for attending meetings from Daichii-Sankyo, all outside the submitted work; TD declares fees for an advisory board from MSD, Pfizer, Eisai and Zuellig Pharma, as an invited speaker from AstraZeneca, Norvartis, Celtrion and Zeullig Pharma and role as a PI for Roche; SG declares honoraria from Lupin, Roche, Novartis, Eli Lilly, Eisai, Cipla, CADILA, Intas and AstraZeneca; honoraria for being on committees of the Indian Council of Medical Research (Government of India), Council of Scientific and Industrial Research (Government of India), Department of Biotechnology (Government of India), India Alliance and institutional; honoraria from Novartis and AstraZeneca for participation in steering committees; leadership roles include President of Indian Society of Medical and Paediatric Oncology and General Secretary of Women's Cancer InitiativedTata Memorial Hospital, both roles unpaid; KH declares fees for advisory boards from Chugai Astra Zeneca, and Takeda, invited speaker fees/honoraria from AstraZeneca, Takeda, MSD, Chugai and Daiichi-Sankyo and institutional research grants from Daiichi Sankyo and Merck; CHL declares fees from MSD Advisory board, DMC member for Novartis and Hygeia and local PI for ENGOT-en11and KEYNOTE 826 trials, President of TGOG; DL reports consultant honoraria from AstraZeneca, Clovis Oncology, GSK, MSD, ImmunoGen, Genmab, Amgen, Seagen and Pharma-Mar, invited member of advisory boards for Merck Serono, Seagen, Immunogen, Genmab, Oncoinvest, Corcept, Sutro; invited speaker and member of advisory boards and receives direct research funding from Clovis Oncology, GSK, MSD and PharmaMar, institutional funding for clinical trials/ contracted research from AstraZeneca, Clovis Oncology, GSK, MSD, Genmab, Seagen, ImmunoGen, Incyte, Novartis and Roche and participates in non-remunerated activities as principal investigator and non-remunerated leadership roles for GCIC; RAM declares fees for Esisai advisory board, MSD expert testimony expert input forum Specialised Therapeutics and acting as local PI for AstraZenca and Novartis; AO has served on advisory boards for AstraZeneca Farmaceutica Spain, SA, AstraZeneca KK, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceutical, Eisai Europe