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Endometrial Cancer
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Incorporating biomarkers into treatment decision-making

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ESGO/ESTRO/ESP treatment algorithms

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Treatment modalities

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Incorporating biomarkers into treatment decision-making

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The European Society for Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) guidelines on management of endometrial cancer published in 2025 emphasise the need to integrate several factors into treatment decision-making. These include International Federation of Gynecology and Obstetrics (FIGO) staging, tumour extension, molecular classification and lymphovascular space invasion (LVSI) status (Table 1). Treatment should be guided by the prognostic risk group of the tumour, defined by estimated overall 5-year risk of recurrence and stratified into low-risk (<8%), intermediate-risk (8–14%), high–intermediate-risk (15–24%) and high-risk groups (≥25%).1

FIGO 2023 staging* Molecular classification
POLEmut dMMR NSMP low-grade and ER-positive NSMP high-grade or ER-negative (or both)† p53abn
I Confined to the uterine corpus
IA IA1 Low-grade endometrioid, confined to polyp or endometrium (no myoinvasion) IAm POLEmut
(LOW RISK)		 (LOW RISK) (LOW RISK) †
(UNCERTAIN RISK)		 IICm p53abn
(UNCERTAIN RISK)
  IA2 Low-grade endometrioid, myoinvasion <50%, no or focal LVSI IAm POLEmut
(LOW RISK)		 (LOW RISK) (LOW RISK) †
(HIGH RISK)		 IICm p53abn
(HIGH RISK)
  IA3 Low-grade endometrioid carcinoma of the endometrium and ovary‡ (LOW RISK) (LOW RISK) (LOW RISK) †
(HIGH RISK)		 (HIGH RISK)
IB   Low-grade endometrioid, myoinvasion ≥50%, no or focal LVSI IAm POLEmut
(LOW RISK)		 (INTERMEDIATE RISK) (INTERMEDIATE RISK) †
(HIGH RISK)		 IICm p53abn
(HIGH RISK)
IC   High-grade histologies,§ limited to polyp
or endometrium		 IAm POLEmut
(LOW RISK)		 (LOW RISK) N/A (UNCERTAIN RISK) (UNCERTAIN RISK)
II Confined to the uterus
IIA   Low-grade endometrioid, invasion of the cervical stroma IAm POLEmut
(LOW RISK)		 (HIGH-INTERMEDIATE RISK) (INTERMEDIATE RISK) †
(HIGH RISK)		 IICm p53abn
(HIGH RISK)
IIB   Low-grade endometrioid, substantial LVSI IAm POLEmut
(LOW RISK)		 (HIGH-INTERMEDIATE RISK) (HIGH-INTERMEDIATE RISK) †
(HIGH RISK)		 IICm p53abn
(HIGH RISK)
IIC   High-grade histologies,§ myoinvasion IAm POLEmut
(LOW RISK)		 Myoinvasion <50%, no or focal LVSI
(INTERMEDIATE RISK)		 N/A (HIGH RISK) IICm p53abn
(HIGH RISK)
      IAm POLEmut
(LOW RISK)		 Myoinvasion ≥50%, no or focal LVSI
(INTERMEDIATE RISK)
      IAm POLEmut
(LOW RISK)		 Cervical stromal invasion, no or focal LVSI
(HIGH-INTERMEDIATE RISK)
      IAm POLEmut
(LOW RISK)		 Substantial LVSI
(HIGH-INTERMEDIATE RISK)
III Local spread, regional spread, or both
IIIA IIIA1 Spread to ovary or fallopian tube (except when meeting stage IA3 criteria) (UNCERTAIN RISK††) (HIGH RISK) (HIGH RISK) (HIGH RISK) (HIGH RISK)
  IIIA2 Involvement of uterine subserosa or spread through the uterine serosa (UNCERTAIN RISK††) (HIGH RISK) (HIGH RISK) (HIGH RISK) (HIGH RISK)
IIIB IIIB1 Metastasis or direct spread to the vagina, parametria,
or both		 (UNCERTAIN RISK††) (HIGH RISK) (HIGH RISK) (HIGH RISK) (HIGH RISK)
  IIIB2 Metastasis to the pelvic peritoneum (UNCERTAIN RISK††) (HIGH RISK) (HIGH RISK) (HIGH RISK) (HIGH RISK)
IIIC IIIC1 Pelvic lymph node metastasis
  IIIC1i Micrometastasis (UNCERTAIN RISK††) (HIGH RISK) (HIGH RISK) (HIGH RISK) (HIGH RISK)
  IIIC1ii Macrometastasis (UNCERTAIN RISK††) (HIGH RISK) (HIGH RISK) (HIGH RISK) (HIGH RISK)
  IIIC2 Para-aortic lymph node metastasis (up to renal vessels)
  IIIC2i Micrometastasis (UNCERTAIN RISK††) (HIGH RISK) (HIGH RISK) (HIGH RISK) (HIGH RISK)
  IIIC2ii Macrometastasis (UNCERTAIN RISK††) (HIGH RISK) (HIGH RISK) (HIGH RISK) (HIGH RISK)
IV Locally advanced disease, metastatic disease, or both
IVA   Invasion of the mucosa and/or the intestinal mucosa (UNCERTAIN RISK††) (HIGH RISK) (HIGH RISK) (HIGH RISK) (HIGH RISK)
  Metastatic disease or residual disease after surgery
III or IVA   With residual disease          
IVB   Peritoneal metastasis beyond the pelvis          
IVC   Distant metastasis          

Table 1. Definition of risk groups based on FIGO 2023 staging and molecular classification.1,2
Table adapted from Concin N et al. 2025.1
*When molecular classification is known, the FIGO stage should be reported with an annotation of m (for molecular), followed by the specific molecular subtype. There are two specific, molecularly defined FIGO stages: IAm POLEmut (Stages I and II disease with a pathogenic POLE mutation) and Stage IICm p53abn (Stages I and II disease with a p53 abnormality and myometrial invasion); †The molecular subgroup NSMP high grade or ER-negative (or both) consists of high grade NSMP endometrial carcinoma, ER-negative NSMP endometrial carcinoma, or of NSMP endometrial carcinomas with a combination of both high grade and ER negativity. Thus, in FIGO stages referring to low-grade endometrioid carcinomas (i.e. IA1, IA2, IA3, IB, IIA and IIB), only the ER-negative cases apply in the molecular subgroup NSMP high grade or ER-negative (or both); ‡Myoinvasion less than 50%, no LVSI and ovarian tumour pT1a; §High-grade histologies are the FIGO 2023 aggressive histotypes that include high-grade endometrioid carcinomas (Grade 3); serous, clear cell carcinomas; carcinosarcomas; and undifferentiated, mixed, mesonephric-like, and gastrointestinal mucinous type carcinoma; 
Substantial LVSI is defined according to WHO criteria in at least one haematoxylin and eosin-based staining slide. †† Uncertain risk classification because of insufficient data
dMMR, mismatch repair deficient; ER, oestrogen receptor; FIGO, International Federation of Gynaecology and Obstetrics; LVSI, lymphovascular space invasion; m, molecular; N/A, not applicable; NSMP, no specific molecular profile; p53abn, abnormal p53; POLEmut, POLE mutation; pT1a, unilateral ovarian tumour confined to the ovary without capsule invasion or breach; WHO, World Health Organization.

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ESGO/ESTRO/ESP treatment algorithms

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The 2025 ESGO/ESTRO/ESP guidelines on management of endometrial cancer recommend the following treatment algorithms (Figure 1A, B & C).1 The guidelines presented here are adapted from the ESGO/ESTRO/ESP guidelines to show only medicine classes. The ESGO/ESTRO/ESP guidelines are pan-European and do not necessarily align with UK marketing authorisations or reimbursement processes, which should be referred to prior to treatment decision-making. Healthcare practitioners should also consult national and/or local guidelines, where available.

Note for Figures 1A, B & C: The content in square brackets represents levels of evidence (I– V, where I is most robust and V is least robust) and grades of guidelines (A–E, where A is strongly recommended and E is never recommended).

Algorithm for adjuvant therapy following surgery in endometrial cancer Stages I–IVA

Figure 1A. Algorithm for adjuvant therapy following surgery in endometrial cancer Stages I–IVA.3
Figure adapted from Concin N et al. 2025.3
*The group of patients with uncertain risk is not depicted in the algorithm: for FIGO 2023 Stage IA1m NSMP high grade or ER-negative (or both), or p53abn. For patients with FIGO Stage ICm NSMP high grade or ER-negative (or both), or p53abn, there are insufficient data, and adjuvant therapy is generally not recommended. For patients with FIGO Stage IIIm POLEmut and IVAm POLEmut, no firm guideline can be given. However, de-escalation from high risk treatment can be considered following MDT discussion; †Especially for patients <60 years or with low grade endometrial carcinoma (II, A); ‡EBRT is recommended for optimal pelvic control; §VBT is an alternative option, especially for patients who have undergone lymph node staging and are pN0; No adjuvant therapy can be considered, especially for patients who have undergone lymph node staging and are pN0 without substantial LVSI and low-grade endometrial carcinoma.
Adj. tx, adjuvant therapy; C&A CT, concurrent and adjuvant chemotherapy; CT, chemotherapy; dMMR, mismatch repair deficient; EBRT, external beam radiotherapy; ER, oestrogen receptor; FIGO, International Federation of Gynaecology and Obstetrics; ICI, immune checkpoint inhibitor; LVSI, lymphovascular space invasion; MDT, multi-disciplinary team; NSMP, no specific molecular profile; p53abn, abnormal p53; pN0, pathological node 0; POLEmut, POLE mutation; VBT, vaginal brachytherapy.

First-line systemic therapy in unresectable Stage III–IV

Figure 1B. First-line systemic therapy in unresectable Stage III–IV or recurrent disease with no prior chemotherapy except in the adjuvant setting.1
Figure adapted from Concin N et al. 2025.1
*The standard chemotherapy regimen is carboplatin + paclitaxel.
dMMR, mismatch repair-deficient; EBRT, external beam radiotherapy; EC, endometrial cancer; ER, oestrogen receptor; HER2, human epidermal growth factor receptor 2; ICI, immune checkpoint inhibitor; MA, megestrol acetate; MPA, medroxyprogesterone acetate; PARPi, poly(ADP-ribose) polymerase inhibitor; VEGFi, vascular endothelial growth factor inhibitor.

Second-line systemic therapy in unresectable, recurrent disease

Figure 1C. Second-line systemic therapy in unresectable, recurrent disease after first-line platinum-based chemotherapy.1
Figure adapted from Concin N et al. 2025.1
1L, first line; 2L, second line; dMMR, mismatch repair deficient; HER2, human epidermal growth factor receptor 2; ICI, immune checkpoint inhibitor; MMR, mismatch repair; VEGFi, vascular endothelial growth factor inhibitor.

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Treatment modalities

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  • Surgery

    For patients with early-stage endometrial cancer, hysterectomy with bilateral salpingo-oophorectomy is the standard initial treatment approach, and is considered a curative option.1,4 Surgery can be done via a laparotomy (open surgery) or using minimally invasive surgery (MIS) techniques, including laparoscopy or robotic-assisted surgery.5 MIS is the preferred approach, and is recommended for patients with Stage I/II and/or high risk endometrial carcinoma by the National Institute for Health and Care Excellence and the ESGO/ESTRO/ESP 2025 guidelines.1,6 However, MIS should be avoided in patients with bulky uterine disease due to risk of morcellation;5 metastatic spread outside the uterus (including lymph node metastasis) is a relative contraindication for MIS.1 Minimally invasive and open techniques show equivalent disease-free and overall survival (OS) in retrospective studies.7 Compared with invasive surgery, MIS is associated with shorter hospital stays, quicker recovery and substantially lower risk of post-operative morbidity.4,6

    For patients with advanced stage disease, surgery may be considered depending on the extent of dissemination of the tumour, its resectability, and associated morbidities.4 The 2025 ESGO/ESTRO/ESP management of endometrial cancer guidelines recommend that patients with Stage III/IV disease should undergo resection only if complete macroscopic resection is feasible with acceptable morbidity and quality of life.1 In cases of advanced disease where the tumour is deemed unresectable due to the extent of disease, delayed surgery can be considered if the patient shows good response to primary systemic therapy and is otherwise suitable for surgery. Palliative surgery for symptomatic management in patients experiencing significant pelvic symptoms may be considered.1

    Lymph node staging and lymphadenectomy

    In early-stage disease, a sentinel lymph node (SLN) biopsy should be performed to establish staging in patients with disease confined to the uterus. If SLNs are not detected, a systematic lymphadenectomy should be performed in those with high–intermediate or high risk disease, and possibly in those with intermediate risk disease.1

    In patients with advanced disease in whom complete cytoreduction is possible and who have subsequently undergone surgery, systematic lymphadenectomy is not recommended, and only suspicious lymph nodes should be resected.1 A lymphadenectomy, consisting of dissection and assessment of pelvic and para-aortic lymph nodes, is a diagnostic procedure and has not been shown to reduce the risk of recurrence or improve survival.5

    Surgical guidelines for endometrial cancer

    Figure 2. Surgical guidelines for endometrial cancer.1
    BSO, bilateral salpingo-oophorectomy; MIS, minimally invasive surgery.

  • Radiotherapy

    Adjuvant radiotherapy, either external beam radiotherapy (EBRT) or vaginal brachytherapy (VBT), are recommended by British and European guidelines to reduce the risk of recurrence in Stage I–IVa intermediate, high–intermediate or high risk endometrial cancers. In high risk cancers, radiotherapy may be administered with concurrent or sequential adjuvant chemotherapy.1,4 Table 2 summarises the key radiotherapy trials in endometrial cancer.

    Trial Years of enrollment No. of patients Surgery Eligibility Randomisation Recurrence risk Survival Adverse events
    GOG-998 1987–1995 392 TH-BSO+LND Stages IB/C; Stage II (occult) EBRT vs NAT Cumulative incidence of recurrence at 2 years: 3.0% vs 12.0%; p=0.007 4 years: 92.0% vs 86.0%; p=0.557 More frequent and more severe toxicities (EBRT vs NAT) with statistically significant (p<0.001) differences in haematologic, gastrointestinal, genitourinary and cutaneous toxicities
    PORTEC-19,10 1990–1997 714 TH-BSO without lymphadenectomy Stages IB G2-3; Stages IC G1-2 EBRT vs NAT

    LRR at 15 years: 5.8% vs 15.5%; HR: 3.46 (1.93–6.18), p<0.0001

    Distant metastasis at 15 years: 9.3% vs 7.1%; p=0.25

    		 OS at 15 years: 52.0% vs 60.0%; p=0.14 5-year rates of 17% vs 4% (p<0.0001). All severe (Grade 3–4) complications were observed in the RT group (3%)
    PORTEC-211 2002–2006 427 TH-BSO (no routine lymphadenectomy) High-intermediate risk disease including those aged >60 years with Stage IB G3 or Stage IC G1–2; or Stage IIA EBRT vs VBT

    LRR at 5 years: 2.1% vs 5.1%; HR 2.08 (0.71–6.09), p=0.17

    Distant metastasis at 5 years: 5.7% vs 8.3%; HR: 1.32 (0.63–2.74), p=0.46

    		 OS at 5 years: 79.6% vs 84.8%; p=0.57 Grade 1 and 2 gastrointestinal toxic effects with EBRT (53.8%) vs VBT (12.6%)
    PORTEC-312,13 2006–2013 660 TH-BSO High risk disease including Stage I G3 with LVSI/deep myometrial invasion/both; Stage II or III; Stages I–III serous or clear cell histology EBRT vs EBRT + 2 cycles of cisplatin followed by 4 cycles of CP

    5-year risk of:
    Distant metastases: 29.1% vs 21.4%; HR: 0.74 (0.55–0.99), p=0.047

    Vaginal recurrence: 0.3%; vs 0.3%; HR: 0.99, (0.06–15.90), p=0.99

    Pelvic recurrence:
    0.9% vs 0.9%; HR: 0.75 (0.17–3.33), p=0.71

    FFS at 5 years:
    69.1% vs 76.5%, HR: 0.70 (0.52–0.94), p =0.016 (see Figure 3)

    OS at 5 years: 76.1% vs 81.4% HR: 0.70 (0.51–0.97), p=0.034 (see Figure 3)

    RFS at 10 years:
    67.4% vs 72.8%; HR: 0.74 (0.56–0.98), p=0.034

    OS at 10 years:
    67.3% vs 74.4%; HR: 0.73 (0.54–0.97), p=0.032

    At 5 years:
    Grade ≥2 AEs 23% vs 38% (p=0.002)

    Grade 3 AE rate did not differ significantly between the two groups (5% vs 8%)

    Grade ≥2 sensory neuropathy persisted at 5 years in 0% vs 6% of patients 
    GOG-25814–16 2009–2014 736 TH-BSO Stage III or IVA, Stage I or II clear cell or serous EC with positive peritoneal washings EBRT + cisplatin followed by 4 cycles of CP vs CP for 6 cycles

    5-year risk of:
    Vaginal recurrence:
    2.0% vs. 7.0%; HR: 0.36 (0.16–0.82)

    Lower pelvis and PA LN recurrence:
    11.0% vs. 20.0%; HR: 0.43 (0.28–0.66)

    Distant recurrence: 27.0% vs 21.0%; HR: 1.36 (1.00–1.86)

    RFS at 5 years: 59.0% vs. 58.0%;
    HR: 0.9: (0.74–1.10) (see Figure 5)

    OS at 10 years:
    36.2% vs 34.2%; HR: 1.05 (0.82–1.34), p=0.72 (see Figure 6)

    		 Grade 3–5 AEs: were reported in 58% of patients in the chemoradiotherapy group compared with 63% in the chemotherapy group

    Table 2. Summary of some of the key radiotherapy trials in endometrial cancer.
    AE, adverse event; CI, confidence interval; CP, carboplatin-paclitaxel; CRT, chemoradiotherapy; CT, chemotherapy; EBRT, external beam radiotherapy; EC, endometrial carcinoma; FFS, failure-free survival; G, grade; GOG, Gynaecologic Oncology Group; HR, hazard ratio; LND, lymph node dissection; LRR, locoregional recurrence rate; NAT, no additional treatment; OS, overall survival; PA LN, paraaortic lymph-node; PORTEC, post-operative radiotherapy for Endometrial Carcinoma; RD, residual disease; RFS, recurrence-free survival; TH-BSO, total hysterectomy and bilateral salpingo-oophorectomy; VBT, vaginal brachytherapy.

    The OS and recurrence-free survival improvement seen with adjuvant chemoradiotherapy compared with radiotherapy in the PORTEC-3 trial underpinned the recommendation for use of chemoradiotherapy in high-risk endometrial cancer in treatment guidelines since original publication in 2019. See Figure 3 for 5-year OS and failure-free survival below.

    5-year overall and failure-free survival in the overall population in the PORTEC-3 trial

    Figure 3. 5-year overall and failure-free survival in the overall population in the PORTEC-3 trial (primary endpoint).12
    Figure adapted from de Boer SM et al. 2019.12
    CI, confidence interval; CRT, chemoradiotherapy; CT, chemotherapy; HR, hazard ratio; OS, overall survival; RT, radiotherapy.

    Biomarker analysis of RFS and OS in patients with POLEmut, dMMR, p53abn and NSMP EC in the PORTEC-3 trial showed statistically significant benefit from chemoradiation vs radiation in the p53abn cohort. There was no statistically significant RFS and OS difference between the arms in the POLEmut, dMMR or NSMP subgroups, despite separation of the 5-year RFS curve in the NSMP subgroup. 

    5-year recurrence-free and overall survival among patients by molecular subgroup in the PORTEC-3 trial

    Figure 4. 5-year recurrence-free and overall survival among patients with POLEmut, MMRd, p53abn and NSMP endometrial cancer in the PORTEC-3 trial.17
    Figure adapted from León-Castillo A et al. 2020.17
    Copyright holder © 2020, Wolters Kluwer Health
    CRT, chemoradiotherapy; MMRd, mismatch repair-deficient; EC, endometrial cancer; HR, hazard ratio; OS, overall survival; POLEmut, POLE mutant; RFS, recurrence-free survival; RT, radiotherapy.

    In the GOG-258 trial, comparing chemotherapy with chemoradiotherapy, adding radiation to the chemotherapy regime did not show improvement in RFS (Figure 5) or in OS (Figure 6) in stage III/IV endometrial cancer.

    Relapse-free survival in the overall population in the GOG-258 trial (primary endpoint)

    Figure 5. Relapse-free survival in the overall population in the GOG-258 trial (primary endpoint).14
    Figure adapted from Matei D et al. 2019.14
    CI, confidence interval; CRT, chemoradiotherapy; CT, chemotherapy; dMMR, mismatch repair-deficient; HR, hazard ratio; RFS, relapse-free survival.

    Overall survival in the overall population and according to Stage in the GOG-258 trial

    Figure 6. Overall survival in the overall population (left) and according to stage (right) in the GOG-258 trial (secondary endpoint).16
    Figure adapted from Matei D et al. 2023.16
    CI, confidence interval; CRT, chemoradiotherapy; CT, chemotherapy; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; OS, overall survival.

  • Chemotherapy

    The 2025 ESGO/ESTRO/ESP management of endometrial cancer guidelines recommend the use of adjuvant chemotherapy in high-risk tumours, as described under the Radiotherapy section, as well as in the first line setting and later recurrence (Figures 1A–C).1

    For patients with primary advanced or first recurrence of endometrial cancer, the doublet carboplatin/paclitaxel was shown to be non-inferior to the triplet paclitaxel/doxorubicin/cisplatin regime in GOG 209 and therefore carboplatin and paclitaxel was adopted as a standard of care. Carboplatin and paclitaxel demonstrated a median OS and median progression-free survival (PFS) of approximately 3 years and 1 year, respectively.18 Table 3 provides a summary of key chemotherapy trials in primary advanced and recurrent endometrial cancer.  

      Chemotherapy trials
    RT agent vs doublet Single agent vs doublet Doublet vs doublet Doublet vs triplet TAP vs CP
    Regimen WART vs Dox-Cis† Dox vs Dox-Cis Dox vs Dox-Cis Dox-Cis vs Dox-Tax Dox-Cis vs TAP TAP vs CP
    Trial GOG 122 (1995)19 EORTC55872 (2003)20 GOG 107 (2004)21 GOG 163 (2004)22 GOG 177 (2004)23 GOG 209 (2012)18
    Population (Stage) Stage III–IV Stage III–IV and recurrent Stage III–IV and recurrent Stage III–IV and recurrent Stage III–IV and recurrent Stage III–IV and recurrent
    N 396 177 281 317 273 1328
    PFS results* HR§ (CI): 0.71 (0.55–0.91) favouring Dox-Cis Dox: 7 months
    Dox-Cis: 8 months (HR: NR)    		 Dox: 3.8 months
    Dox-Cis: 5.7 months (HR: 0.74)    		 Dox-Cis: 7.2 months Dox-Tax: 6.0 months (HR:1.01, NS) Dox-Cis: 5.3 months TAP: 8.3 months (HR: 0.60) TAP: 14 months CP: 13 months (HR: 1.03, NS)**
    OS results* HR§ (CI): 0.68
    (0.52–0.89) favouring Dox-Cis    		 Dox: 7 months
    Dox-Cis: 9 months (HR 1.46, NS)    		 Dox: 9.2 months Dox-Cis: 9.0 months (NS) Dox-Cis: 12.6 months Dox-Tax: 13.6 months (HR 1.00, NS) Dox-Cis: 12.3 months TAP: 15.3 months (HR: 0.75) TAP: 41 months CP: 37 months (HR: 1.00, NS)**

    Table 3. Summary of the key chemotherapy trials in primary Stage III/IV and recurrent endometrial cancer.
    *Median PFS and OS reported unless noted otherwise. Results met the requirements for significance unless noted otherwise; †WART trial Dox-Cis x7 with 8th cycle of single-agent Cis; §HR was adjusted for stage; When stratifying for WHO performance status, the result reached significance. **Trial was tested for non-inferiority.
    CI, confidence interval; Cis, cisplatin; CP, carboplatin-paclitaxel; Dox, doxorubicin; HR, hazard ratio; NR, not reported; NS, not significant; OS, overall survival; PFS, progression-free survival; RT, radiotherapy; TAP, paclitaxel-doxorubicin-cisplatin; Tax, paclitaxel; WART, whole abdominal radiation therapy; WHO, World Health Organization.

    There are limited treatment options that exist after failure of first-line therapy in advanced or recurrent endometrial cancer.24 No established standard of care exists for second-line chemotherapy,24 although cisplatin, doxorubicin, weekly paclitaxel and carboplatin/paclitaxel rechallenge may be considered.25 Overall prognosis of advanced or recurrent measurable disease remains poor with a 5-year survival rate of approximately 17% and median OS of <12 months.26

    Drug Dose and schedule Response rate
    Cisplatin 50 mg/m² Q3W 4.0%
    Docetaxel 36 mg/m² Q1W 7.7%
    Pegylated liposomal doxorubicin 50 mg/m² Q4W 9.5%
    Ixabepilone 40 mg/m² Q3W 12.0%
    Oxaliplatin 130 mg/m² Q3W 13.5%
    Ifosfamide 1.2 mg/m² (5 days) Q4W 15.0%
    Paclitaxel 110-200 mg/m² (over 3 hours) Q3W 27.3%

    Table 4. Response rate for patients with endometrial carcinoma treated with second-line chemotherapy.27
    Table adapted from Moxley KM and McMeekin DS. 2010.27
    Q1W, every week; Q3W, every 3 weeks; Q4W, every 4 weeks.

  • Immunotherapy

    Immune checkpoint pathways which prevent excessive T-cell activation can be exploited by tumours to promote tumour growth.28,29 Immune checkpoint inhibitors, or immunotherapy agents, are used to help restore T-cell function and kill tumour cells.29,30

    Mechanism of PD-1/PD-L1 pathway-induced immunosuppression within the tumour

    Figure 7. Mechanism of PD-1/PD-L1 pathway-induced immunosuppression within the tumour microenvironment.29
    Figure adapted from Varricchi G et al. 2017.29
    Ab, antibody; APC, antigen presenting cell; CD, cluster of differentiation; MHC, major histocompatibility complex; PD(L)-1, programmed death (ligand)-1; TCR, T-cell receptor.

    Mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) tumours carry 10–100 times as many somatic mutations compared with MMR-proficient /microsatellite stable (MMRp/MSS) tumours and the proteins expressed by these mutations can be recognised by the immune system.31 dMMR/MSI-H tumours may strongly express immune checkpoint proteins such as programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte activation gene 3 (LAG-3) and indoleamine 2,3-dioxygenase (IDO).32 Endometrial tumours with dMMR/MSI are therefore optimal candidates for immunotherapy due to their high mutational load.33

    Additionally, the combination of anti-PD-(L)1 therapy and chemotherapy can have synergistic effects producing:34,35

    • Myeloid-derived suppressor cell depletion
    • Increased expression of tumour antigens
    • Homeostatic proliferation of T-cells
    • Regulatory T-cell depletion
    • Tumour cell death

    Chemotherapy primes and reshapes the tumour microenvironment by enhancing antigen release, reducing immune suppression, and promoting immune infiltration. While immunotherapy sustains and amplifies these effects, its combination with chemotherapy creates synergistic activity in both dMMR and MMRp tumours.36,37

  • Anti-angiogenic agents

    Combining immunotherapy with anti-angiogenic therapy has reciprocal effects. Anti-angiogenic drugs block the negative immune signals by increasing the ratio of anti-/pro-tumour immune cells and decreasing immune checkpoint expression. Immunotherapy restores the immune-supportive microenvironment and promotes vascular normalisation, increasing lymphocyte infiltration and activation.38

  • Poly (ADP-ribose) polymerase (PARP) inhibitors

    PARP inhibitors and immunotherapy combinations have been shown to have potentially synergistic mechanisms of action, as evidenced in pre-clinical models by:39–41

    • Increasing neoantigen load and enhancing antigen presentation
    • Increasing tumour infiltrating lymphocytes (TILs)
    • Upregulating PD-L1
    • Favourably influencing the tumour microenvironment
    • Blocking the protective effects of PD-L1 upregulation

  • Hormonal therapy

    Hormones, such as oestrogen and/or progesterone, can aid tumour proliferation. Hormone therapy uses hormones or hormone-blocking drugs to treat cancer.

    The recent ESGO/ESTRO/ESP 2025 guidelines recommend hormone therapy as a treatment option in low-grade oestrogen receptor-positive, low volume or asymptomatic, advanced tumours or slowly growing recurrent tumours. Progestins are recommended, with aromatase inhibitors and tamoxifen as alternatives.1

    In a Phase 2 study of 63 patients with recurrent or advanced endometrial cancer who failed to respond to, or were considered incurable with, local therapy, treatment with high dose megestrol acetate showed an overall response rate (ORR) of 24%; median progression-free survival (mPFS) of 2.5 months; and median OS of 7.6 months.42

    In another Phase 2 trial of 61 patients with measurable recurrent or advanced endometrial cancer, the combination of alternating courses of megestrol acetate and tamoxifen showed an ORR of 27%; mPFS of 2.7 months; and median OS of 14 months.43

    There are no modern era trials of adjuvant hormone therapy in endometrial cancer. A meta-analysis of seven randomised studies carried out mainly in the 1980s showed no significant impact on OS.44

References (All URLs accessed July 2026):

  1. Concin N et al. Lancet Oncol 2025;26:e425–e435 (plus supplementary appendix);
  2. Berek JS et al. Int J Gynaecol Obstet 2023;162:383–394;
  3. Concin N et al. ESGO-ESTRO-ESP Guidelines on the management of endometrial carcinoma – Update 2025. Presented at ESGO, 20-23 February 2025; Rome, Italy;
  4. Morrison J et al. Eur J Obstet Gynecol Reprod Biol 2022;270:50–89;
  5. Morice P et al. Lancet 2016;387;1094–1108;
  6. National Institute of Health and Care Excellence. Laparoscopic hysterectomy (including laparoscopic total hysterectomy and laparoscopically assisted vaginal hysterectomy) for endometrial cancer. HealthTech guidance HTG229. https://www.nice.org.uk/guidance/HTG229 (accessed March 2026);
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