Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

stage IA endometrioid carcinoma not considering fertility preservation

1st line – surgery

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ACUTE
|
stage IA endometrioid carcinoma not considering fertility preservation
1st line – 

surgery

Surgery is the most important component of management for potentially curable disease.

Surgery stages the disease to guide treatment planning, and removes malignant disease.[97]​​

Standard surgery requires a total hysterectomy, bilateral salpingo-oophorectomy, and sentinel lymph node mapping (for select patients managed in institutions with suitable expertise) and/or lymphadenectomy.[9]​​[83][123]

Total hysterectomy may be done via laparoscopy (including robotic-assisted laparoscopy) or via laparotomy. One Cochrane review found similar survival outcomes for both approaches.[173] However, laparoscopy may be associated with significantly shorter hospital stays and fewer complications compared with laparotomy and is gaining in popularity with patients.[174][175][176][177][178][179][180] [ Cochrane Clinical Answers logo ] ​​

Lymphadenectomy for patients with stage I disease is not beneficial with regards to survival or recurrence.​​​ [ Cochrane Clinical Answers logo ] Therefore, less-aggressive surgical approaches can be adopted for grade 1 or 2 endometrioid tumors with <50% myometrial invasion, <2 cm in length, and no obvious other macroscopic disease.[183][184][185][186][187][188]​​​ 

In patients with apparent uterine-confined disease, sentinel lymph node (SLN) mapping, with ultrastaging to detect low-volume metastasis, is preferred to lymphadenectomy to assess pelvic lymph node metastases during surgical staging.[83][189][190]​

SLN mapping results in lower morbidity than lymphadenectomy. Patients who have SLN mapping have noninferior survival and recurrence outcomes compared with those who have complete lymphadenectomy.​[191][192][193][194][195][196]

If SLN mapping fails, side-specific lymphadenectomy should be carried out.[83]​​​

Obesity and comorbidities make patients more prone to perioperative risks and complications.[171][172]​​

Plus – postoperative observation

Back
ACUTE
|
stage IA endometrioid carcinoma not considering fertility preservation
|
low-risk or low-intermediate risk
Plus – 

postoperative observation

Treatment recommended for ALL patients in selected patient group

Patients with stage IA disease without myometrial invasion have a low risk of recurrence following surgical staging; therefore, adjuvant therapy is generally not required.[155][202][238]​​​​​​​[239] Observation is preferred.

Patients with stage IA disease with myometrial invasion who are classified as low-intermediate risk using GOG-99 study criteria have a low risk of recurrence following surgical staging. Therefore, adjuvant therapy is generally not required.[154] Observation is preferred.

Consider – vaginal brachytherapy

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ACUTE
|
stage IA endometrioid carcinoma not considering fertility preservation
|
high-intermediate risk
Consider – 

vaginal brachytherapy

Treatment recommended for SOME patients in selected patient group

Patients with stage IA disease with myometrial invasion who are classified as high-intermediate risk using GOG-99 study criteria have a 26% risk of recurrence without adjuvant radiation therapy following surgical staging.[154] Therefore, adjuvant radiation therapy is offered (preferably vaginal brachytherapy).[83][201][206][244]​​​​

Vaginal brachytherapy is associated with less bowel toxicity and better quality of life than external beam radiation therapy (EBRT), with the exception of sexual dysfunction, which appears to be similar for both therapies; however, this is a complex issue.[83][205][206]​​ EBRT is associated with late toxicities, including urinary and bowel symptoms, as well as lower physical and role-physical functioning.[207][208]​​ EBRT may increase the risk of second malignancy, particularly in younger patients.[207][209]​​ Many clinicians reserve EBRT for patients with lymphovascular space invasion or node-positive disease.[9][83]

Adjuvant radiation therapy can improve progression-free survival in patients with high-intermediate risk, but it does not improve overall survival.[9][203][204]

stage IA endometrioid carcinoma considering fertility preservation

1st line – surgery or careful counseling + progestin therapy

Back
ACUTE
|
stage IA endometrioid carcinoma considering fertility preservation
1st line – 

surgery or careful counseling + progestin therapy

Highly selected patients with well-differentiated stage IA (noninvasive) endometrioid carcinoma who wish to preserve their fertility, and have been referred to a specialist center and received counseling, may be considered for fertility-sparing treatment. Imaging with pelvic MRI (preferred) or pelvic transvaginal ultrasound is required to confirm disease extent.[83]

Fertility-sparing treatment is with a levonorgestrel intrauterine device (IUD) or an oral progestin (medroxyprogesterone or megestrol).​[83][240]​​​​ 

A dual-progestin regimen, with a levonorgestrel IUD plus medroxyprogesterone or megestrol, can be considered, which may improve response rate and pregnancy rate.[83][241]​​​

Aggressive monitoring is warranted, including pelvic examination and ultrasound at 3-month intervals, and dilation and curettage or hysteroscopy with endometrial sampling every 3-6 months. A treatment duration of 6-12 months is recommended; if there is no response or there is progression of disease, total hysterectomy plus BSO should be considered.

Patients who are successfully treated with fertility-sparing therapy are advised to consider hysterectomy once childbearing is completed.[9][83][116][125]​​​[242][243]​​​

See local specialist protocol for dosing guidelines.

Primary options

levonorgestrel intrauterine device

OR

megestrol

OR

medroxyprogesterone acetate

OR

levonorgestrel intrauterine device

-- AND --

megestrol

or

medroxyprogesterone acetate

stage IB or II endometrioid carcinoma

1st line – surgery

Back
ACUTE
|
stage IB or II endometrioid carcinoma
1st line – 

surgery

Surgery is the most important component of management for potentially curable disease.

Surgery stages the disease to guide treatment planning and removes malignant disease.[97]​​

Standard surgery requires a total hysterectomy, bilateral salpingo-oophorectomy, and sentinel lymph node mapping (for select patients managed in institutions with suitable expertise) and/or lymphadenectomy.[9][83][123]​​​

Some patients with stage II endometrial carcinoma may be offered a radical hysterectomy, particularly if there is known cervical involvement by endometrial cancer before surgery. Radical hysterectomy includes resection of the parametrium and upper part of the vagina in addition to a total hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy.

Total hysterectomy may be done via laparoscopy (including robotic-assisted laparoscopy) or via laparotomy. One Cochrane review found similar survival outcomes for both approaches.[173] However, laparoscopy may be associated with significantly shorter hospital stays and fewer complications compared with laparotomy and is gaining in popularity with patients.[174][175][176][177][178][179][180] [ Cochrane Clinical Answers logo ]

Lymphadenectomy for patients with stage I disease is not beneficial with regards to survival or recurrence. [ Cochrane Clinical Answers logo ] Therefore, less-aggressive surgical approaches can be adopted for grade 1 or 2 endometrioid tumors with <50% myometrial invasion, <2 cm in length, and no obvious other macroscopic disease.[183][184][185][186][187][188]​​ 

In patients with apparent uterine-confined disease, sentinel lymph node (SLN) mapping, with ultrastaging to detect low-volume metastasis, is preferred to lymphadenectomy to assess pelvic lymph node metastases during surgical staging.[83][189][190]​​

SLN mapping results in lower morbidity than lymphadenectomy. Patients who have SLN mapping have noninferior survival and recurrence outcomes compared with those who have complete lymphadenectomy.​[191][192][193][194][195][196]

If SLN mapping fails, side-specific lymphadenectomy should be carried out.​[83]

Obesity and comorbidities make patients more prone to perioperative risks and complications.[171][172]​​

Plus – postoperative observation

Back
ACUTE
|
stage IB or II endometrioid carcinoma
|
low-intermediate risk
Plus – 

postoperative observation

Treatment recommended for ALL patients in selected patient group

Patients with stage IB or II disease classified as low-intermediate risk using GOG-99 study criteria have a low risk of recurrence following surgical staging. Therefore, adjuvant therapy is not required.[154] Observation is preferred.

Consider – vaginal brachytherapy

Back
ACUTE
|
stage IB or II endometrioid carcinoma
|
high-intermediate risk
Consider – 

vaginal brachytherapy

Treatment recommended for SOME patients in selected patient group

Patients with stage IB or II disease classified as high-intermediate risk using GOG-99 study criteria have a 26% risk of recurrence without adjuvant radiation therapy following surgical staging.[154] Therefore, adjuvant radiation therapy is offered (preferably vaginal brachytherapy).[83][201][206]​​​​​[244]

Vaginal brachytherapy is associated with less bowel toxicity and better quality of life than EBRT, with the exception of sexual dysfunction, which appears to be similar for both therapies; however, this is a complex issue.[83][205][206]​​​ EBRT is associated with late toxicities, including urinary and bowel symptoms, as well as lower physical and role-physical functioning.[207][208]​​​ EBRT may increase the risk of second malignancy, particularly in younger patients.[207][209]​​​ Many clinicians reserve EBRT for patients with lymphovascular space invasion or node-positive disease.[9][83]

Adjuvant radiation therapy can improve progression-free survival in patients with high-intermediate risk, but it does not improve overall survival.[9][203][204]

Consider – external beam radiation therapy and/or vaginal brachytherapy ± chemotherapy

Back
ACUTE
|
stage IB or II endometrioid carcinoma
|
high risk
Consider – 

external beam radiation therapy and/or vaginal brachytherapy ± chemotherapy

Treatment recommended for SOME patients in selected patient group

Stage IB or II disease may be considered high risk if there is deep myometrial invasion, gross cervical involvement, and/or tumor grade 3. These patients may be offered adjuvant external beam radiation therapy (EBRT) and/or vaginal brachytherapy. Many clinicians reserve EBRT for node-positive disease.[9][83]

Vaginal brachytherapy is associated with less bowel toxicity and better quality of life than EBRT, with the exception of sexual dysfunction, which appears to be similar for both therapies; however, this is a complex issue.[83][205][206]​​ EBRT is associated with late toxicities, including urinary and bowel symptoms, as well as lower physical and role-physical functioning.[207][208]​​ EBRT may increase the risk of second malignancy, particularly in younger patients.[207][209]

For patients having EBRT, pelvic intensity-modulated radiation therapy should be considered to reduce acute and late toxicity.[83][205]​​​[210]​​

Adjuvant radiation therapy can improve progression-free survival in patients with high-intermediate risk, but it does not improve overall survival.[9][203][204]

Chemotherapy, in addition to adjuvant radiation therapy, can be considered for these patients, but this remains controversial. Cisplatin plus radiation therapy followed by paclitaxel plus carboplatin is the preferred regimen.[83]​​​​​[220]​ 

Studies combining chemotherapy with adjuvant radiation therapy (chemoradiation) in patients with high-risk early-stage disease have found no benefit compared with radiation therapy alone, but further analysis of these findings (e.g., by molecular subtype) is ongoing.[219][220][221][245]​​​

See local specialist protocol for dosing guidelines.

Primary options

cisplatin

and

paclitaxel

and

carboplatin

stages III to IV endometrioid carcinoma; all nonendometrioid carcinomas (high risk)

1st line – staging surgery + adjuvant chemotherapy

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ACUTE
|
stages III to IV endometrioid carcinoma; all nonendometrioid carcinomas (high risk)
1st line – 

staging surgery + adjuvant chemotherapy

Patients with stage III to IV disease, and those with nonendometrioid carcinomas (e.g., serous, clear-cell, undifferentiated carcinoma, carcinosarcoma), have a high risk of recurrence. Optimal adjuvant treatment has not been determined, but chemotherapy is the mainstay of treatment.

Adjuvant chemotherapy is recommended for surgically staged stage III and IV disease; paclitaxel plus carboplatin is the preferred chemotherapy regimen.[83]​  

See local specialist protocol for dosing guidelines.

Primary options

paclitaxel

and

carboplatin

Consider – immunotherapy

Back
ACUTE
|
stages III to IV endometrioid carcinoma; all nonendometrioid carcinomas (high risk)
Consider – 

immunotherapy

Treatment recommended for SOME patients in selected patient group

​Guidelines recommend chemotherapy in combination with immunotherapy (with dostarlimab, pembrolizumab, or durvalumab), followed by immunotherapy maintenance treatment, as a preferred treatment option for stage III and IV disease (although pembrolizumab is not recommended for carcinosarcoma).[83] Dostarlimab or pembrolizumab can be considered regardless of MMR status. Durvalumab is recommended only for patients with MMR-deficient tumors.[83] 

Phase 3 trials of women with advanced or recurrent endometrial cancer report improved progression-free survival with chemotherapy plus immunotherapy (followed by immunotherapy maintenance treatment) compared with chemotherapy alone. Benefit was seen in both MMR-deficient and MMR-proficient disease, although greater benefit was observed in patients with MMR-deficient tumors.​[215][216][247][248][249] Results for overall survival appear favorable, although data are immature.

The addition of bevacizumab (a vascular endothelial growth factor [VEGF]-directed monoclonal antibody) to chemotherapy has shown favorable results, although the evidence is more limited.[250][251][252] Bevacizumab in combination with chemotherapy is recommended as a further option for stage III and IV measurable disease.[83][250][251][252]​​​ 

For patients with HER2-positive uterine serous carcinoma, guidelines recommend trastuzumab in combination with chemotherapy (carboplatin plus paclitaxel). This regimen may also be considered for patients with HER2-positive carcinosarcoma.[83][237]

A significant proportion of nonendometrioid cancers test positive for HER2 gene overexpression or amplification, in particular serous carcinomas and carcinosarcomas. One phase 2 trial suggested that the addition of trastuzumab to chemotherapy regimens improves progression-free and overall survival compared with chemotherapy alone in patients with advanced or recurrent HER2-positive uterine serous carcinoma. Toxicity was similar with and without trastuzumab.[237]

See local specialist protocol for dosing guidelines.

Primary options

dostarlimab

OR

pembrolizumab

OR

durvalumab

OR

bevacizumab

OR

trastuzumab

Consider – radiation therapy

Back
ACUTE
|
stages III to IV endometrioid carcinoma; all nonendometrioid carcinomas (high risk)
Consider – 

radiation therapy

Treatment recommended for SOME patients in selected patient group

Chemotherapy plus radiation therapy may be an option for stages IIIB and IIIC disease. External beam radiation therapy (EBRT), with or without brachytherapy, may be considered, taking into account locoregional and distant metastatic risk.[83]

Retrospective analyses suggest that chemoradiation therapy (e.g., cisplatin plus radiation therapy followed by carboplatin and paclitaxel) may be of benefit in these patients.[253][254][255]​​ However, the results of randomized trials are equivocal.[245][256][257]​​ 

Radiation therapy may be considered for all patients with nonendometrioid carcinomas, although its impact on survival is not yet known given the rarity of these subtypes.

ONGOING

recurrent or incurable disease

1st line – supportive care

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ONGOING
|
recurrent or incurable disease
1st line – 

supportive care

Supportive care addresses physical, psychological, social, and spiritual issues.

Common medical challenges include pain, nausea and vomiting, lymphedema, bleeding, obstruction (urinary and gastrointestinal), and fistulae formation.[258]

Consider – salvage radiation therapy and/or surgical resection ± systemic therapy

Back
ONGOING
|
recurrent or incurable disease
|
with isolated and symptomatic disease
Consider – 

salvage radiation therapy and/or surgical resection ± systemic therapy

Treatment recommended for SOME patients in selected patient group

In the setting of an isolated and symptomatic vaginal recurrence, salvage radiation therapy and/or surgical resection are considered, depending on prior therapy.

Salvage radiation therapy involves a combination of external beam radiation therapy and vaginal brachytherapy, and results in 5-year survival rates of 40% to 70%.[259][260]

Survival rates following salvage radiation therapy for pelvic or para-aortic nodal recurrence are disappointing (approximately 10%), but advances in radiation treatment planning and delivery (e.g., intensity-modulated radiation therapy) may improve outcomes.[261]

Systemic therapy in addition to radiation therapy and/or surgery can be considered for locoregional recurrence that is not amenable to radiation therapy or surgery.[83]

Consider – palliative chemotherapy

Back
ONGOING
|
recurrent or incurable disease
|
with estrogen/progesterone receptor-negative tumor
Consider – 

palliative chemotherapy

Treatment recommended for SOME patients in selected patient group

Palliative chemotherapy is recommended for patients with recurrent estrogen/progesterone receptor-negative tumors.

Paclitaxel plus carboplatin is the preferred regimen. Other chemotherapy options may be considered, such as docetaxel plus carboplatin, or paclitaxel plus carboplatin plus bevacizumab. Paclitaxel plus doxorubicin and cisplatin is associated with increased toxicity and is recommended only as a second-line or subsequent option.[83][262]​[263]​​​​​​​​​​ Single-agent chemotherapy may be used if multiagent chemotherapy is contraindicated or for subsequent therapy.[83]​​

See local specialist protocol for dosing guidelines.

Primary options

paclitaxel

and

carboplatin

Secondary options

docetaxel

and

carboplatin

OR

paclitaxel

and

carboplatin

and

bevacizumab

OR

paclitaxel

and

doxorubicin

and

cisplatin

Consider – dostarlimab or pembrolizumab or durvalumab

Back
ONGOING
|
recurrent or incurable disease
|
with estrogen/progesterone receptor-negative tumor
Consider – 

dostarlimab or pembrolizumab or durvalumab

Treatment recommended for SOME patients in selected patient group

​Guidelines recommend the addition of dostarlimab, pembrolizumab, or durvalumab to chemotherapy for stage III or IV recurrent disease (although pembrolizumab is not recommended for carcinosarcoma).[83] Dostarlimab or pembrolizumab can be considered regardless of MMR status. Durvalumab is recommended only for patients with MMR-deficient tumors.[83]

Phase 3 trials of women with advanced or recurrent endometrial cancer report improved progression-free survival with chemotherapy plus immunotherapy (dostarlimab, pembrolizumab, or durvalumab) followed by maintenance immunotherapy, compared with chemotherapy alone. Benefit was seen in both MMR-deficient and MMR-proficient disease, although greater benefit was observed in patients with MMR-deficient tumors.[215][216][247][248][249] ​Results for overall survival appear favorable, although data are immature.​​

See local specialist protocol for dosing guidelines.

Primary options

dostarlimab

OR

pembrolizumab

OR

durvalumab

Consider – hormonal therapy

Back
ONGOING
|
recurrent or incurable disease
|
with estrogen/progesterone receptor-positive tumor
Consider – 

hormonal therapy

Treatment recommended for SOME patients in selected patient group

Patients with an estrogen/progesterone receptor (ER/PR)-positive endometrioid tumor (preferably low-grade, and small or slow-growing) may be treated with hormonal therapy, such as tamoxifen alternating with a progestin (megestrol or medroxyprogesterone).[222][264]

Combination treatment with the aromatase inhibitors letrozole plus everolimus (an mTOR inhibitor) may also be an option for recurrent or inoperable ER/PR-positive tumors.[83][228] Other options include single-agent hormonal therapy with megestrol or medroxyprogesterone, an aromatase inhibitor, tamoxifen, or fulvestrant.[83] Aromatase inhibitors may be better tolerated than tamoxifen in some patients, based on extrapolations from the breast cancer literature.[265]

A clinical response to progestins is consistently reported in around one third of patients with inoperable tumors or recurrence (15% to 34%), a rate comparable to that of tamoxifen.[223][225][226]

The results for GnRH agonists and oral medroxyprogesterone are probably similar to the highest reported response rate with tamoxifen alternating with megestrol (32%).[224]​​[227]

Everolimus plus letrozole may be beneficial (22% response rate) in women with advanced or recurrent endometrial cancer. A clinical response was only seen in endometrioid tumors; median progression-free survival was higher in patients who had not received prior chemotherapy.[83][228]

See local specialist protocol for dosing guidelines.

Primary options

tamoxifen

-- AND --

megestrol

or

medroxyprogesterone acetate

OR

letrozole

and

everolimus (oncologic)

OR

megestrol

OR

medroxyprogesterone acetate

OR

letrozole

OR

anastrozole

OR

tamoxifen

OR

fulvestrant

Consider – dostarlimab or pembrolizumab

Back
ONGOING
|
recurrent or incurable disease
|
with microsatellite instability-high or mismatch repair-deficient tumor (recurrence after chemotherapy)
Consider – 

dostarlimab or pembrolizumab

Treatment recommended for SOME patients in selected patient group

Patients with inoperable or advanced (stages III-IV) endometrial cancer and microsatellite instability-high (MSI-H) or mismatch repair (MMR)-deficient tumors can be treated with immunotherapy alone (dostarlimab or pembrolizumab), if recurrence occurs following neoadjuvant or adjuvant platinum-based chemotherapy.[83][231][232][233][234]​ Pembrolizumab is also indicated for patients with a tumor mutation burden ≥10 mutations/megabase with progression and no satisfactory alternative treatment options.[83]

See local specialist protocol for dosing guidelines.

Primary options

dostarlimab

OR

pembrolizumab

Consider – pembrolizumab + lenvatinib

Back
ONGOING
|
recurrent or incurable disease
|
with mismatch repair-proficient tumor (recurrence after chemotherapy)
Consider – 

pembrolizumab + lenvatinib

Treatment recommended for SOME patients in selected patient group

For patients with mismatch repair (MMR) proficiency, a combination of pembrolizumab plus lenvatinib may be an option for recurrence following chemotherapy.[83][235]

The combination of pembrolizumab and lenvatinib was associated with significantly longer progression-free and overall survival in patients with advanced endometrial cancer who had previously received at least one platinum-based chemotherapy regimen, compared with chemotherapy, in one phase 3 trial.[235]

See local specialist protocol for dosing guidelines.

Primary options

pembrolizumab

and

lenvatinib

Consider – palliative chemotherapy + trastuzumab

Back
ONGOING
|
recurrent or incurable disease
|
with HER2-positive nonendometrioid carcinoma
Consider – 

palliative chemotherapy + trastuzumab

Treatment recommended for SOME patients in selected patient group

For patients with HER2-positive uterine serous carcinoma or carcinosarcoma, guidelines recommend the addition of trastuzumab to chemotherapy (paclitaxel plus carboplatin) for recurrent disease that has not been treated with trastuzumab previously.

A significant proportion of nonendometrioid cancers test positive for HER2 gene overexpression or amplification, in particular serous carcinomas and carcinosarcomas. One phase 2 trial suggested that the addition of trastuzumab to chemotherapy regimens improves progression-free and overall survival compared with chemotherapy alone in patients with advanced or recurrent HER2-positive uterine serous carcinoma. Toxicity was similar with and without trastuzumab.[237]

See local specialist protocol for dosing guidelines.

Primary options

paclitaxel

and

carboplatin

and

trastuzumab

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Choose a patient group to see our recommendations

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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