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 either completely or as much as possible.[132]

Standard surgery requires a total hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy.[7]​​[76][111]

Total hysterectomy may be done via laparoscopy (including robotic-assisted laparoscopy) or via laparotomy. One Cochrane review found similar survival outcomes for both approaches.[156] However, laparoscopy may be associated with significantly shorter hospital stays and fewer complications compared with laparotomy and is gaining in popularity with patients.[157][158][159][160][161][162][163] [ Cochrane Clinical Answers logo ] ​​

Lymphadenectomy for patients with stage I disease is not beneficial with regards to survival or recurrence.​​​ [ Cochrane Clinical Answers logo ] s 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.[166][167][168][169][170][171]​​​ 

In patients with apparent uterine-confined disease, sentinel lymph node (SLN) mapping with ultrastaging is preferred to lymphadenectomy to assess pelvic lymph node metastases during surgical staging.[76][146][147] SLN mapping results in lower morbidity than lymphadenectomy. Patients who have SLN mapping have noninferior survival and recurrence outcomes compared to those who have complete lymphadenectomy.​[148][149][150][151][152][153]​​

Obesity and comorbidities make patients more prone to perioperative risks and complications.[155]

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.[134][176][212]​​​​​​​[213] Observation is preferred.

Patients with stage IA disease with myometrial invasion who are classified as low-intermediate risk (based on age and the following risk factors: tumor grade 2 or 3; lymphovascular space invasion; and outer third myometrial invasion) have a low risk of recurrence following surgical staging. Therefore, adjuvant therapy is generally not required.[133] 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 (based on age and the following risk factors: tumor grade 2 or 3; lymphovascular space invasion; and outer third myometrial invasion) have a 26% risk of recurrence without adjuvant radiation therapy following surgical staging.[133] Therefore, adjuvant radiation therapy is offered (preferably vaginal brachytherapy).[76][175][180][217]​​​

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.[76][179][180]​ EBRT is associated with late toxicities, including urinary and bowel symptoms, as well as lower physical and role-physical functioning.[181][182]​ EBRT may increase the risk of second malignancy, particularly in younger patients.[181][183]​ Many clinicians reserve EBRT for patients with lymphovascular space invasion or node-positive disease.[7][76]

For patients having EBRT, pelvic intensity-modulated radiation therapy should be considered to reduce acute and late toxicity.[76][179]​​[184]​​

Adjuvant radiation therapy can improve progression-free survival in patients with high-intermediate risk, but it does not improve overall survival.[7][177][178]

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. Continuous progestin-based therapy with a levonorgestrel intrauterine device or an oral progestin (medroxyprogesterone or megestrol) is recommended.​[76][214]​​​ 

Hysteroscopic resection before progestin treatment may improve outcomes compared with progestin treatment alone.[76][131]​​

Aggressive monitoring is warranted, including pelvic examination and ultrasound at 3-month intervals, and 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, radical surgery should be considered. Patients who are successfully treated are advised to consider hysterectomy once childbearing is completed.[7][76][106][131]​​[215][216]​​

See local specialist protocol for dosing guidelines.

Primary options

levonorgestrel intrauterine device

OR

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 either completely or as much as possible.[132]

Standard surgery requires a total hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy.[7][76][111]​​

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.[156] However, laparoscopy may be associated with significantly shorter hospital stays and fewer complications compared with laparotomy and is gaining in popularity with patients.[157][158][159][160][161][162][163] [ 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.[166][167][168][169][170][171]​​ 

In patients with apparent uterine-confined disease, sentinel lymph node (SLN) mapping with ultrastaging is preferred to lymphadenectomy to assess pelvic lymph node metastases during surgical staging.[76][146][147]​ SLN mapping results in lower morbidity than lymphadenectomy. Patients who have SLN mapping have noninferior survival and recurrence outcomes compared to those who have complete lymphadenectomy.​[148][149][150][151][152][153]

Obesity and comorbidities make patients more prone to perioperative risks and complications.[155]

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 (based on age and presence of the following risk factors: tumor grade 2 or 3; lymphovascular space invasion; and/or outer third myometrial invasion) have a low risk of recurrence following surgical staging. Therefore, adjuvant therapy is not required.[133] Observation is preferred.

Consider – vaginal brachytherapy ± chemotherapy

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

vaginal brachytherapy ± chemotherapy

Treatment recommended for SOME patients in selected patient group

Patients with stage IB or II disease classified as high-intermediate risk (based on age and presence of the following risk factors: tumor grade 2 or 3; lymphovascular space invasion; and/or outer third myometrial invasion) have a 26% risk of recurrence without adjuvant radiation therapy following surgical staging.[133] Therefore, adjuvant radiation therapy is offered (preferably vaginal brachytherapy).[76][175][180]​​​[217]

Patients with stage IB or II disease with deep myometrial invasion, gross cervical involvement, and/or tumor grade 3 may be offered adjuvant external beam radiation therapy (EBRT) with or without vaginal brachytherapy (because they have an increased risk of local and distant recurrence).

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.[76][179][180]​​ EBRT is associated with late toxicities, including urinary and bowel symptoms, as well as lower physical and role-physical functioning.[181][182]​​ EBRT may increase the risk of second malignancy, particularly in younger patients.[181][183]​​ Many clinicians reserve EBRT for patients with lymphovascular space invasion or node-positive disease.[7][76]

For patients having EBRT, pelvic intensity-modulated radiation therapy should be considered to reduce acute and late toxicity.[76][179]​​[184]​​

Adjuvant radiation therapy can improve progression-free survival in patients with high-intermediate risk, but it does not improve overall survival.[7][177][178]

Chemotherapy may also be offered for high-risk disease, but this remains controversial. Paclitaxel plus carboplatin is the preferred regimen.[218][219][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.[193][194]

See local specialist protocol for dosing guidelines.

Primary options

paclitaxel

and

carboplatin

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, although many clinicians reserve EBRT for node-positive disease.[7][76]

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.[76][179][180]​​ EBRT is associated with late toxicities, including urinary and bowel symptoms, as well as lower physical and role-physical functioning.[181][182]​​ EBRT may increase the risk of second malignancy, particularly in younger patients.[181][183]

For patients having EBRT, pelvic intensity-modulated radiation therapy should be considered to reduce acute and late toxicity.[76][179]​​[184]​​

Adjuvant radiation therapy can improve progression-free survival in patients with high-intermediate risk, but it does not improve overall survival.[7][177][178]

Chemotherapy may also be offered for high-risk disease, but this remains controversial. Paclitaxel plus carboplatin is the preferred regimen.[218][219][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.[193][194]

See local specialist protocol for dosing guidelines.

Primary options

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.[76]

In one randomized trial, radiation followed by carboplatin plus paclitaxel did not provide a benefit compared with chemotherapy alone with respect to relapse-free survival in patients with stage III or IVA endometrial carcinoma (all histologic types and stage I or II uterine papillary serous/clear cell histologic types).[225]  

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 dostarlimab or pembrolizumab in combination with chemotherapy, followed by immunotherapy maintenance treatment, as a preferred treatment option for stage III and IV disease (although pembrolizumab is not recommended for carcinosarcoma).[76][189][190]

Phase 3 trials of women with advanced or recurrent endometrial cancer report improved progression-free survival with chemotherapy plus immunotherapy (dostarlimab or pembrolizumab), 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.[189][190]​​

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.[76][211]

A significant proportion of nonendometrioid cancers test positive for HER2 gene overexpression or amplification, in particular serous carcinomas. 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.[211]

See local specialist protocol for dosing guidelines.

Primary options

dostarlimab

OR

pembrolizumab

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

Combination therapy with chemotherapy and 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.[76]

Retrospective analyses suggest that radiation given following chemotherapy, or concurrently or sequentially (e.g., cisplatin plus radiation therapy followed by carboplatin and paclitaxel), may be of benefit in these patients.[222][223][224]​ 

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.[226]

Consider – salvage radiation therapy and/or surgical resection

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

salvage radiation therapy and/or surgical resection

Treatment recommended for SOME patients in selected patient group

Salvage radiation therapy and/or surgical resection are considered if recurrence is isolated and symptomatic.

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%.[227][228]

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.[229]

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 has been used, but it is associated with increased toxicity and is recommended only as a second-line or subsequent option.[76][218][219][220]​​​​ Single-agent chemotherapy may be used if multiagent chemotherapy is contraindicated or for subsequent therapy.[76]​​

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

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

dostarlimab or pembrolizumab

Treatment recommended for SOME patients in selected patient group

​Guidelines recommend the addition of dostarlimab or pembrolizumab to chemotherapy for stage III or IV recurrent disease (although pembrolizumab is not recommended for carcinosarcoma).[76][189][190]

Phase 3 trials of women with advanced or recurrent endometrial cancer report improved progression-free survival with chemotherapy plus immunotherapy (dostarlimab or pembrolizumab), 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.[189][190]

See local specialist protocol for dosing guidelines.

Primary options

dostarlimab

OR

pembrolizumab

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 may be treated with tamoxifen alternating with a progestin (megestrol or medroxyprogesterone).[196][230]

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.[76][202] Other options include single-agent hormonal therapy with megestrol or medroxyprogesterone, an aromatase inhibitor, tamoxifen, or fulvestrant.[76] Aromatase inhibitors may be better tolerated than tamoxifen in some patients, based on extrapolations from the breast cancer literature.[231]

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.[197][199][200]

The results for GnRH agonists and oral medroxyprogesterone are probably similar to the highest reported response rate with tamoxifen alternating with megestrol (32%).[198]​​[201]

Preliminary findings indicate that 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.[76][202]

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
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-deficient (MMR-D) tumors can be treated with immunotherapy alone (dostarlimab or pembrolizumab), if recurrence occurs following neoadjuvant or adjuvant platinum-based chemotherapy.[76][205][206][207][208] Pembrolizumab is also indicated for patients with a tumor mutation burden ≥10 mutations/megabase with progression and no satisfactory alternative treatment options.[76]

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
Consider – 

pembrolizumab + lenvatinib

Treatment recommended for SOME patients in selected patient group

For patients with MMR proficiency, a combination of pembrolizumab plus lenvatinib may be an option for recurrence following chemotherapy.[76][209]

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.[209]

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, guidelines recommend the addition of trastuzumab to chemotherapy (paclitaxel plus carboplatin) for recurrent disease that has not been treated with trastuzumab previously. This regimen may also be considered for recurrent HER2-positive carcinosarcoma not treated with trastuzumab previously.[76][211]

A significant proportion of nonendometrioid cancers test positive for HER2 gene overexpression or amplification, in particular serous carcinomas. 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.[211]

See local specialist protocol for dosing guidelines.

Primary options

paclitaxel

and

carboplatin

and

trastuzumab

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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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