Endometrial cancer

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Endometrial cancer is treated by surgery, radiation therapy, chemotherapy, hormonal therapy, immunotherapy, or, commonly, a combination of these therapies, with the goal of maximizing the chance of cure, with minimal morbidity.[76][117][144]

Surgery is the primary treatment option. It is the most important component of management for potentially curable disease, and has two important roles: to stage the disease to guide treatment planning; and to remove malignant disease.[132]

Surgical staging

Following preoperative evaluation, all patients with a biopsy-proven diagnosis of endometrial carcinoma will undergo surgical staging, which may include:[7][76][111][118][132][145]

Total abdominal or laparoscopic hysterectomy
Exploratory laparotomy or laparoscopy
Bilateral salpingo-oophorectomy (BSO)
Peritoneal cytology
Omental biopsy (commonly performed for high-grade tumors: e.g., serous, clear cell, or carcinosarcoma)
Pelvic node dissection (lymphadenectomy) or sentinel lymph node (SLN) mapping for surgical staging in uterine-confined disease
Excision of suspicious or enlarged nodes to exclude nodal metastasis
Para-aortic nodal evaluation for staging of select high-risk tumors, such as deeply invasive lesions or high-grade tumors, including serous, clear cell, or carcinosarcoma
Removal of intraperitoneal disease if found at the time of surgery.

In patients with apparent uterine-confined disease, 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]

Around 25% of women with apparent clinical stage I disease (limited to the endometrium) and 50% of women with clinical stage II disease (extending to involve the cervix) have disease spread outside the uterus at the time of surgical staging.[145][154] Furthermore, extensive preoperative testing offers the patient little clinical benefit.[130]

Stratification based on risk of recurrence

Following surgical staging, patients with endometrial cancer can be stratified based on risk of recurrence to help guide treatment planning.

Low risk:

Stage IA endometrioid carcinoma without myometrial invasion.

Intermediate risk:

Stage IA endometrioid carcinoma with myometrial invasion
Stage IB or II endometrioid carcinoma.

High risk:

Stages III-IV endometrioid carcinoma
Nonendometrioid (type 2) carcinomas (e.g., serous, clear-cell, undifferentiated carcinoma, carcinosarcoma).

Surgical treatment

Surgery removes malignant disease either completely or as much as possible. Standard surgery requires a total hysterectomy, BSO, and lymphadenectomy.[7][76][111]

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

Laparoscopy versus laparotomy

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] [ ] Robotic-assisted laparoscopic hysterectomy was associated with reduced blood loss, fewer conversions to laparotomy, fewer overall complications, and a shorter hospital stay than standard laparoscopic hysterectomy in one meta-analysis.[164] Robotic and laparoscopic hysterectomy are associated with longer operative times compared with laparotomy.[165]

Lymphadenectomy

Lymphadenectomy for patients with stage I disease (confined to the endometrium) or stage II disease (extending to involve the cervix) is not beneficial with regards to survival or recurrence. [ ] Therefore, less-aggressive surgical approaches can be adopted for grade 1 or 2 endometrioid tumors with less than 50% myometrial invasion, under 2 cm in length, and no obvious other macroscopic disease.[166][167][168][169][170][171]

There is an emerging role for SLN mapping, which is noninferior to, and has lower morbidity than, lymphadenectomy, to guide subsequent therapy (surgery, radiation, and chemotherapy).[76][106][146][147][148][149][150][151][152][153]

Debulking metastatic disease

May improve survival in carefully selected patients, although there are no randomized data to inform this controversial issue.[172][173][174]

Radiation therapy: postoperative

Radiation therapy (e.g., vaginal brachytherapy or pelvic external beam radiation therapy [EBRT]) may be indicated in the postoperative (adjuvant) setting to reduce the risk of local or locoregional recurrence in patients with high-intermediate risk or high-risk disease.[7][76][111][175][176] Adjuvant radiation therapy can improve progression-free survival in patients with high-intermediate risk or high-risk disease, but it does not improve overall survival.[7][177][178]

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 (IMRT) should be considered to reduce acute and late toxicity.[76][176][179][184]

More extensive radiation therapy (extended field) may be indicated in carefully selected patients with no or microscopic residual disease.[185]

Radiation therapy: preoperative and palliative

Radiation therapy may be considered in the preoperative setting for locally advanced disease.[186][187]

Radiation therapy may also be delivered with palliative intent for symptomatic metastases (brain or bone metastases, pelvic pain, or bleeding).

Patients who are unsuitable for surgery due to comorbidities may be treated with primary radiation therapy.[188]

Chemotherapy

Adjuvant chemotherapy has an established role in the management of advanced (stage III and IV) and recurrent disease. Optimal adjuvant treatment has not been determined, but chemotherapy is the mainstay of treatment for advanced disease. Progression-free survival may be improved with the addition of immunotherapy or radiation therapy (chemoradiation).[189][190][191][192]

Studies combining chemotherapy with adjuvant radiation therapy (chemoradiation) in 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][195]

Hormonal treatment

Hormonal therapy is recommended only for patients with recurrent or inoperable tumors that are estrogen receptor/progesterone receptor (ER/PR) positive.[196][197][198] 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.[196][197][199][200]

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

Tamoxifen can be used in conjunction with progestins for the treatment of recurrent or incurable disease, even though it increases the risk for endometrial cancer. Its use increases the expression of progesterone receptors, thereby theoretically improving the response to treatment with progestins.

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 greater in patients who had not received prior chemotherapy.[76][202]

Hormonal therapy (e.g., progestins, tamoxifen) is not recommended in the adjuvant setting because it provides no survival benefit and may increase cardiovascular mortality.[203][204]

Immunotherapy

Immunotherapy has an increasing role in managing advanced (stage III and IV) and recurrent endometrial cancer.[76]

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]

Immunotherapy may be an option for managing incurable, advanced disease that has progressed after first-line chemotherapy. Pembrolizumab and dostarlimab as single agents are recommended for MMR-deficient or MSI-high disease.[205][206][207][208] Pembrolizumab in combination with lenvatinib (a multikinase inhibitor) is recommended for tumors that are not MMR-deficient or MSI-high.[209][210]

A significant proportion of nonendometrioid cancers test positive for HER2 gene overexpression or amplification, in particular serous carcinomas. HER2-targeted therapy with trastuzumab is recommended as an option for these tumors.[76] 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]

Stage IA (without myometrial invasion) endometrioid carcinoma (low risk)

These patients have a low risk of recurrence following surgical staging; therefore, adjuvant therapy is generally not required.[134][176][212][213] Observation is preferred.

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]

Stages IA (with myometrial invasion), IB, or II endometrioid carcinoma (intermediate risk)

These patients can be further stratified as low- or high-intermediate risk according to age and presence of the following risk factors (based on the GOG-99 study criteria): tumor grade 2 or 3; lymphovascular space invasion; and outer third myometrial invasion:[133]

Low-intermediate risk:

Age <50 years and ≤2 risk factors
Age 50-69 years and ≤1 risk factor
Age ≥70 years and no risk factors.

High-intermediate risk:

Any age and 3 risk factors
Age 50-69 years and ≥2 risk factors
Age ≥70 years and ≥1 risk factor.

Low-intermediate risk patients have a low risk of recurrence following surgical staging; therefore, adjuvant therapy is generally not required.[133] Observation is preferred.

Following surgery, the risk of recurrence in high-intermediate risk patients is 6% with adjuvant radiation therapy and 26% without.[133] Therefore, adjuvant radiation therapy is offered (preferably vaginal brachytherapy).[76][175][180][217]

Radical hysterectomy (removal of the parametrium and upper vagina in addition to a total hysterectomy) may be offered if cervical involvement by endometrial cancer is detected prior to surgery.

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 EBRT and/or vaginal brachytherapy. Many clinicians reserve EBRT for patients with lymphovascular space invasion or node-positive disease.[7][76] Chemotherapy may also be offered for high-risk disease, but this remains controversial. Paclitaxel plus carboplatin is the preferred regimen.[76][218][219][220]

Adjuvant radiation therapy may provide locoregional control in some patients, but it does not improve survival.[133][134][181][186][188][221]

Stages III-IV endometrioid carcinoma, and all nonendometrioid carcinomas (high risk)

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]

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]

For patients with HER2-positive uterine serous carcinoma, guidelines recommend trastuzumab in combination with chemotherapy. This regimen may also be considered for patients with HER2-positive carcinosarcoma.[76][211]

Combination therapy with chemotherapy and radiation therapy may be an alternative option for stages IIIB and IIIC disease. 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] However, 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]

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.

Recurrent or incurable disease

Most recurrences occur within 2 years.[132] Signs and symptoms suggestive of recurrence include vaginal bleeding, abdominal or pelvic pain, persistent cough, unexplained weight loss, and new-onset neurologic symptoms.

These patients are likely to have widespread metastases from high-grade carcinomas. The best supportive care addresses physical, psychological, social, and spiritual issues. Common medical challenges include: pain, nausea and vomiting, lymphedema, bleeding, obstruction (urinary and gastrointestinal), and fistula formation.[226]

In the setting of an isolated and symptomatic vaginal recurrence, salvage radiation therapy and/or surgical resection are considered. Salvage radiation therapy involves a combination of EBRT 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]

Hormone receptor-negative tumors

Palliative chemotherapy is recommended for patients with recurrent estrogen receptor/progesterone receptor (ER/PR)-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]

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]

ER/PR-positive tumors

Patients who have an 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]

Microsatellite instability-high or mismatch repair deficient tumors

Patients with inoperable or advanced (stages III to IV) endometrial cancer and microsatellite instability-high (MSI-H) or mismatch repair deficient (MMR-D) tumors can be treated with immunotherapy alone (e.g., pembrolizumab or dostarlimab), if recurrence occurs following 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]

Mismatch repair proficient tumors

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]

HER2-positive nonendometrioid carcinoma

For patients with HER2-positive uterine serous carcinoma, guidelines recommend the addition of trastuzumab to chemotherapy 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]

Use of this content is subject to our disclaimer