Endometrial cancer

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

Endometrial cancer is treated by surgery, radiotherapy, chemotherapy, hormonal therapy, immunotherapy, or, commonly, a combination of these therapies, with the goal of maximising the chance of cure, with minimal morbidity.[83][130][164]

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.[96]

Surgical staging

Following preoperative evaluation, all patients with a biopsy-proven diagnosis of endometrial carcinoma will undergo surgical staging, which may include:[9][83][123][131][165]

Total abdominal or laparoscopic hysterectomy
Exploratory laparotomy or laparoscopy
Bilateral salpingo-oophorectomy (BSO)
Peritoneal cytology
Omental biopsy (commonly performed for high-grade tumours: e.g., serous, clear cell, or carcinosarcoma)
Pelvic node dissection (lymphadenectomy) or sentinel lymph node (SLN) mapping (preferred 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 tumours, such as deeply invasive lesions or high-grade tumours, including serous, clear cell, or carcinosarcoma
Removal of intraperitoneal disease if found at the time of surgery

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.[165][166] Furthermore, extensive preoperative testing offers the patient little clinical benefit.[167]

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
Non-endometrioid (type 2) carcinomas (e.g., serous, clear-cell, undifferentiated carcinoma, carcinosarcoma)

Molecular classification

Molecular studies are encouraged to complement surgical staging.[83] Molecular classification (POLE-mutated, mismatch repair [MMR]-deficient, p53-abnormal, and no specific molecular profile) can be incorporated into conventional histopathological classification and risk stratification.[116][123][152][168]

If molecular analysis of stage I or II tumours reveals p53-abnormal tumours, upstaging to IICm(p53abn) is recommended to reflect the poorer prognosis associated with these tumours. If a POLE-mutated tumour is identified, it may be downstaged to IAm(POLEmut) due to more favourable prognosis.[116][152]

Surgical treatment

Surgery removes malignant disease either completely or as much as possible. Standard surgery requires a total hysterectomy, BSO, and sentinel lymph node mapping (for select patients managed in institutions with suitable expertise) and/or lymphadenectomy.[9][83][123]

Obesity and comorbidities make patients more prone to perioperative risks and complications.[169][170]

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.[171] However, laparoscopy may be associated with significantly shorter hospital stays and fewer complications compared with laparotomy, and is gaining in popularity with patients.[172][173][174][175][176][177][178] [ ] 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.[179] Robotic and laparoscopic hysterectomy are associated with longer operative times compared with laparotomy.[180]

Lymphadenectomy and sentinel lymph node (SLN) mapping

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 tumours with less than 50% myometrial invasion, under 2 cm in length, and no obvious other macroscopic disease.[181][182][183][184][185][186]

In patients with apparent uterine-confined disease, SLN mapping, with ultrastaging to detect low-volume metastasis, is preferred to lymphadenectomy to assess pelvic lymph node metastases during surgical staging.[83][187][188]

SLN mapping results in lower morbidity than lymphadenectomy. Patients who have SLN mapping have non-inferior survival and recurrence outcomes compared with those who have complete lymphadenectomy.[189][190][191][192][193][194]

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

The role of SLN mapping in high-grade endometrial cancer is being investigated.[187][195]

Debulking metastatic disease

May improve survival in carefully selected patients, although there are no randomised data to inform this controversial issue.[196][197][198]

Radiotherapy: post-operative

Radiotherapy (e.g., vaginal brachytherapy or pelvic external beam radiotherapy [EBRT]) may be indicated in the post-operative (adjuvant) setting to reduce the risk of local or locoregional recurrence in patients with high-intermediate risk or high-risk disease.[9][83][123][199][200] Adjuvant radiotherapy can improve progression-free survival in patients with high-intermediate risk or high-risk disease, but it does not improve overall survival.[9][201][202]

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][203][204] EBRT is associated with late toxicities, including urinary and bowel symptoms, as well as lower physical and role-physical functioning.[205][206] EBRT may increase the risk of second malignancy, particularly in younger patients.[205][207] Many clinicians reserve EBRT for patients with lymphovascular space invasion or node-positive disease.[9][83]

For patients having EBRT, pelvic intensity-modulated radiotherapy (IMRT) should be considered to reduce acute and late toxicity.[83][203][200][208]

More extensive radiotherapy (extended field) may be indicated in carefully selected patients with no or microscopic residual disease.[209]

Radiotherapy: preoperative and palliative

Radiotherapy may be considered in the preoperative setting for locally advanced disease.[210][211]

Radiotherapy 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 radiotherapy.[212]

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 radiotherapy (chemoradiation).[213][214][215][216]

Studies combining chemotherapy with adjuvant radiotherapy (chemoradiation) in high-risk early-stage disease have found no benefit compared with radiotherapy alone, but further analysis of these findings (e.g., by molecular subtype) is ongoing.[217][218][219]

Hormonal treatment

Hormonal therapy is recommended only for patients with recurrent or inoperable tumours that are oestrogen receptor/progesterone receptor (OR/PR) positive.[220][221][222] A clinical response to progestins is consistently reported in around one third of patients with inoperable tumours or recurrence (15% to 34%), a rate comparable to that of tamoxifen.[221][223][224]

The results for gonadotrophin-releasing hormone (GnRH) agonists and oral medroxyprogesterone are probably similar to the highest reported response rate with tamoxifen alternating with megestrol (32%).[222][225]

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.

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 tumours; median progression-free survival was greater in patients who had not received prior chemotherapy.[83][226]

Hormonal therapy (e.g., progestins, tamoxifen) is not recommended in the adjuvant setting because it provides no survival benefit and may increase cardiovascular mortality.[227][228] [ ]

Immunotherapy

Immunotherapy has an increasing role in managing advanced (stage III and IV) and recurrent endometrial cancer.[83]

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.[229][230][231][232] Pembrolizumab in combination with lenvatinib (a multikinase inhibitor) is recommended for tumours that are not MMR-deficient (i.e., MMR-proficient).[233][234]

A significant proportion of non-endometrioid cancers test positive for HER2 gene overexpression or amplification, in particular serous carcinomas and carcinosarcomas. HER2-targeted therapy with trastuzumab is recommended as an option for these tumours.[83] 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.[235]

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.[155][200][236][237] Observation is preferred.

Highly selected patients with well-differentiated stage IA (non-invasive) endometrioid carcinoma who wish to preserve their fertility, and have been referred to a specialist centre and received counselling, 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][238] A dual-progestin regimen, with a levonorgestrel IUD plus medroxyprogesterone or megestrol, can be considered, which may improve response rate and pregnancy rate.[83][239]

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][240][241]

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): tumour grade 2 or 3; lymphovascular space invasion; and outer third myometrial invasion:[154]

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.[154] Observation is preferred.

Following surgery, the risk of recurrence in high-intermediate risk patients is 6% with adjuvant radiotherapy and 26% without.[154] Therefore, adjuvant radiotherapy is offered (preferably vaginal brachytherapy).[83][199][204][242]

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 tumour 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.[9][83] Chemotherapy, in addition to adjuvant radiotherapy, can be considered for these patients, but this remains controversial. Cisplatin plus radiotherapy followed by paclitaxel plus carboplatin is the preferred regimen.[83][218]

Adjuvant radiotherapy may provide locoregional control in some patients, but it does not improve survival.[154][155][205][210][212][244]

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

Patients with stage III to IV disease, and those with non-endometrioid 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]

Stage III-IV: chemotherapy plus immunotherapy

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 tumours.[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 tumours.[213][214][245][246][247] Results for overall survival appear favourable, although data are immature.

The addition of bevacizumab (a vascular endothelial growth factor [VEGF]-directed monoclonal antibody) to chemotherapy has shown favourable results in advanced and recurrent disease, although the evidence is limited.[248][249][250] Bevacizumab in combination with chemotherapy is recommended as a further option for stage III and IV measurable disease.[83][248][249][250]

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.[83][235]

Stage III-IV: chemotherapy plus radiotherapy

Chemotherapy plus radiotherapy may be an option for stages IIIB and IIIC disease. 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 radiotherapy followed by carboplatin and paclitaxel) may be of benefit in these patients.[251][252][253] However, the results of randomised trials are equivocal.[243][254][255]

Radiotherapy may be considered for all patients with non-endometrioid carcinomas, although its impact on survival is not yet known given the rarity of these subtypes.

Recurrent or incurable disease

Most recurrences (65% to 85%) occur within 3 years of treatment and are symptomatic.[9] Signs and symptoms suggestive of recurrence include vaginal bleeding, abdominal or pelvic pain, persistent cough, unexplained weight loss, and new-onset neurological 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, lymphoedema, bleeding, obstruction (urinary and gastrointestinal), and fistula formation.[256]

In the setting of an isolated and symptomatic vaginal recurrence, salvage radiotherapy and/or surgical resection are considered, depending on prior therapy. Salvage radiotherapy involves a combination of EBRT and vaginal brachytherapy, and results in 5-year survival rates of 40% to 70%.[257][258] Survival rates following salvage radiotherapy for pelvic or para-aortic nodal recurrence are disappointing (approximately 10%), but advances in radiation treatment planning and delivery (e.g., intensity-modulated radiotherapy) may improve outcomes.[259]

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

Treatment options for widespread metastatic disease include systemic therapy (with or without palliative radiotherapy).[83]

Hormone receptor-negative tumours

Palliative chemotherapy is recommended for patients with recurrent oestrogen receptor/progesterone receptor (OR/PR)-negative tumours. 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][260][261] Single-agent chemotherapy may be used if multiagent chemotherapy is contraindicated or for subsequent therapy.[83]

Guidelines recommend the addition of dostarlimab or pembrolizumab to chemotherapy for stage III or IV recurrent disease (although pembrolizumab is not recommended for carcinosarcoma).[83][213][214][246] For patients with MMR-deficient tumours, durvalumab is a further option in combination with paclitaxel plus carboplatin.[83][245]

OR/PR-positive tumours

Patients who have an OR/PR-positive endometrioid tumour (preferably low grade, and small or slow-growing) may be treated with hormonal therapy, such as tamoxifen alternating with a progestin (megestrol or medroxyprogesterone).[220][262] Combination treatment with the aromatase inhibitors letrozole plus everolimus (an mTOR inhibitor) may also be an option for recurrent or inoperable OR/PR-positive tumours.[83][226] 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.[263]

Microsatellite instability-high or mismatch repair deficient tumours

Patients with inoperable or advanced (stages III to IV) endometrial cancer and microsatellite instability-high (MSI-H) or MMR-deficient tumours can be treated with immunotherapy alone (e.g., pembrolizumab or dostarlimab), if recurrence occurs following chemotherapy.[83][229][230][231][232] Pembrolizumab is also indicated for patients with a tumour mutation burden ≥10 mutations/megabase with progression and no satisfactory alternative treatment options.[83]

Mismatch repair proficient tumours

For patients with MMR proficiency, a combination of pembrolizumab plus lenvatinib may be an option for recurrence following chemotherapy.[83][233] 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.[233]

HER2-positive non-endometrioid carcinoma

For patients with HER2-positive uterine serous carcinoma or carcinosarcoma, guidelines recommend the addition of trastuzumab to chemotherapy for recurrent disease that has not been treated with trastuzumab previously.[83][235]

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