What are the treatment options for endometrial cancer?

Treatment Options for Endometrial Cancer

Total hysterectomy with bilateral salpingo-oophorectomy (TH/BSO) is the cornerstone of treatment for endometrial cancer, with adjuvant therapy decisions guided by surgical staging, tumor grade, depth of myometrial invasion, and lymphovascular space invasion (LVSI). 1

Surgical Management

Primary Surgical Approach

• TH/BSO is the standard surgical treatment for apparent uterine-confined endometrial cancer, performed via laparotomy, vaginal approach, or minimally invasive techniques (laparoscopy or robotic surgery) 1

• Minimally invasive surgery is recommended for low- and intermediate-risk disease and can be considered for high-risk disease, offering shorter hospital stays, less pain, lower complication rates, and improved quality of life compared to laparotomy 2

• Systematic exploration, inspection, and palpation of the entire abdomen must be performed during surgery 1

• Peritoneal cytology should be obtained at the time of surgery, though it no longer affects FIGO staging 1

Lymph Node Assessment Strategy

The approach to lymphadenectomy depends on risk stratification:

Low-risk disease (Grade 1-2, <50% myometrial invasion):

• Lymphadenectomy can be considered for staging but is not mandatory 2
• Sentinel lymph node dissection (SLND) is an option 2

Intermediate-risk disease (Grade 3 with <50% invasion OR Grade 1-2 with ≥50% invasion):

• Complete surgical staging with pelvic and para-aortic lymphadenectomy is recommended to guide adjuvant therapy 2

High-risk disease (Grade 3 with ≥50% invasion, non-endometrioid histology):

• Systematic pelvic and para-aortic lymphadenectomy up to the level of the renal veins is recommended as part of comprehensive staging 2

Important caveat: Two large randomized trials (Italian study and ASTEC) showed that routine systematic pelvic lymphadenectomy did not improve disease-free or overall survival in stage I disease 2. However, lymphadenectomy remains highly valuable for determining prognosis and tailoring adjuvant therapy 2.

Special Surgical Considerations

• Modified radical hysterectomy (Piver type II) is recommended for stage II cancers with macroscopic cervical lesions 1

• Omentectomy is commonly performed for serous adenocarcinoma, clear cell adenocarcinoma, or carcinosarcoma histology 1

• Ovarian preservation may be considered in women <50 years with low-grade, early-stage endometrioid cancer, as it does not worsen overall survival 1

Adjuvant Treatment Based on Risk Stratification

Low-Risk Disease (Stage IA, Grade 1-2)

• Follow-up alone is standard after surgery 2, 1, 3
• No adjuvant therapy is required 2

Intermediate-Risk Disease (Stage I, Grade 1-2, ≥50% myometrial invasion, LVSI negative)

If surgical nodal staging performed and node-negative:

• Vaginal brachytherapy is recommended 2
• No adjuvant treatment is an option, especially for patients <60 years old 2

If Grade 3 or LVSI unequivocally positive:

• Adjuvant chemotherapy (combined and/or sequential with radiotherapy) should be considered 2

If no surgical nodal staging performed:

• Adjuvant external beam radiotherapy (EBRT) is recommended 2

The PORTEC-2 trial demonstrated that vaginal brachytherapy and external beam radiation showed no difference in overall survival or progression-free survival in intermediate-risk patients, but quality of life was better with vaginal brachytherapy 2.

High-Risk Disease (Stage I, Grade 3, ≥50% myometrial invasion)

If surgical nodal staging performed and node-negative:

• Adjuvant EBRT with limited fields is recommended 2
• Adjuvant brachytherapy is an alternative option 2
• Adjuvant chemotherapy (combined and/or sequential) should be considered, with greater evidence supporting combined chemotherapy plus EBRT than either modality alone 2

If no surgical nodal staging performed:

• Adjuvant EBRT is recommended 2
• Adjuvant chemotherapy (combined and/or sequential) can be considered 2

High-Risk Non-Endometrioid Histology (Serous, Clear Cell, Undifferentiated, Carcinosarcoma)

• Platinum-based chemotherapy is recommended for stage I with adverse risk factors (patient age, LVSI, high tumor volume) 2
• Combined chemoradiation has shown improved recurrence-free and overall survival, particularly for stage III disease 1

Stage II Disease

Stage IIA (endocervical glandular involvement only):

• Postoperative vaginal brachytherapy is standard if myometrial invasion is <50% and tumor is grade 1-2 2, 3
• External pelvic radiotherapy with brachytherapy boost if myometrial invasion is >50% or grade 3 disease 2

Stage IIB (cervical stromal invasion):

• Postoperative external pelvic radiotherapy with brachytherapy boost is standard 2, 3
• Radical hysterectomy with bilateral salpingo-oophorectomy and systematic pelvic lymphadenectomy (with or without para-aortic lymphadenectomy) is the traditional surgical approach 2

Stage III Disease

Stage IIIA (serosa/adnexa involvement or positive peritoneal cytology):

• Abdomino-pelvic radiotherapy is standard for tumors involving multiple extrauterine sites 2
• External pelvic radiotherapy or abdomino-pelvic radiotherapy are options for ovarian involvement only or positive cytology only 2, 3

Stage IIIB (vaginal involvement):

• Pelvic external beam irradiation with brachytherapy (if possible) is standard 2, 3

Stage IIIC (lymph node metastasis):

• Pelvic nodes involved: Postoperative pelvic radiotherapy with brachytherapy boost is standard 2, 3
• Para-aortic nodes involved: Extended field radiotherapy (pelvic and para-aortic) with brachytherapy is standard 2, 3
• IIIC2 disease: Chemotherapy plus extended field EBRT should be considered 2

For all stage III disease:

• Combined chemoradiation has shown improved recurrence-free and overall survival compared to radiotherapy alone 1

Stage IV Disease

Stage IVA/IVB:

• Cytoreductive surgery with TH/BSO and maximal debulking of metastatic disease is standard when optimal cytoreduction (no residual disease) can be achieved and performance status permits 1, 4
• Surgery includes bowel resection if necessary, partial or total bladder resection with urinary diversion if required, and pelvic clearance 2, 4
• Pelvic and para-aortic lymph node assessment should be performed 4
• Omentectomy is recommended, especially if ovaries are involved 4

Adjuvant therapy after cytoreductive surgery:

• Postoperative external beam radiotherapy with or without brachytherapy boost may be considered 2, 4
• Extended field radiotherapy (pelvic and para-aortic) if para-aortic nodes are involved 4
• Clinical trials of hormone therapy or chemotherapy are recommended options 2, 4

If surgery is not feasible:

• If performance status is poor, TH/BSO by abdominal approach may be preferable to radiotherapy alone 2, 4
• Palliative radiotherapy may be considered for symptom control 4

Chemotherapy Regimens

• Platinum-based chemotherapy (cisplatin, doxorubicin, and cyclophosphamide) can be considered in stage I Grade 3 with adverse risk factors and in patients with stage II-III 2

• Carboplatin plus paclitaxel represents an efficacious, lower-toxicity alternative regimen 3

• The combination of cisplatin and doxorubicin has shown significant improvement in progression-free and overall survival for optimally debulked stage III and IV disease compared to radiation therapy alone 3

Common Pitfalls and Caveats

• Preoperative imaging cannot reliably distinguish between stage I and stage II disease, despite its role in evaluating operability 1

• CA125 has no diagnostic value for endometrial cancer but may predict extra-uterine extension at levels >35 U/ml 1

• Failing to perform adequate surgical staging can lead to suboptimal treatment decisions, particularly in intermediate- and high-risk disease 4

• Overlooking the importance of maximal cytoreduction in stage IV disease can result in decreased survival rates 4

• Fertility-sparing options should only be considered in well-differentiated (grade 1) endometrioid adenocarcinoma limited to the endometrium in patients who wish to preserve fertility, with medroxyprogesterone acetate (MPA), megestrol acetate (MA), or progestin-loaded IUD as options 2, 1