What are the treatment options for endometrial endometrioid carcinoma?

Treatment of Endometrial Endometrioid Carcinoma

Total hysterectomy with bilateral salpingo-oophorectomy is the cornerstone of treatment for endometrial endometrioid carcinoma, with adjuvant therapy stratified by risk category based on stage, grade, depth of myometrial invasion, and lymphovascular space invasion (LVSI). 1, 2

Primary Surgical Management

Standard Surgical Approach

• Total hysterectomy with bilateral salpingo-oophorectomy is the standard surgical procedure for all stages of endometrial endometrioid carcinoma. 1, 3
• Minimally invasive surgery (laparoscopic or robotic) is recommended over open surgery for low- and intermediate-risk disease, and can be considered for high-risk disease, as it reduces blood loss and hospital stay while maintaining equivalent oncological outcomes. 1, 4
• Robotic-assisted surgery demonstrates fewer intra-operative complications (OR = 0.38) and reduced ileus (OR = 0.40) compared to laparoscopic surgery. 4

Lymph Node Assessment

• For low-risk disease (G1-2, <50% myometrial invasion): lymphadenectomy can be considered for staging, with sentinel lymph node dissection (SLND) as an option. 1, 2
• For intermediate-risk disease: lymphadenectomy can be considered for staging purposes, with SLND as an option. 1, 2
• For high-risk disease (G3 and/or ≥50% myometrial invasion, all non-endometrioid types): systematic pelvic and para-aortic lymphadenectomy up to the renal veins is recommended to guide staging and adjuvant therapy. 1

Adjuvant Treatment by Risk Category

Low-Risk Disease (Stage IA, G1-2, <50% myometrial invasion, LVSI negative)

• No adjuvant treatment is recommended—observation only after surgery. 1, 2, 5
• The recurrence risk is approximately 10.4% for this group. 5

Intermediate-Risk Disease (Stage I, G1-2, ≥50% myometrial invasion, LVSI negative)

• Adjuvant vaginal brachytherapy is the recommended treatment. 1, 2, 5
• No adjuvant treatment is an acceptable option, especially for patients <60 years old. 1, 2
• The recurrence risk is approximately 22.4% for Stage IB disease. 5
• Vaginal brachytherapy provides equivalent survival to external beam radiation but with superior quality of life. 2, 5

High-Intermediate Risk (G3 or LVSI unequivocally positive)

• If surgical nodal staging performed and node negative with G1-2 and LVSI negative: vaginal brachytherapy. 1
• If G3 or LVSI unequivocally positive: limited field external beam radiotherapy (EBRT). 1
• Adjuvant chemotherapy (combined and/or sequential with radiotherapy) should be considered for G3 or unequivocally positive LVSI. 1, 2, 5

High-Risk Disease (Stage I, G3, ≥50% myometrial invasion)

• If surgical nodal staging performed and node negative: adjuvant EBRT with limited fields. 1
• If no surgical nodal staging: adjuvant EBRT is recommended. 1
• Adjuvant chemotherapy (combined and/or sequential with EBRT) should be considered, with greater evidence supporting combined chemotherapy plus EBRT than either modality alone. 1, 5
• Platinum-based chemotherapy (carboplatin/paclitaxel for 3-6 cycles) should be strongly considered with adverse risk factors including patient age, LVSI, and high tumor volume. 5

Stage II Disease

• Stage IIA (endocervical glandular involvement only): treat as Stage I based on other risk factors. 1
• Stage IIB (cervical stromal invasion): radical hysterectomy with bilateral salpingo-oophorectomy and systematic pelvic lymphadenectomy with or without para-aortic lymphadenectomy. 1
• Adjuvant pelvic radiotherapy (with or without intravaginal brachytherapy) is recommended for high-risk features. 1

Stage III Disease

• Maximal surgical cytoreduction is indicated in patients with good performance status and resectable tumor. 1
• Stage IIIA: postoperative pelvic radiotherapy or abdomino-pelvic radiotherapy; chemotherapy should be considered. 1
• Stage IIIB: pelvic external beam irradiation with brachytherapy if possible. 1
• Stage IIIC (pelvic nodes positive): postoperative pelvic radiotherapy ± brachytherapy boost. 1
• Stage IIIC (para-aortic nodes positive): extended postoperative radiotherapy (pelvic and para-aortic) ± brachytherapy. 1
• For Stage IIIC disease, combined chemoradiotherapy with carboplatin/paclitaxel plus EBRT is the optimal adjuvant treatment. 6
• Consider extended-field radiation to para-aortic nodes, especially for positive para-aortic lymph nodes. 6

Evidence for Combined Modality Treatment in High-Risk Disease

• Two randomized trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) demonstrated that sequential chemotherapy plus radiotherapy reduced the risk of relapse or death by 36% (HR 0.64, P=0.04) compared to radiotherapy alone. 1, 5
• Cancer-specific survival significantly favored combined modality treatment (HR 0.55, P=0.01). 1, 5
• The PORTEC-3 trial demonstrated improved 5-year overall survival with chemoradiotherapy versus radiotherapy alone (81.4% vs 76.1%) for high-risk endometrial cancer. 6

Stage IV Disease

• Stage IVA: anterior or posterior pelvectomy depending on location, with postoperative pelvic radiotherapy ± brachytherapy. 1
• Stage IVB (distant metastases): surgery only if optimal cytoreduction (no residual disease) can be achieved. 1, 6
• Standard first-line chemotherapy is six cycles of paclitaxel/carboplatin. 6
• The GOG-122 trial demonstrated significant improvement in both progression-free survival (50% vs 38%, P=0.07) and overall survival (55% vs 42%, P=0.004) favoring chemotherapy over whole abdominal radiation. 1

Advanced/Metastatic and Recurrent Disease

Locoregional Recurrence

• For isolated vaginal relapse after surgery: curative radiotherapy (external beam plus vaginal brachytherapy) is the standard treatment, achieving 5-year survival of 50%. 1
• For central pelvic recurrence: surgery or radiation therapy. 1
• For regional pelvic recurrences: radiation therapy, associated if possible with chemotherapy. 1

Systemic Treatment

• For patients without visceral involvement or rapidly progressive disease with G1/2 endometrioid, hormone receptor-positive disease: progestins (medroxyprogesterone acetate 200 mg daily or megestrol acetate) are the preferred front-line treatment. 1
• Overall response to progestins is approximately 25%. 1
• For chemotherapy-naïve patients with metastatic disease: carboplatin plus paclitaxel is the standard regimen, achieving response rates up to 40%. 1, 7

Fertility-Sparing Treatment

• For young women desiring fertility preservation with well-differentiated (G1) endometrioid adenocarcinoma confined to the endometrium: medroxyprogesterone acetate (MPA) or megestrol acetate (MA) is recommended; progestin-loaded IUD is also an option. 1
• After completion of childbearing, hysterectomy and salpingo-oophorectomy is recommended. 1
• Careful oncologic, psychotherapeutic, genetic, and reproductive counseling is mandatory before offering non-standard treatment, as there is risk of concurrent ovarian pathology. 8

Common Pitfalls and Caveats

• Overtreatment with external beam radiation when vaginal brachytherapy would suffice for intermediate-risk disease is a common error. 2, 5
• Undertreatment with radiation therapy alone or chemotherapy alone for Stage IIIC disease leads to increased recurrence risk compared to combined modality therapy. 6
• Not recognizing that patients with G3 histology or positive LVSI may benefit from more aggressive adjuvant treatment approaches (combined chemotherapy and radiotherapy) is a critical oversight. 2, 5
• Whole abdominal radiation therapy as a single modality is inferior to chemotherapy and too toxic; it is no longer recommended. 6
• Progestins in the adjuvant treatment of endometrial cancer do not increase survival and are not recommended (Level I evidence). 1, 5
• Most recurrences occur within the first 3 years after treatment, justifying intensive surveillance during this period with 3-4 monthly evaluations including history, physical, and gynecological examination. 1, 5