Endometrial Cancer Treatment Protocols

Treatment protocols for endometrial cancer are provided below, including the following:

• General treatment recommendations
• Recommendations for limited, metastatic, recurrent, and high-risk disease
• Risk classifications

General treatment recommendations for endometrial cancer

See the list below:

• Endometrial cancer is treated primarily with surgery, including hysterectomy, bilateral salpingo-oophorectomy, abdominopelvic washings, and lymph node evaluation; advanced disease may be treated with maximal surgical cytoreduction.

• There is no general agreement as to what constitutes the best chemotherapy choice, as very few phase III studies have been done comparing different regimens.

• Salvage agents such as paclitaxel may be an option for second-line therapy in patients who have disease recurrence even after first-line chemotherapy.

• Biomarker-directed systemic therapy may be used for second-line therapy. ^[1]

Treatment recommendations for limited disease

Standard treatments for localized endometrial cancer are as follows ^[2] :

• Hysterectomy with bilateral salpingo-oophorectomy
• Hysterectomy with bilateral salpingo-oophorectomy and adjuvant radiation therapy (when > 50% invasion of the myometrium or grade 3 tumor with myometrial invasion is present)

See also the list below:

• Radiation therapy (RT) is directed at sites of known or suspected tumor involvement and may include external beam radiation therapy (EBR), brachytherapy, or both. ^[1]

• Radiation therapy has proven to be effective and tolerated for patients who are not candidates for surgery and whose disease is limited to the uterus.

• Patients with suspected or gross cervical involvement who are candidates for surgery should be recommended for radical hysterectomy with bilateral salpingo-oophorectomy, cytology, and dissection of pelvic and para-aortic lymph nodes and inoperable patients should be treated with radiation therapy (75-80 Gy)

• Patients with suspected extrauterine disease should be evaluated through imaging studies (MRI or CT) or lab tests (CA 125 levels); if negative results return, treat patients as for disease limited to the uterus.

• Patients with extrauterine pelvic disease should be treated with radiation therapy and brachytherapy with or without surgery and chemotherapy

In patients who wish to preserve fertility, continuous progestin-based therapy with megestrol, medroxyprogesterone, or a levonorgestrel intrauterine device and surveillance with endometrial sampling every 3-6 months may be considered if all the following criteria are met ^[1] :

• Well-differentiated (grade 1) endometrioid adenocarcinoma on dilation and curettage (D&C) confirmed by expert pathology review
• Disease limited to the endometrium on MRI (preferred) or transvaginal ultrasound
• Absence of suspicious or metastatic disease on imaging
• No contraindications to medical therapy or pregnancy
• The patient has undergone counseling that a fertility-sparing option is NOT standard of care for the treatment of endometrial carcinoma

Risk classification for patients with endometrial cancer

Patients with endometrial cancer can be stratified into treatment groups based on the estimated risk of disease recurrence ^[3] :

• Low risk – Endometrioid cancers that are confined to the endometrium

• Intermediate risk – Disease is confined to the uterus but invades the myometrium, or demonstrates occult cervical stromal invasion; includes some patients with stage IA disease, stage IB disease, and a subset of patients with stage II disease

• High risk – Includes gross involvement of the cervix (a subset of stage II disease; stage III or IV disease, regardless of grade; papillary serous or clear cell uterine tumors

Postoperative adjuvant chemotherapy based on risk classification

See the list below:

• Low risk to low-intermediate risk: There is no evidence showing adjuvant chemotherapy after surgery decreases risk of recurrent disease or death from low-risk or low-intermediate risk endometrial cancer; adjuvant therapy with chemotherapy or progestational agents is not recommended ^[1]

• High-intermediate risk: Patients may benefit from postoperative adjuvant radiation therapy

• High-risk: Adjuvant therapy is recommended for all patients including radiation therapy and chemotherapy

Chemotherapy recommendations for metastatic, recurrent, or high-risk disease

Single-agent therapy ^[1] :

• Cisplatin 50-100 mg/m² IV over 30min with vigorous hydration; repeat every 3wk or

• Carboplatin AUC 5-7 IV over 30min; repeat every 3wk (see the Carboplatin AUC Dose Calculation [Calvert formula] calculator) or

• Paclitaxel 175 mg/m² IV over 3h; repeat every 3wk or

• Doxorubicin 60-75 mg/m² IV bolus; repeat every 3wk or

• Liposomal doxorubicin 50 mg/m² IV; repeat every 3-4wk

Combination therapy ^{[1, 4, 5, 6]} :

• Carboplatin AUC 5-7 IV plus  paclitaxel 175 mg/m² IV over 3h on Day 1 ^{[5, 7]}  or

• Doxorubicin 60 mg/m² IV plus  cisplatin 50 mg/m² IV on Day 1; repeat every 21d or

• Doxorubicin 45 mg/m² IV plus  cisplatin 50 mg/m² IV on Day 1 plus  paclitaxel 160 mg/m² over 3h on Day 2; repeat every 21d (this regimen is not widely used, because of concerns regarding toxicity ^[1] ) or

• Cisplatin 50 mg/m² IV plus  doxorubicin 50 mg/m² IV on Day 1; repeat every 21 cycles or

• Doxorubicin 45 mg/m² IV on Day 2 plus  cisplatin 50 mg/m² IV on Day 1 plus  paclitaxel 160 mg/m² IV over 3h on Day 2 plus filgrastim 5 μg/kg SC on Days 3-12; regimen repeated every 21d or

• For stage III/IV or recurrent HER2-positive uterine serous carcinoma: Carboplatin AUC 5 IV plus  paclitaxel 175 mg/m² IV over 3h plus trastuzumab 8 mg/kg IV over 90min on Day 1 then 6 mg/kg on Day 21; six cycles, with trastuzumab continued every 21 days after completion of cytotoxic therapy, until disease progression or unacceptable toxicity ^{[1, 8]}

• Pembrolizumab 200 mg IV q3Weeks or 400 mg q6Weeks plus lenvatinib 20 mg PO qDay; continue until disease progression, unacceptable toxicity, or for pembrolizumab up to 24 months in patients without disease progression ^{[9, 10]}

• For primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H): Dostarlimab 500 mg IV over 30 min on Day 1 plus  carboplatin AUC 5 IV on Day 1 plus  paclitaxel 175 mg/m² IV on Day 1 every 3 weeks for 6 doses, then  dostarlimab 1000 mg monotherapy IV q6Weeks until disease progression, unacceptable toxicity, or up to 3 years ^[11]

Investigational Regimens

Treatment options under clinical evaluation for advanced and recurrent endometrial cancer include the following ^[2] :

• Paclitaxel and carboplatin with or without metformin in stages III, IV, and recurrent endometrial cancer
• Samotolisib (PI3K/mTOR inhibitor) in recurrent or persistent endometrial cancer
• Everolimus and letrozole in recurrent or persistent endometrial cancer; a phase II study of this combination therapy  in patients with recurrent endometrial carcinoma reported a clinical benefit rate (CBR) of 40% (14 of 35 patients); responders underwent a median of 15 cycles. ^[12]
• Everolimus and letrozole plus metformin in patients with advanced or recurrent endometrioid endometrial cancer; a phase II study reported a CBR of 50% (27 of 54 patients), with partial response in 28% of patients and stable disease in 22%; CBR rates were significantly higher in patients with progesterone receptor–positive tumors. ^[13]