Endometrial%20cancer Treatment

• Management of endometrial cancer should be divided based on risk, disease stage and patient's desire for fertility
• Cytoreduction therapy, which includes debulking with surgery and chemotherapy or radiation therapy, improves survival rate and helps reduce recurrence in patients with intra-abdominal disease
• Surgical approach should include total (extrafascial) hysterectomy-bilateral salpingo-oophorectomy (TAH-BSO), lymphadenectomy, pelvic washing cytology

Adjuvant Therapy

• May be considered depending on the extent, risk group and staging

Low Risk

• Observation is preferred for patients without any risk factors, both for surgically and nonsurgically staged disease
• In patients with any risk factors eg ≥60 years of age, depth of invasion, lymphovascular space invasion, adjuvant vaginal brachytherapy may be considered
  • Vaginal brachytherapy is strongly suggested if patient has ≥2 risk factors

Intermediate Risk

• Adjuvant vaginal brachytherapy is preferred
• Observation may be considered if without myoinvasion and lymphovascular space invasion

High-Intermediate Risk

• Adjuvant vaginal brachytherapy is preferred
• For patients who did not undergo surgical nodal staging, adjuvant EBRT is recommended
  
  • May consider adjuvant brachytherapy for those with grade 3 tumors but negative for lymphovascular space invasion 

• Participation in clinical studies should be encouraged

High Risk

• Adjuvant vaginal brachytherapy and/or EBRT with limited fields should be considered for high-risk stage I endometrial cancer patients with grade 3 tumor if surgical nodal staging was performed and confirmed negative for node involvement
  • For patients ≥60 years of age, with extensive lymphovascular space invasion or with >50% myoinvasion, addition of systemic therapy to radiation therapy is recommended
• For high-risk stage I endometrial cancer patients with grade 1-2 tumor who underwent surgical staging, adjuvant vaginal brachytherapy is preferred and may consider observation for patients negative for risk factors
• For high-risk stage I endometrial cancer patients who did not undergo surgical nodal staging, adjuvant EBRT is recommended and sequential adjuvant chemotherapy may be considered
• For high-risk patients with stage II endometrial cancer who underwent simple hysterectomy, surgical nodal staging and confirmed node-negative:
  
  • Vaginal brachytherapy and/or EBRT is recommended for patients with grade 1-2 tumor
    • Observation or adjuvant vaginal brachytherapy is a management option for patients who had radical hysterectomy with negative surgical margins and no extrauterine disease
  • Limited field EBRT is recommended for grade 3 patients or those positive for lymphovascular space invasion
    • May also consider vaginal brachytherapy and/or chemotherapy 
  • For patients ≥60 years of age, with extensive lymphovascular space invasion or with >50% myoinvasion, addition of systemic therapy to radiation therapy is recommended

• For high-risk patients with stage II endometrial cancer who underwent simple hysterectomy but did not undergo surgical nodal staging, EBRT is recommended, and brachytherapy is recommended
  
  • Sequential adjuvant chemotherapy should be considered in patients with grade 3 tumor 

• EBRT, vaginal brachytherapy, and chemotherapy are recommended for patients with surgically-staged high-risk stage III-IV endometrial cancer
  
  • Combination EBRT with or without vaginal brachytherapy with or without chemotherapy is recommended in patients with stage IIIA-IVA FIGO classes
    • Alternative regimen includes chemotherapy with or without vaginal brachytherapy
  • Chemotherapy with or without extended field EBRT with or without vaginal brachytherapy is recommended in patients with stage IVB FIGO classification 

• For patients with high-risk non-endometrioid cancer with serous and clear cell type based on staging, chemotherapy should be given
  
  • Vaginal brachytherapy may be considered in patients with stage IA lymphovascular space invasion-negative disease
  • Chemotherapy plus EBRT may be considered in patients with stage ≥IB, especially in patients positive for node invasion 

• For patients with high-risk non-endometrioid cancer and undifferentiated tumors based on staging, chemotherapy is recommended, and ERBT and participation in clinical trials are encouraged

Neoadjuvant Therapy

• May benefit patients expected to have residual disease after primary debulking surgery

Uterine Cavity-limited Disease

• After surgical confirmation, endometrial cancer confined within the uterine walls are best managed by surgery
• It is recommended that surgery includes TH-BSO and lymphadenectomy with pelvic washing cytology
• Sentinel node mapping may also be considered
• For patients with uterine-confined disease with contraindications to surgery, EBRT and/or brachytherapy is preferred, and may consider systemic therapy in patients with high-risk disease

Cervical Involvement Suspected or Confirmed

• For operable patients with cervical involvement, total hysterectomy or radical hysterectomy with bilateral salpingo-oophorectomy, pelvic washing cytology, lymphadenectomy is recommended
  
  • Radical or modified radical hysterectomy are options to TH-BSO
  • EBRT with brachytherapy prior to TH-BSO and surgical staging is also recommended for initial management

• For patients with gross cervical involvement with contraindications to surgery, EBRT and brachytherapy are preferred
  • May consider addition of systemic therapy to radiotherapy for patients with high-risk disease
  • Systemic therapy alone may also be considered, then followed by adjuvant EBRT and brachytherapy if still not suitable for surgery

Suspected Extrauterine Disease

• Neoadjuvant systemic therapy may be considered
• Goal of surgical treatment is to eradicate all residual disease, thus debulking is recommended for patients with abdomen- or pelvis-confined endometrial carcinoma
• For patients with extrauterine disease who are not suitable for primary surgery, EBRT with or without brachytherapy and systemic therapy is recommended
  
  • Systemic therapy alone may also be considered 

• For patients with distant visceral metastasis, systemic therapy and EBRT and/or hormone therapy are recommended
• Palliative TH-BSO may also be considered

Fertility-preserving Treatments

• Conservative treatments may be considered for young women of childbearing age and those considering pregnancy in the future
• Criteria for inclusion:
  
  • Pathologically-confirmed well-differentiated grade 1 endometrioid adenocarcinoma on dilatation and curettage
  • Disease limited to the endometrium as confirmed in MRI or transvaginal ultrasound
  • No metastasis or extrauterine involvement on imaging studies
  • No contraindications to medical therapy or pregnancy
  • Patients should have been informed that fertility-sparing therapies are not standard treatment for endometrial cancer and that close follow-up is required

• Continuous progestin-based therapy with either Megestrol, Medroxyprogesterone or intrauterine device-containing Levonorgestrel (LNG-IUD) is the preferred primary treatment regimen for patients who chose to preserve their childbearing potential
• Patient counselling on weight management and healthy lifestyle changes is recommended
• Strict monitoring with endometrial evaluation every 3-6 months is recommended until conception or disease progression 
• After completion of childbearing, treatment failure after 6-12 months of progestin-based therapy, or disease progression, TH-BSO with surgical staging is recommended

Systemic Therapy

• Combination regimens are recommended for high-risk disease, recurrent or metastatic endometrial cancer
• Single-agent therapy is used when multi-agent regimens are contraindicated
• Post-operative platinum-based chemotherapy may benefit patients with high-risk endometrioid disease (eg increased progression-free survival, overall survival

Preferred Regimens

• Carboplatin/Paclitaxel: Preferred combination regimen and adjuvant treatment for uterine-confined disease
• Carboplatin/Paclitaxel/Trastuzumab: Preferred for patients with HER2-positive advanced or recurrent uterine serous carcinoma 

Other Recommended Regimens - Combination Therapy

• Carboplatin/Docetaxel: May be considered in patients with contraindications to Paclitaxel therapy 
• Cisplatin/Doxorubicin
• Cisplatin/Doxorubicin/Paclitaxel
• Carboplatin/Paclitaxel/Bevacizumab
• Ifosfamide/Paclitaxel: For patients with carcinosarcoma
• Cisplatin/Ifosfamide: For patients with carcinosarcoma

Other Recommended Regimens - Monotherapy

• Albumin-bound Paclitaxel: For patients with hypersensitivity to Paclitaxel but negative for skin testing 
• Bevacizumab: May be considered in patients unresponsive to cytotoxic chemotherapeutic agents 
• Cisplatin
• Carboplatin
• Docetaxel
• Doxorubicin
• Ifosfamide: For patients with carcinosarcoma
• Liposomal Doxorubicin
• Paclitaxel
• Topotecan
• Temsirolimus

Biomarker-directed Systemic Therapy for Second-line Treatment
Preferred Regimens

• Lenvatinib/Pembrolizumab: For patients with non-MSI-H/dMMR advanced or recurrent endometrial cancer
• Pembrolizumab: May be used in patients with tumor mutational burden-high (TMB-H) or MSI-H/dMMR tumors unresponsive to cytotoxic chemotherapeutic agents

Other Recommended Regimens

• Avelumab: For patients with MSI-H/dMMR tumors
• Cabozantinib
• Dostarlimab-gxly: For patients with MSI-H/dMMR tumor recurrent or advanced endometrial carcinoma that has progressed on or following prior treatment with a platinum-containing regimen
• Larotrectinib, Entrectinib: For patients with NTRK gene fusion-positive tumors
• Nivolumab: For patients with dMMR/MSI-H tumors

Hormone Therapy

• Treatment option for patients with metastatic, recurrent, or high-risk
  
  • May also be considered in patients with lower grade endometriod histology only with small or slow-growing tumors

• Indicated for advanced (grade 1 or 2) endometrioid-type endometrial cancer
• Preferred 1st-line systemic treatment for hormone-positive grade 1-2 tumors negative for rapid disease progression
• Close monitoring with endometrial biopsy every 3-6 months is required if to undergo this management option

Preferred Regimens

• Progestin-based agents
• Alternating treatment with Megestrol and Tamoxifen or Medroxyprogesterone and Tamoxifen
• Aromatase inhibitors
• Tamoxifen
• Fulvestrant

Other Recommended Regimens

• Everolimus/Letrozole: For patients with endometrioid histology

Progestin-based Therapy

• Eg Megestrol acetate, Medroxyprogesterone acetate, intrauterine device-containing Levonorgestrel (LNG-IUD)
• Conservative treatment in select patients with non-invasive disease, or young patients with endometrial hyperplasia, who wish to preserve their fertility
• Contraindicated in patients at increased risk for breast cancer, stroke, myocardial infarction, pulmonary embolism, and/or deep vein thrombosis

Aromatase Inhibitors

• Eg Anastrozole, Exemestane, Letrozole
• May be used as alternative therapy for progestin-based agents and Tamoxifen in patients with asymptomatic or low-grade disseminated metastasis
• Usually used in the management of breast cancer, but are being considered in endometrial cancer due to its interaction with estrogen and progesterone receptors
• Further studies are needed to prove the efficacy and safety of aromatase inhibitors for the treatment of endometrial cancer

Tamoxifen

• Used for metastatic or recurrent disease
• Prevents estrogen-stimulated growth of oncologic cells

Recurrent Endometrial Cancer

• Hormone therapy and/or systemic therapy is recommended for patients with disseminated metastases
  • May also consider palliative EBRT in patients given systemic therapy

• Radiotherapy may be considered in patients not qualified for surgery and those at moderate-high risk for recurrence
• Used as adjuvant therapy, together with chemotherapy, for patients with extrauterine disease
• Confirmation of tumor extent and absence of distant metastases using imaging techniques are required prior to initiation of radiation therapy

External Beam Radiotherapy (EBRT)

• May be considered in intermediate to high-risk endometrial cancer patients with suspected or gross cervical involvement (grade 3 tumor, ≥50% myometrial invasion or cervical stroma invasion) following EH-BSO and surgical staging
  
  • Several studies have shown that adjuvant EBRT decreased recurrence rate and improved overall survival in patients with high-intermediate- or high-risk and those with grade 3 tumors 

• Recommended for pelvic control in high-risk, stage I patients
• Limited-field EBRT is recommended for patients with grade 3 tumors who are positive for lymph node involvement
• Recommended doses include:
  • Microscopic disease: 45-50 Gy
  • Gross nodal disease boost dose: 60-65 Gy with normal tissue constraints
  • Post-operative boost dose: Total dose of 60-70 Gy low-dose rate equivalent
  • Neoadjuvant radiation: 45-50 Gy; 1-2 high-dose rate insertions to a total of 75-80 Gy low-dose rate equivalent may be considered

Vaginal Brachytherapy (Internal Radiation Therapy)

• Adjuvant treatment of choice over whole pelvic radiation therapy in patients with intermediate-risk, and high-intermediate-risk patients for recurrence prevention
• Treatment option for patients with grade 1 or 2 tumors with ≤50% myometrial invasion, no lymphovascular space invasion, and microscopic cervical invasion or grade 3 tumors with <50% myometrial invasion 
• May be considered as an alternative treatment in high-risk patients
• Should be considered for patients after EH-BSO if with high-intermediate patients or low-risk patients but with signs of higher-risk disease
• May provide locoregional control with competitive overall survival rates in the following patients:
  • >60 years old with intermediate- to high-intermediate-risk
  • Endocervical glandular involvement present but disease confined to the uterus
  • Patients with high-intermediate-risk for recurrent endometrial cancer 

• Should be initiated once vaginal cuff has healed, 6-8 weeks or <12 weeks post-surgery
• Recommended post-operative high-dose rates include:
  • 6 Gy x 5 fractions to the vaginal surface
  • 7 Gy x 3 fractions or 5.5 Gy x 4 fractions 5 mm below the vaginal surface
• Recommended dose to boost EBRT: 4-6 Gy x 2-3 fractions to the vaginal mucosa; 15-25 Gy for macroscopic residual disease
• For patients not suitable for primary surgery, dose should be individualized based on patient's clinical status
• Studies revealed lesser gastric toxic effects and better quality of life with vaginal compared to whole pelvic irradiation

Recurrent Endometrial Cancer

• Radiotherapy may be considered in patients with localized vaginal relapse post-surgery
  • EBRT with or without brachytherapy with or wthout systemic therapy is recommended for patients with no history of radiotherapy
  • If with history of brachytherapy, surgical resection with exploration is recommended
    • Intraoperative radiotherapy (IORT) may also be considered
    • EBRT with brachytherapy boost is also recommended
  • If previously given EBRT, the following may be considered:
    • Surgical resection with exploration with or without IORT
    • Systemic therapy with or without palliative EBRT
    • Vaginal brachytherapy with or without systemic therapy
  • Radical re-irradiation using stereotactic body radiation therapy (SBRT), permanent seed implants, or proton therapy may be considered if surgical management is not feasible
• EBRT with or without systemic therapy may be considered for patients with pelvic or para-aortic or common iliac node recurrence at high risk for systemic relapse
• Systemic therapy with or without EBRT may be considered for patients with upper abdominal/peritoneal disease relapse with microscopic residual disease
• EBRT with or without systemic therapy with or without vaginal brachytherapy may be considered for patients with disease confined to the vagina or paravaginal soft tissue

Palliative Surgery

• Palliative TH/BSO may be considered in patients with distant metastases suitable for primary surgery
  
  • Minimally invasive surgery is the preferred approach when technically feasible

Palliative Radiotherapy

• EBRT may be considered for the palliation of symptoms in patients with painful node recurrences, bleeding, or bone metastasis
• May also consider palliative radiotherapy in patients with metastatic disease given chemotherapy