endometrial%20cancer
ENDOMETRIAL CANCER

Endometrial cancer is also known as uterine cancer, cancer of the corpus uteri, uterine corpus cancer, endometrical carcinoma.

It is the 6th most common malignancy worldwide.

Management of endometrial cancer should be divided based on risk, disease stage & patient's desire for fertility.

Endometrial%20cancer Treatment

Principles of Therapy

  • 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 salphingo-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 salphingo-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 Levonorgestrel is the preferred primary treatment regimen for patients who chose to preserve their childbearing potential
  • 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

Pharmacotherapy

Chemotherapy

  • 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

Recommended Combination Regimens

  • Carboplatin/Paclitaxel: Preferred combination regimen and adjuvant treatment region for uterine-confined disease
  • Carboplatin/Paclitaxel/Trastuzumab: Preferred for patients with HER2-positive advanced or recurrent uterine serous carcinoma 
  • 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
  • Everolimus/Letrozole: For patients with endometrioid histology
  • Lenvatinib/Pembrolizumab: For patients with advanced or recurrent endometrial cancer

Recommended Single-agent IV Regimens

  • 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
  • Pembrolizumab: May be used in patients with MSI-H or dMMR tumors unresponsive to cytotoxic chemotherapeutic agents
  • Topotecan
  • Temsirolimus

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
  • Hormone therapy or chemotherapy is recommended for patients with disseminated metastases

Recommended Hormone Therapy Regimens

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

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

Radiotherapy

  • 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
    • 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
    • Same efficacy in patients with grade 1 or 2 tumors with 50% myometrial 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 0.5 cm from the vaginal surface
  • Recommended dose to boost EBRT: 4-6 Gy x 2-3 fractions to the vaginal mucosa
  • 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 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
    • If previously given EBRT, surgical resection with exploration together with systemic therapy is recommended
      • IORT and palliative radiotherapy may also be considered
  • Chemoradiotherapy may be considered for patients with vaginal or pelvic node recurrence at high risk for systemic relapse
    • May provide the best outcome
  • Adjuvant systemic therapy or surgery prior to radiotherapy may be considered in select patients with bulky disease positive for vaginal or pelvic node recurrence

Supportive Therapy

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
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