Endometrial Carcinoma Guidelines

Guidelines Contributor: Jori S Carter, MD, MS Assistant Professor, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine

Screening

Currently, no major organization recommends screening for cancer of the uterus for asymptomatic women. According to the National Cancer Institute (NCI) PDQ cancer information summary for endometrial cancer screening, no evidence suggests that transvaginal sonography reduces mortality from endometrial cancer, and there is inadequate evidence that endometrial sampling (biopsy) reduces mortality. The early clinical presentation and high early detection rate (85%) make it unlikely that screening will have a successful impact on earlier detection and increased survival rate. ^[21]

The American Cancer Society (ACS) recommends that at the time of menopause, all women should be made aware of the risks and symptoms of endometrial cancer and strongly encouraged to report any unexpected bleeding or spotting to their physician. ^[22]

Additionally, the NCI’s PDQ cancer information summary and ACS agree that for women at increased risk for endometrial cancer due to a history of receiving either estrogen therapy or tamoxifen therapy, there is no indication that routine screening would improve early detection or survival rates. As with women at average risk, these women generally present with symptoms at an early stage when the prognosis is good. ^{[21, 22]}

The Spanish Society of Medical Oncology (SEOM) and the Spanish Group for Investigation in Ovarian Cancer (GEICO) do not recommend routine screening for endometrial cancer in women who are at average or high risk for endometrial cancer and do not have abnormal uterine bleeding; this recommendation includes patients who are taking tamoxifen. Metrorrhagia should always be investigated in postmenopausal women or those with risk factors, using transvaginal ultrasound with a cutoff level of 3 mm. ^[23]

Lynch Syndrome

Women with Lynch syndrome (hereditary nonpolyposis colorectal cancer) have up to an 80% increased risk for colorectal cancer and a 60% increased risk for endometrial cancer. ^[24]  

The National Comprehensive Cancer Network (NCCN) guidelines endorse universal immunohistochemistry (IHC) or microsatellite instability (MSI) testing, regardless of family history, on all individuals diagnosed with colorectal or endometrial cancers to identify which patients should have genetic testing for Lynch syndrome. In addition, Lynch syndrome genetic testing should be done for all women diagnosed with endometrial cancer before age 50 and family members of anyone with Lynch syndrome. ^[24]  

The NCCN guidelines include the following recommendations for surveillance and risk reduction in women with Lynch syndrome:

• Hysterectomy and bilateral salpingo-oophorectomy should be offered to women who have completed child bearing and carry MLH1, MSH2, or MSH6 mutations

• Annual endometrial sampling for carriers of MLH1 or MSH2

• Annual colonoscopy (to decrease risk of colorectal cancer)

• Routine transvaginal ultrasound and serum CA-125 testing are not recommended

In 2014, the American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncology (SGO) published joint guidelines that recommend that all women who are diagnosed with endometrial cancer should be screened for Lynch syndrome. Genetic testing is preferred when resources are available, but clinical screening that includes focused family history is acceptable. Asymptomatic women with a first-degree relative diagnosed with either endometrial or colorectal cancer before age 60 should also be tested. ^[25]

The ACOG/SGO recommendations for surveillance and risk reduction include the following:

• Colonoscopy every 1-2 years, beginning at age 20-25

• Endometrial sampling every 1-2 years beginning at age 30-35

• Prophylactic hysterectomy and bilateral salpingo-oophorectomy should be offered to women in their early to mid-40s

Consensus guidelines issued jointly by the European Society for Medical Oncology, the European Society of Gynaecological Oncology, and the European Society of Radiotherapy and Oncology (ESMO/ESGO/ESTRO) recommends annual surveillance by transvaginal ultrasound and biopsy starting from the age of 35 until hysterectomy for all Lynch syndrome mutation carriers. In addition, for management of women with Lynch syndrome, recommendations include ^[26] :

• Annual screening beginning at age 35
• Regular hysteroscopy and endometrial biopsies 
• The application of local progesterone using the levonorgestrel intrauterine device
• Treatment of premalignant disease (i.e, atypical endometrial hyperplasia or endometrial intraepithelial neoplasia)
• Hysterectomy and bilateral oophorectomy

In women with Lynch syndrome, the SEOM and the GEICO recommend screening for endometrial cancer with annual endometrial sampling, transvaginal ultrasound (TVUS), and CA125 measurement, beginning at age 30-35, or 5-10 years prior to the earliest age of first diagnosis of Lynch-associated cancer of any kind. ^[23]

National Cancer Institute

The NCI’s PDQ cancer information summary notes that the use of oral contraceptives containing estrogen and progesterone for at least 1 year reduces the risk for developing endometrial cancer. The decreased risk is proportionate to duration of use, and the benefit persists for at least 15 years after cessation. However, use of oral contraceptives is also associated with increased risk for blood clots, stroke, and myocardial infarction, particularly in women who smoke and are older than 35. ^[21]

American Cancer Society

The ACS recommends the following measures to reduce the risk of developing endometrial cancer ^[22] :

• Asymptomatic women who have Lynch syndrome or a family history of colon cancer should be tested annually with endometrial biopsy beginning at age 35
• Progestin should added to estrogen in hormone replacement therapy

Women who are undergoing surgery for colorectal cancer and who do not wish to preserve fertility should be offered prophylactic hysterectomy and/or oophorectomy

The National Comprehensive Cancer Network (NCCN) guidelines provide the following recommendations for the initial evaluation for suspected endometrial cancer ^[20] :

• History and physical examination
• Endometrial biopsy
• Expert pathology review to determine histopathologic subtype
• Because of a high false-negative rate (10%), a negative biopsy in symptomatic patients requires followup with a fractional dilation and curettage (D&C) under anesthesia.
• Imaging studies (eg, CT, MRI, PET) and optional CA-125 testing for evaluation of extrauterine disease

The Society of Gynecologic Oncology (SGO) and European Society of Medical Oncology (ESMO) guidelines provide overall similar recommendations, but both include hysteroscopy with biopsy as another diagnostic option. ^{[27, 28]} Because of its high accuracy, the SGO considers hysteroscopy with biopsy the gold standard for diagnosis. ^[27]

The following two major staging systems are commonly used in endometrial cancer:

• The International Federation of Gynecology and Obstetrics (FIGO) system, developed in collaboration with the World Health Organization (WHO) and revised in 2009 ^[12]

• The TNM system, developed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) ^[29]

• See Endometrial Cancer Staging for details.

In the past, uterine sarcomas were staged as endometrial cancers. This did not reflect clinical behavior, however, so a new corpus sarcoma staging system was developed, based on the criteria used in other soft tissue sarcomas. See the Table below.

Table. Uterine Sarcomas (Leiomyosarcoma, Endometrial Stromal Sarcoma, and Adenosarcoma) (Open Table in a new window)

Positive cytology is an adverse risk factor. Although peritoneal cytology results do not affect staging, FIGO and AJCC continue to recommend that peritoneal cytology be obtained and reported. ^{[12, 29]}

The European Society of Medical Oncology (ESMO) guidelines stratify patients into treatment groups based on the estimated risk of disease recurrence, as follows ^[28] :

• Low risk: Endometrioid cancers that are confined to the endometrium
• Intermediate risk: Disease that 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)

The National Comprehensive Cancer Network guidelines use the following categories for delineating endometrioid cancer treatment groups ^[20] :

• Disease limited to the uterus
• Suspected or gross cervical involvement
• Suspected extrauterine disease

The major guidelines are in agreement that the primary treatment for stage I disease limited to the uterus is surgery (total hysterectomy and bilateral salpingo-oophorectomy) and complete surgical staging including pelvic washings, bilateral pelvic and paraaortic lymphadenectomy. ^{[20, 27, 28, 30, 26]}

The recommended surgical approach varies among the guidelines. The National Comprehensive Cancer Network (NCCN) considers that hysterectomy and adnexectomy may be performed through laparotomy, vaginally, or via minimally invasive techniques such as laparoscopy or robotic surgery. ^[20]  The European Society for Medical Oncology, the European Society of Gynaecological Oncology, and the European Society of Radiotherapy and Oncology (ESMO/ESGO/ESTRO) recommends minimally invasive surgery because of the significant reduction in complications reported. ^[26]

The Society of Gynecologic Oncology (SGO) recommends laparoscopy as the standard approach, and finds robotic-assisted techniques acceptable. Both the American College of Obstetricians and Gynecologists (ACOG) and SGO reserve vaginal hysterectomy for selected women who are at high risk for surgical morbidity. ^{[27, 30]}

In younger women with noninvasive, grade 1 cancers who wish to preserve fertility, NCCN, SGO, and ACOG all recommend progestin therapy. Total hysterectomy and bilateral salpingo-oophorectomy is indicated when childbearing is complete, or sooner if cancer is still present after 6-9 months of therapy or disease progression occurs. Women receiving fertility-sparing treatment should be monitored closely with endometrial biopsy every 3 months. ^{[20, 30, 31]}

For patients who are medically inoperable, radiation therapy or hormone therapy are options, according to both the NCCN and ESMO/ESGO/ESTRO guidelines. ^{[20, 26]}  

American Society of Radiation Oncology

In 2014, the American Society of Radiation Oncology (ASTRO) published evidence-based guidelines for the role of postoperative radiation therapy. The recommendations include the following ^[32] :

• After total hysterectomy, no radiation therapy is required for patients with grade 1 or 2 tumors with < 50% myometrial invasion
• Vaginal brachytherapy is an option for patients with grade 3 tumors without myometrial invasion or grade 1 or 2 tumors with high risk factors
• Vaginal brachytherapy is comparable to pelvic radiation in preventing recurrence for patients with grade 1 or 2 tumors ≥50% myometrial invasion; or grade 3 tumors with < 50% myometrial invasion; vaginal brachytherapy is preferred
• Pelvic radiation for patients with grade 3 tumors with ≥50% myometrial invasion or cervical stroma invasion; or grade 1 or 2 tumors with ≥50% myometrial invasion with high risk factors
• For patients with positive nodes, or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum: external beam radiation therapy as well as adjuvant chemotherapy
• Use of vaginal brachytherapy in patients also undergoing pelvic external beam radiation is not generally warranted
• For patients with metastatic disease, concurrent chemoradiation followed by adjuvant chemotherapy is indicated; alternative sequencing strategies with external beam radiation and chemotherapy are also acceptable

Spanish Society of Medical Oncology (SEOM) and Spanish Group for Investigation in Ovarian Cancer (GEICO)

The standard surgical treatment recommended by the Spanish Society of Medical Oncology (SEOM) and the Spanish Group for Investigation in Ovarian Cancer (GEICO) in early-stage endometrial cancer is total hysterectomy and bilateral salpingo-oophorectomy without vaginal cuff resection, using a minimally invasive surgery approach. ^[23]

In low-risk endometrial cancer, systematic lymph node dissection (LND) is not recommended. In intermediate and high-risk cases, LND is recommended to guide surgical staging and adjuvant therapy. Sentinel lymph node biopsy can be considered for staging purposes.

Adjuvant treatment recommendations are as follows:

• Low-risk patients – Adjuvant treatment not required
• Intermediate-risk patients – Vaginal brachytherapy (VBT); VBT plus pelvic radiation in patients with no surgical nodal staging
• High-risk patients - Adjuvant chemotherapy (carboplatin-paclitaxel) with concurrent or sequential external beam radiation therapy, or chemotherapy alone

Hormonal therapy could be an appropriate therapeutic alternative for patients with low-grade, hormone-receptor–positive disease, without rapidly progressive metastatic disease. The treatment of choice is progestogens or progestogens alternating with tamoxifen.

Pembrolizumab plus lenvatinib should be considered for second-line treatment, particularly for mismatch repair (MMR)–proficient tumors; dostarlimab or pembrolizumab can be considered for second-line therapy of MMR-deficient tumors.

The European Society of Medical Oncology (ESMO) and the Society of Gynecologic Oncology (SGO) offer similar recommendations for treatment of advanced and metastatic disease that include the following ^{[31, 28]} :

• Combination chemotherapy and radiation therapy should be considered before a single-modality treatment

• Chemotherapy with a paclitaxel with carboplatin regimen is as effective as other regimens and had less toxicity

• For treatment of metastatic disease, hormonal therapy with progestational agents may be considered; tamoxifen and aromatase inhibitors are also acceptable ^[28]

• Based on preliminary studies, a targeted agent such as temsirolimus or ridaforolimus may be considered as a second-line agent ^[28]

• National Comprehensive Cancer Network (NCCN) guidelines for relapse or metastatic disease are as follows: ^[20]

• Hormone therapy followed by chemotherapy on progression for low-grade metastases

• Chemotherapy and palliative radiation therapy for symptomatic, high-grade, or large-volume metastases

• Persistent progression should be treated with best supportive care and enrollment in a clinical trial

American College of Obstetricians and Gynecologists (ACOG) and European Society of Medical Oncology (ESMO) guidelines concur that following surgical treatment, patients should receive a pelvic exam every 3-4 months for the first 2-3 years, then every 6 months until year 5 to monitor for recurrent disease. ^{[30, 28]} The Society of Gynecologic Oncology (SGO) and the National Comprehensive Cancer Network (NCCN) recommend review of symptoms and pelvic exam every 3 to 6 months for the first 2 years and every 6 to 12 months thereafter. ^{[20, 33]}

ESMO and SGO guidelines prefer PET/CT over CT alone for assessment of suspected recurrence. ^{[28, 33]}

According to the Spanish Society of Medical Oncology (SEOM) and the Spanish Group for Investigation in Ovarian Cancer (GEICO), surveillance consists mainly of monitoring symptoms and physical examination that includes a speculum and pelvic examination every 3-6 months for 2 years, and every 6-12 months thereafter. Patients with low-risk endometrial cancer can be followed less frequently: 6-12 months for first 2 years, then yearly thereafter. Follow-up imaging may be useful in selected high-risk patients. ^[23]