Endometrial cancer is usually endometrioid adenocarcinoma. Typically, it manifests as postmenopausal uterine bleeding. Diagnosis is by biopsy. Staging is surgical. Treatment requires hysterectomy, bilateral salpingo-oophorectomy, and, for high-risk histology, usually pelvic and para-aortic lymphadenectomy. For advanced cancer, radiation therapy, endocrine therapy, or chemotherapy is usually indicated.
Endometrial cancer is more common in high-resource countries where obesity rates are high. In the United States, this cancer is the 4th most common cancer among women. The American Cancer Society estimates that in 2023, approximately 66,200 new cases of endometrial cancer will be diagnosed and that approximately 13,030 women will die of this cancer (1). Approximately 80% of these new cases will be early stage with good prognosis, and the remaining 20% will have high-grade or advanced-stage disease (2).
In the United States, endometrial cancer incidence is higher than average in Black, American Indian, and Alaska Native women (Hispanic 26.1/100,000; Non-Hispanic American Indian or Alaska Native 28.8; Non-Hispanic Asian or Pacific Islander 22.7; Non-Hispanic Black 29.4; Non-Hispanic White 27.6) (3). Mortality is highest in Black women (Hispanic 4.3/100,000; Non-Hispanic American Indian or Alaska Native 4.5; Non-Hispanic Asian or Pacific Islander 3.5; Non-Hispanic Black 9.1; Non-Hispanic White 4.6) (3).
Endometrial cancer affects mainly postmenopausal women. Median patient age at diagnosis is 63 years (3). Most cases are diagnosed in women aged 55 to 64 years.
Довідкові матеріали загального характеру
1. American Cancer Society: Key Statistics for Endometrial Cancer. Accessed July 14, 2023.
2. American Cancer Society: Cancer Facts & Figures 2023.Atlanta: American Cancer Society; 2023. Accessed July 14, 2023.
3. National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program: Cancer Stat Facts: Uterine Cancer. Accessed July 14, 2023
Etiology of Endometrial Cancer
Risk factors for endometrial cancer are
Unopposed estrogen (high serum levels of estrogen and no or low progesterone)
Age > 45 years
Obesity
Tamoxifen use for > 2 years
Lynch syndrome
Previous pelvic radiation therapy
Increased exposure to extrinsic or intrinsic estrogen may be associated with
Obesity
Estrogen therapy without progesterone
Nulliparity
Early menarche
Late menopause
Estrogen-producing tumors
Most endometrial cancers are caused by sporadic mutations. However, in approximately 5% of patients, inherited mutations cause endometrial cancer; endometrial cancer due to inherited mutations tends to occur at a younger age and is often diagnosed 10 to 20 years earlier than sporadic cancer. About half of cases that involve heredity occur in families with Lynch syndrome (hereditary nonpolyposis colorectal cancer (HNPCC]). Patients who have Lynch syndrome have a high risk of developing other cancers (eg, colorectal cancer, ovarian cancer).
Pathology of Endometrial Cancer
Endometrial cancer is usually preceded by endometrial hyperplasia. Endometrial carcinoma is commonly classified into 2 types.
Type I (non-aggressive) tumors are more common, are usually estrogen-responsive, and are usually diagnosed in women with obesity and at younger ages (perimenopause or early in menopause). They are preceded by endometrial hyperplasia. These tumors are usually low-grade; the prognosis is good. Endometrioid adenocarcinoma (grades 1 and 2) is the most common histology. These tumors may show microsatellite instability and have mutations in PTEN, PIK3CA, KRAS, and CTNNB1.
Type II (aggressive) tumors are usually high-grade and include grade 3 endometrioid carcinomas and tumors with nonendometrioid histology (eg, serous, clear cell, mixed cell, undifferentiated, mixed, mesonephric-like, gastrointestinal mucinous-type, and carcinosarcoma). They tend to occur in older women. Approximately 10 to 30% have p53 mutations (1). Up to 10% of endometrial carcinomas are type II (2). The prognosis is poor.
Endometrioid adenocarcinomas account for approximately 75 to 80% of endometrial cancers (3).
There are 4 distinct molecular subtypes of endometrioid endometrial carcinomas (4):
POLE ultramutated (POLEmut): Characterized by pathogenic mutations in the exo nuclease domain of DNA polymerase-ε, resulting in an ultra-high tumor mutational burden and a good prognosis
Mismatch repair-deficient (MMRd): Has loss of mismatch repair proteins, resulting in microsatellite instability and an intermediate prognosis
No specific molecular profile (NSMP): Has no single identifying molecular feature and tumor stage- and grade-dependent outcomes and an intermediate prognosis
p53-mutant: Has a low tumor mutational burden and high somatic copy-number alterations resulting in a poor prognosis
Determining the molecular subtype, if feasible, adds valuable information to the standard clinicopathological risk factors to classify patients with endometrial cancer into risk groups, predict prognosis, and guide treatment recommendations.
Uterine papillary serous carcinomas (10%), clear cell carcinomas (< 5%), and carcinosarcomas (< 5%) are considered more aggressive, high-risk histologies and are associated with a higher incidence of extrauterine disease at presentation. Carcinosarcomas used to be categorized as sarcomas but are now considered and treated as high-grade epithelial tumors (carcinomas).
Mucinous carcinomas are typically low-grade; the prognosis is good. KRAS mutations are common in these tumors.
Other histopathologic types of endometrial carcinoma are neuroendocrine, undifferentiated, and mixed carcinoma (composed of more than one type, with at least 10% of each component).
Endometrial cancer may spread as follows:
From the surface of the uterine cavity to the cervical canal
Through the myometrium to the serosa and into the peritoneal cavity
Via the lumen of the fallopian tube to the ovary, broad ligament, and peritoneal surfaces
Via the bloodstream, leading to distant metastases
Via the lymphatics
The higher (more undifferentiated) the grade of the tumor, the greater the likelihood of deep myometrial invasion, pelvic or para-aortic lymph node metastases, or extrauterine spread.
Довідкові матеріали щодо лабораторних методів дослідження
1. Cancer Genome Atlas Research Network, Kandoth C, Schultz N, et al: Integrated genomic characterization of endometrial carcinoma [published correction appears in Nature 2013 Aug 8;500(7461):242]. Nature 497(7447):67-73, 2013. doi:10.1038/nature12113
2. Faber MT, Frederiksen K, Jensen A, et al: Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978-2014. Gynecol Oncol 146(2):359-367, 2017. doi:10.1016/j.ygyno.2017.05.015
3. Lu KH, Broaddus RR: Endometrial cancer. N Engl J Med 383(21):2053-2064, 2020. doi:10.1056/NEJMra1514010
4. WHO Classification of Tumours Editorial Board: 2020 WHO Classification of Tumours, 5th Edition, Volume 4: Female Genital Tumors.
Symptoms and Signs of Endometrial Cancer
Most (> 90%) women with endometrial cancer present with abnormal uterine bleeding (eg, postmenopausal bleeding, premenopausal intermenstrual bleeding, ovulatory dysfunction). Depending on age and risk factors, 6 to 19% of women with postmenopausal bleeding have endometrial cancer (1).
Довідковий матеріал щодо симптомів та ознак
1. Clarke MA, Long BJ, Del Mar Morillo A, et al: Association of endometrial cancer risk with postmenopausal bleeding in women: a systematic review and meta-analysis. JAMA Intern Med 178(9):1210-1222, 2018. doi:10.1001/jamainternmed.2018.2820
Diagnosis of Endometrial Cancer
Endometrial biopsy
The following suggest endometrial cancer:
Postmenopausal bleeding
Abnormal bleeding in premenopausal women (intermenstrual bleeding, ovulatory dysfunction), particularly in women > 45 years
A routine Papanicolaou (Pap) test showing endometrial cells in postmenopausal women
A routine Pap test showing atypical endometrial cells in any woman
If endometrial cancer is suspected, outpatient endometrial biopsy is done; sensitivity is > 90%. An alternative for average-risk postmenopausal women is transvaginal ultrasonography; biopsy is required if endometrial lining thickness is > 4 mm and results are inconclusive (1).
If biopsy results are inconclusive or suggest precancer (eg, complex hyperplasia with atypia) or cancer, dilation and curettage (D & C), often with hysteroscopy, is done.
Once endometrial cancer is diagnosed, pretreatment evaluation includes a complete blood count (CBC) and other blood tests (serum electrolytes, kidney, and liver). A chest x-ray is done. If an abnormality is seen on chest x-ray, CT should be done. The following should be considered:
Pelvic MRI to determine the origin of the tumor (cervix or uterus) and local extension
For high-grade carcinomas, chest, abdomen, and pelvic CT
If metastatic disease is suspected based on physical examination or blood tests, positive emission tomography (PET)-CT
Because endometrial cancer sometimes results from an inherited mutation, genetic counseling and/or testing should be considered if patients are < 50 years or have a significant family history of endometrial cancer, ovarian cancer, or colorectal cancer or known Lynch syndrome (HNPCC).
Стадії
Staging of endometrial cancer is based on non-aggressive versus aggressive histology; extent of spread, including invasion depth, extension to surrounding structures, and extrauterine or lymph node metastases; lymphovascular space invasion; and molecular classification (see table FIGO Staging of Uterine Corpus Carcinoma and Carcinosarcoma).
Staging is surgical and includes exploration of the abdomen and pelvis, biopsy or excision of suspicious extrauterine lesions, total abdominal hysterectomy, and, in patients with high-risk features (grade 1 or 2 cancer plus deep myometrial invasion, grade 3 cancer, all cancers with high-risk histology), pelvic and para-aortic lymphadenectomy. Staging can be done via laparotomy, laparoscopy, or robotic-assisted surgery. If cancer appears to be confined to the uterus, an alternative to pelvic and para-aortic lymphadenectomy is sentinel lymph node mapping.
Визначення стадії раку тіла матки та карциносаркоми за FIGO
Stage* | Definition |
|---|---|
I† | Confined to the uterine corpus and ovaryǂ |
| Disease limited to the endometrium OR non-aggressive histologic type#, with invasion of less than half of myometrium with no or focal lymphovascular space involvement (LVSI)§ OR good prognosis disease |
| Non-aggressive histologic type limited to an endometrial polyp OR confined to the endometrium |
| Non-aggressive histologic type involving less than half of the myometrium with no or focal LVSI |
| Low-grade endometrioid endometrial carcinomas (EECs) limited to the uterus and ovaryǂ |
| Non-aggressive histologic types# with invasion of half or more of the myometrium, and with no or focal LVSI§ |
| Aggressive histologic types# limited to a polyp or confined to the endometrium |
II† | Invasion of the cervical stroma without extension outside the uterus OR with substantial LVSI OR aggressive histologic types with myometrial invasion |
IIA | Invasion of the cervical stroma of non-aggressive histologic types |
IIB | Substantial LVSI§ of non-aggressive histologic types |
IIC | Aggressive histologic types with any myometrial involvement |
III | Local and/or regional spread of the tumor of any histologic subtype |
| Invasion of uterine serosa, adnexa, or both (direct extension or metastasis) |
| Spread to ovary or fallopian tube (except when meeting stage IA3 criteria)ǂ |
| Involvement of uterine subserosa or spread through the uterine serosa |
| Metastasis or direct spread to the vagina and/or spread to the parametria or pelvic peritoneum |
| Metastasis or direct spread to the vagina and/or the parametria |
| Metastasis to the pelvic peritoneum |
| Metastases to pelvic or para-aortic lymph nodes or to both¶ |
| Metastases to pelvic lymph nodes |
| Micrometastasis |
| Macrometastasis |
| Metastasis to para-aortic lymph nodes up to the renal vessels, with or without metastasis to the pelvic lymph nodes |
| Micrometastasis |
| Macrometastasis |
IV | Spread to the bladder and/or intestinal mucosa and/or distant metastasis |
| Invasion of the bladder, intestinal mucosa, or both |
| Abdominal peritoneal metastasis beyond the pelvis |
| Distant metastasis, including metastasis to any extra- or intra-abdominal lymph nodes above the renal vessels, lungs, liver, brain, or bone |
Endometrial cancer stage with molecular classification (examples) | |
| Molecular findings in patients with early endometrial cancer (Stages I and II after surgical staging) |
| POLEmut endometrial carcinoma, confined to the uterine corpus or with cervical extension, regardless of the degree of LVSI or histological type |
| p53abn endometrial carcinoma confined to the uterine corpus with any myometrial invasion, with or without cervical invasion, and regardless of the degree of LVSI or histological type |
* In all stages, the grade of the lesion, the histologic type, and LVSI must be recorded. | |
† If available and feasible, molecular classification testing (POLEmut, MMRd, NSMP, p53abn) is encouraged in all patients with endometrial cancer for prognostic risk-group stratification and as factors that might influence adjuvant and systemic treatment decisions. | |
‡ Low-grade endometrioid endometrial carcinomas (EECs) involving both the endometrium and the ovary are considered to have a good prognosis, and no adjuvant treatment is recommended, only if all criteria are met to distinguish disease limited to low-grade endometrioid carcinomas involving the endometrium and ovaries (Stage IA3) from extensive spread of the endometrial carcinoma to the ovary (Stage IIIA1). These criteria are: (1) no more than superficial myometrial invasion is present (< 50%); (2) absence of extensive/substantial LVSI; (3) absence of additional metastases; and (4) the ovarian tumor is unilateral, limited to the ovary, without capsule invasion/rupture. | |
# Non-aggressive histologic types are composed of low-grade (grade 1 and 2) EECs. Aggressive histologic types are composed of high-grade EECs (grade 3), serous, clear cell, undifferentiated, mixed, mesonephric-like, gastrointestinal mucinous type carcinomas, and carcinosarcomas. | |
§ LVSI as defined as extensive/substantial, ≥ 5 vessels involved. | |
¶ Micrometastases are considered to be metastatic involvement (pN1 (mi)). The prognostic significance of isolated tumor cells (ITCs) is unclear. The presence of ITCs should be documented and is regarded as pN0(i+). According to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th ed, macrometastases are > 2 mm in size, micrometastases are 0.2–2 mm and/or > 200 cells, and isolated tumor cells are ≥ 0.2 mm and ≤ 200 cells. | |
Berek JS, Matias-Guiu X, Creutzberg C, et al: FIGO staging of endometrial cancer: 2023. Int J Gynaecol Obstet 2023;162(2):383-394. doi:10.1002/ijgo.14923 | |
When the molecular classification is known:
FIGO Stages I and II are based on surgical/anatomical and histologic findings. For POLEmut or p53abn status, the FIGO stage is modified in the early stage of the disease. This is depicted in the FIGO stage by the addition of “m” for molecular classification, and a subscript is added to denote POLEmut or p53abn status. MMRd or NSMP status do not modify early FIGO stages; however, these molecular classifications should be recorded for the purpose of data collection. When molecular classification reveals MMRd or NSMP, it should be recorded as Stage Im or Stage Im and Stage IIm or Stage IIm.
FIGO Stages III and IV are based on surgical/anatomical findings. The stage category is not modified by molecular classification; however, the molecular classification should be recorded if known, as Stage IIIm or Stage IVm with the appropriate subscript for the purpose of data collection. For example, when molecular classification reveals p53abn, it should be recorded as Stage IIIm or Stage IVm.
Картування сторожових лімфатичних вузлів при раку ендометрія
Sentinel lymph node (SLN) mapping can be considered for the surgical staging of cancer that appears confined to the uterus—stage I (2). In many centers, SLN mapping is currently the standard for cancers with high-risk histology—ie, papillary serous carcinoma, clear cell carcinoma, and carcinosarcoma (3).
The role of SLN mapping in endometrial cancer has been evaluated in several studies. The FIRES trial showed that in patients with clinical stage I endometrial cancer, SLN mapping with indocyanine green (ICG) is highly accurate for the diagnosis of endometrial cancer metastases; it was recommended as a replacement for complete lymphadenectomy (4). SLN mapping is done as for cervical cancer using the same tracers (blue dye, technetium-99 [99Tc] ICG). Sentinel lymph node mapping can be performed via open or minimally invasive surgery, such as robotic-assisted surgery or laparoscopy (5).
Where to inject the tracer in patients with endometrial carcinoma has been controversial. Evidence suggests that in endometrial cancer, cervical injection with ICG results in a higher detection rate than hysteroscopic injection, and anatomic nodal distribution is similar (6). Dye is usually injected into the cervix both superficially (1 to 3 mm) and deep (1 to 2 cm) at 3 and 9 o’clock. With this technique, dye penetrates to the uterine lymphatic trunks (which meet in the parametria) and appears in the broad ligament leading to pelvic and occasionally para-aortic SLNs.
If sentinel lymph nodes are identified bilaterally, no lymphadenectomy is indicated, regardless of tumor characteristics. If one side (or both) has no identified sentinel node, complete lymphadenectomy is necessary on that side. Whether dissection of the para-aortic nodes is necessary is left up to surgeon discretion.
The most common locations of pelvic SLNs are
Medial to the external iliac blood vessels
Ventral to the internal iliac blood vessels
In the superior part of the obturator region
Less common locations are the iliac and/or presacral regions.
A complete pelvic lymphadenectomy should be done when any of the following occur:
Mapping does not detect any SLNs in patients with high-risk tumors.
A hemipelvis cannot be mapped.
There are any suspicious or grossly enlarged nodes, regardless of mapping.
An ongoing phase III randomized trial (ENDO-3) is evaluating SLN biopsy with no retroperitoneal node dissection compared with no nodal dissection in clinical stage 1 FIGO grade 1 to 3 endometrioid, clear cell, serous, or carcinosarcoma (7).
Довідкові матеріали щодо діагностики
1. ACOG (American College of Obstetricians and Gynecologists) Committee Opinion No. 734: The role of transvaginal ultrasonography in evaluating the endometrium of women with postmenopausal bleeding. Obstet Gynecol 131 (5):e124-e129, 2018. doi: 10.1097/AOG.0000000000002631
2. Cusimano MC, Vicus D, Pulman K, et al: Assessment of sentinel lymph node Biopsy vs lymphadenectomy for intermediate- and high-grade endometrial cancer staging. JAMA Surg 156 (2):157–164, 2021. doi: 10.1001/jamasurg.2020.5060
3. Schlappe BA, Weaver AL, McGree ME, et al: Multicenter study comparing oncologic outcomes after lymph node assessment via a sentinel lymph node algorithm versus comprehensive pelvic and paraaortic lymphadenectomy in patients with serous and clear cell endometrial carcinoma. Gynecol Oncol 156 (1):62–69, 2020. doi: 10.1016/j.ygyno.2019.11.002
4. Rossi EC, Kowalski LD, Scalici J, et al: A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): A multicentre, prospective, cohort study. Lancet Oncol 18 (3):384–392, 2017. doi: 10.1016/S1470-2045(17)30068-2
5. Segarra-Vidal B, Dinoi G, Zorrilla-Vaca A, et al: Minimally invasive compared with open hysterectomy in high-risk endometrial cancer. Obstet Gynecol 138 (6):828–837, 2021. doi: 10.1097/AOG.0000000000004606
6. Rossi EC, Jackson A, Ivanova A, Boggess JF: Detection of sentinel nodes for endometrial cancer with robotic assisted fluorescence imaging: cervical versus hysteroscopic injection. Int J Gynecol Cancer 23 (9):1704–1711, 2013. doi: 10.1097/IGC.0b013e3182a616f6
7. Obermair A, Nicklin J, Gebski V, et al: A phase III randomized clinical trial comparing sentinel node biopsy with no retroperitoneal node dissection in apparent early-stage endometrial cancer - ENDO-3: ANZGOG trial 1911/2020. Int J Gynecol Cancer 31(12):1595-1601, 2021. doi:10.1136/ijgc-2021-003029
Treatment of Endometrial Cancer
Total hysterectomy and bilateral salpingo-oophorectomy
Pelvic and para-aortic lymphadenectomy for grade 1 or 2 with deep (> 50%) myometrial invasion, any grade 3, and for all cancers with high-risk histology
Pelvic radiation therapy with or without chemotherapy for stage II or III
Multimodal therapy usually recommended for stage IV
(See also National Comprehensive Cancer Network (NCCN): NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms.)
Endometrial cancer should be removed en bloc, usually by doing a total hysterectomy and bilateral salpingo-oophorectomy. Intraperitoneal tumor fragmentation or morcellation must be avoided.
Surgery can be done by any route (vaginal, open, robotic, laparoscopic). For patients with tumors confined to the uterus, minimally invasive surgery is the preferred approach because its rate of perioperative and postoperative complications is lower, hospital stays are shorter (1), cost is lower, and oncologic outcomes are comparable (2).
Evidence generally supports comparable oncologic outcomes for laparoscopic surgery and laparotomy. In the Gynecologic Oncology Group LAP2 study, women with clinical stage I to IIA uterine cancer were randomly assigned to have laparoscopic surgery or laparotomy in a 2 to 1 ratio. The study did not demonstrate the statistical noninferiority of the laparoscopic approach. However, after a median follow-up time of 59 months, survival rates for both approaches were similar; 5-year overall survival rate was 90% in both groups. Estimated 5-year recurrence rates were also similar (14% versus 12% [3]). The Laparoscopic Approach to Cancer of the Endometrium (LACE) trial was a prospective, international, randomized trial that included 760 patients with stage I endometrioid uterine cancer. They were randomly assigned to have laparoscopic hysterectomy or open hysterectomy. Disease-free survival at 4.5 years (82% versus 81%) and overall survival (mortality: 7.4% versus 6.8%) were similar (4).
In patients with grade 1 or 2 endometrial cancer and < 50% invasion, the probability of lymph node metastasis is < 2% (5). In these patients, treatment is usually total hysterectomy and bilateral salpingo-oophorectomy via laparotomy, laparoscopy, or robotic-assisted surgery. However, for young women with stage IA or IB endometrioid adenocarcinoma, ovarian preservation is usually safe and recommended to preserve ovarian function.
If patients have any of the following, pelvic and para-aortic lymphadenectomy is also done (unless SLN mapping identified bilateral SLNs):
Grade 1 or 2 cancer with deep (> 50%) myometrial invasion
Any grade 3 cancer
All cancers with high-risk histology (papillary serous carcinoma, clear cell carcinoma, carcinosarcoma)
Any suspicious or grossly enlarged nodes, regardless of mapping
If SLNs are identified bilaterally, no lymphadenectomy is indicated, regardless of tumor characteristics. If a sentinel node is not identified on one side, complete lymphadenectomy is necessary on that side.
Stage II or III endometrial cancer requires pelvic radiation therapy with or without chemotherapy. Treatment of stage III cancer must be individualized, but surgery is an option; generally, patients who have combined surgery and radiation therapy have a better prognosis. Except in patients with bulky parametrial disease, a total abdominal hysterectomy and bilateral salpingo-oophorectomy should be done.
Treatment of stage IV endometrial cancer is variable and patient-dependent but typically involves a combination of surgery, radiation therapy, and chemotherapy. Occasionally, endocrine therapy should also be considered.
Treatment of stage IV endometrial cancer is variable and patient-dependent but typically involves a combination of surgery, radiation therapy, and chemotherapy. Occasionally, endocrine therapy should also be considered (6).
Several cytotoxic drugs (particularly carboplatin plus paclitaxel) are effective. They are given mainly to women with metastatic or recurrent cancer. Another option is doxorubicin.
For advanced cancer, chemotherapy with carboplatin and paclitaxel has been the standard. However, recent data support the use of lenvatinib, a multitargeted tyrosine kinase inhibitor of VEGF (vascular endothelial growth factor) receptors, and pembrolizumab, a monoclonal antibody that inhibits programmed cell death-1 (PD-1) activity. A recent phase II trial showed an objective response rate of 39.6% in patients taking this combination (7).
Поширений та рецидивуючий рак
Several studies have shown a benefit for more targeted therapy for recurrent cancer as an alternative to standard chemotherapy (usually carboplatin and paclitaxel). In a phase II trial of patients with recurrent endometrial cancer, the combination of everolimus (an mTOR inhibitor) and letrozole (an aromatase inhibitor) showed a clinical benefit rate of 40% and an objective response rate of 32% (8).
In patients with recurrent uterine papillary serous carcinoma, standard chemotherapy with carboplatin and paclitaxel has been the routine recommendation. However, recent data from a prospective phase II trial suggest that adding trastuzumab provides further benefit. In this trial, patients who had uterine serous carcinoma and who tested positive for human epidermal growth factor receptor 2 (HER2)/neu were randomized to either carboplatin plus paclitaxel (control arm) for 6 cycles or carboplatin plus paclitaxel plus IV trastuzumab (experimental arm). The addition of trastuzumab increased progression-free survival from 8 months to 12.6 months (9).
The combination of chemotherapy and immunotherapy has shown synergistic effects in endometrial cancer treatment. In a phase III global randomized double-blind placebo-controlled trial, dostarlimab plus carboplatin–paclitaxel compared with placebo plus carboplatin–paclitaxel significantly increased progression-free survival (PFS) among patients with advanced (stage III or IV) or recurrent endometrial cancer (PFS at 24 months was 36.1% in the dostarlimab group versus 18.1% in the placebo group; hazard ratio, 0.64) (10). Overall survival (OS) at 24 months was 71.3% with dostarlimab and 56.0% with placebo (hazard ratio for mortality, 0.64). Subgroup analysis showed a substantial benefit in patients with high microsatellite instability/mismatch repair-deficient tumors (PFS at 24 months was 61.4% in the dostarlimab group versus 15.7% in the placebo group; hazard ratio for progression or death, 0.28).
Adding pembrolizumab to chemotherapy appears to provide additional PFS benefit for patients with advanced or recurrent endometrial cancer. A phase III randomized double-blind placebo-controlled trial in patients with stage III-IVB mismatch repair-deficient endometrial cancer treated with chemotherapy (paclitaxel plus carboplatin) with pembrolizumab compared with chemotherapy with placebo found increased PFS in the pembrolizumab group (PFS 74% versus 38%; 13.1 versus 8.7 months; hazard ratio, 0.54) (11).
Збереження фертильності при гіперплазії ендометрія та ранньому раку ендометрія
Patients with complex endometrial hyperplasia and atypia have up to a 50% risk of having concurrent endometrial cancer. Treatment of endometrial hyperplasia consists of progestins or definitive surgery, depending on the complexity of the lesion and the patient’s desire to preserve fertility.
If young patients with grade 1 tumors and no myometrial invasion (documented by MRI) wish to preserve fertility, progestin alone is an option. approximately 46 to 80% of patients have a complete response within 3 months of initiation of therapy. After 3 months, patients should be evaluated via dilation and curettage (D & C) rather than endometrial biopsy.
Alternatively, use of a levonorgestrel-releasing intrauterine device (IUD) is being increasingly used to treat patients with complex atypical hyperplasia or grade 1 endometrial cancer. In a prospective, single-arm trial, the 12-month pathologic response rate was 90.6% for complex atypical hyperplasia and 66.7% for grade 1 endometrioid endometrial cancer. Adverse events were mild, and treatment had no negative effects on quality of life (12).
Surgery is recommended if conservative treatment is not effective (endometrial cancer is still present after 6 to 9 months of treatment) or if patients have completed childbearing. Fertility-sparing treatment is contraindicated in patients with high-grade endometrioid adenocarcinomas, uterine papillary serous carcinoma, clear cell carcinoma, or carcinosarcoma.
In young women with stage IA or IB endometrioid adenocarcinoma, ovarian preservation is safe and recommended.
Гістологія високого ризику
Uterine papillary serous carcinoma, clear cell carcinomas, and carcinosarcomas are considered histologically aggressive, high-risk cancers and are thus more likely to have spread outside the uterus at presentation.
Multimodality therapy is typically recommended for these histologically aggressive endometrial tumors. Primary treatment includes abdominal hysterectomy, bilateral salpingo-oophorectomy with pelvic and para-aortic lymphadenectomy, and omental and peritoneal biopsies.
In patients with gross extrauterine disease, cytoreduction should be done to reduce the bulk of the tumor to no gross residual disease.
Adjuvant therapy for papillary serous and clear cell carcinomas depends on the stage:
Stage IA without myometrial invasion and without residual disease in the hysterectomy specimen: Observation and close follow-up (an acceptable approach)
Other stage IA and IB or stage II cancers: Usually vaginal brachytherapy followed by systemic chemotherapy with carboplatin and paclitaxel
More advanced disease: Standard chemotherapy with carboplatin and paclitaxel
Adjuvant therapy for carcinosarcoma also depends on the stage:
Stage IA without myometrial invasion and without residual disease in the hysterectomy specimen: Observation and close follow-up (an acceptable approach)
All other stages: Usually systemic chemotherapy with ifosfamide plus paclitaxel
Довідкові матеріали щодо лікування
1. Walker JL, Piedmonte MR, Spirtos NM, et al: Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. Clin Oncol 27 (32):5331-5336, 2009. doi: 10.1200/JCO.2009.22.3248
2. Galaal K, Donkers H, Bryant A, Lopes AD: Laparoscopy versus laparotomy for the management of early stage endometrial cancer. Cochrane Database Syst Rev 10 (10):CD006655, 2018. doi: 10.1002/14651858.CD006655.pub3
3. Walker JL, Piedmonte MR, Spirtos NM, et al: Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 Study. J Clin Oncol 30 (7):695–700, 2012. doi: 10.1200/JCO.2011.38.8645
4. Janda M, Gebski V, Davies LC, et al: Effect of total laparoscopic hysterectomy vs total abdominal hysterectomy on disease-free survival among women with stage I endometrial cancer: A randomized clinical trial. JAMA 317 (12):1224-1233, 2017. doi: 10.1001/jama.2017.2068
5. Kumar S, Podratz KC, Bakkum-Gamez JN, et al: Prospective assessment of the prevalence of pelvic, paraaortic and high paraaortic lymph node metastasis in endometrial cancer. Gynecol Oncol 132(1):38-43, 2014. doi:10.1016/j.ygyno.2013.10.002
6. Decruze SB, Green JA: Hormone therapy in advanced and recurrent endometrial cancer: a systematic review. Int J Gynecol Cancer 17(5):964-978, 2007. doi:10.1111/j.1525-1438.2007.00897.x
7. Makker V, Rasco D, Vogelzang NJ, et al: Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: An interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 20 (5):711–718, 2019. doi: 10.1016/S1470-2045(19)30020-8
8. Slomovitz BM, Jiang Y, Yates MS, et al: Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J Clin Oncol 33 (8):930–936, 2015. doi: 10.1200/JCO.2014.58.3401
9. Fader AN, Roque DM, Siegel E, et al: Randomized phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/neu. J Clin Oncol 36 (20):2044–2051, 2018. doi: 10.1200/JCO.2017.76.5966
10. Mirza MR, Chase DM, Slomovitz BM, et al: Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. N Engl J Med 388(23):2145-2158, 2023. doi:10.1056/NEJMoa2216334
11. Eskander RN, Sill MW, Beffa L, et al: Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer. N Engl J Med 388(23):2159-2170, 2023. doi:10.1056/NEJMoa2302312
12. Westin SN, Fellman B, Sun CC, et al: Prospective phase II trial of levonorgestrel intrauterine device: Nonsurgical approach for complex atypical hyperplasia and early-stage endometrial cancer. Am J Obstet Gynecol 224 (2):191.e1-191.e15, 2021. doi: 10.1016/j.ajog.2020.08.032
Prognosis for Endometrial Cancer
Prognosis is worse with higher-grade tumors, more extensive spread, and older patient age.
Average 5-year survival rates for patients with endometrial cancer are (1)
Stage I or II: 70 to 95%
Stage III or IV: 10 to 60%
Overall, 63% of patients are cancer-free ≥ 5 years after treatment.
Довідковий матеріал щодо прогнозу
1. National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program: Cancer Stat Facts: Uterine Cancer. Accessed August 31, 2023
Ключові моменти
Endometrial cancer is one of the most common cancers among women.
Prognosis is better with type I tumors, which are grade 1 or 2 endometrioid adenocarcinomas; they tend to be estrogen-responsive and diagnosed at a younger age.
Recommend endometrial sampling for women with abnormal uterine bleeding, particularly those > 45 years; ultrasound assessment of endometrial thickness is an alternative for average-risk postmenopausal women.
Stage endometrial cancer surgically via laparotomy, laparoscopy, or a robotic-assisted surgery.
Treatment is usually total hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy and sometimes radiation therapy and/or chemotherapy.
Consider sentinel lymph node mapping for cancers that appear to be confined to the uterus.
Consider fertility-sparing treatment for patients with grade 1 endometrioid adenocarcinoma or endometrial complex atypical hyperplasia.
Consider genetic counseling and testing for patients < 50 years and those with a significant family history of endometrial, ovarian, and/or colorectal cancer (Lynch syndrome [hereditary nonpolyposis colorectal cancer]).
Додаткова інформація
The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
National Cancer Institute: Endometrial Cancer Treatment: This web site provides information about endometrial cancer, its classification, staging, and treatment by stage.
