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Managing endometrial cancer
Cancer of the corpus uteri (uterine cancer) accounted for nearly 7 percent of all female cancers in Singapore between 2011 and 2015 and was the fourth most frequent female cancer among all Singaporeans. The majority of patients are diagnosed with cancer confined to the uterus and have a 5-year survival rate exceeding 90 percent, while the survival rate of stage IV endometrial cancer is approximately 20 percent. This highlights the importance of recognizing and detecting endometrial cancers early in the natural history.
Introduction
The majority of uterine cancers originate from the endometrium, the most common histological subtype being endometrioid adenocarcinoma (73 percent). [Singapore Cancer Registry Report No. 8, https://www.nrdo.gov.sg/docs/librariesprovider3/default-document-library/cancertrends_7312_web128e09a5c9d76bafab5aff000014cdee.pdf?sfvrsn=0, accessed October 10, 2018]
Abnormal uterine bleeding (AUB) is the cardinal symptom of endometrial cancer, seen in up to 90 percent of cases. GPs should be cognisant of endometrial cancer and its precursor lesion, atypical hyperplasia (AH)/endometrial intraepithelial neoplasia (EIN), as differential diagnoses when approaching a patient who first presents with AUB, in particular post-menopausal bleeding.
Early evaluation of AUB by a gynaecologist is important for the early detection and treatment of endometrial cancer.
Diagnosing endometrial cancer
AUB workup involves clinical examination, pelvic ultrasonography, and endometrial biopsy in cases of increased endometrial thickness. The endometrial biopsy can be office-based pipelle sampling or other techniques. When the diagnosis is uncertain or pipelle sampling is infeasible because of cervical stenosis, hysteroscopy, dilatation, and curettage is the next step and remains the gold standard for diagnosis of endometrial cancer.
Sometimes, endometrial cancer is incidentally diagnosed in a hysterectomy specimen in which the operation was performed for a non-oncological purpose. Upon histological diagnosis of endometrial cancer, staging is radiological and, in operable cases, surgical. Magnetic resonance imaging (MRI) of the pelvis and computed tomography (CT) of the chest and abdomen are usually employed for assessment of locoregional extent of disease and distant metastases, respectively.
Less commonly, endometrial cancer may be incidentally diagnosed because of abnormal Pap smear results. Women with atypical glandular cells or endometrial cells (in symptomatic or high-risk women) on cervical cytology require evaluation for endometrial neoplasia by a gynaecologist.
Routine screening for endometrial cancer is not recommended for women with an average or increased risk for endometrial cancer. Women who are overweight/obese should be informed by their GP about the risks of endometrial cancer, and encouraged to consult their physician immediately in case of AUB.
Even for women with Lynch syndrome which predisposes them to develop endometrial cancer, there is no proven screening strategy. Due to the frequency of interval cancers, annual clinical examination and pelvic ultrasound would probably still be ineffective.
Diagnostic challenges
Patients with advanced endometrial cancer may have symptoms similar to those of advanced ovarian cancer, such as abdominal or pelvic pain and abdominal distension. Even patients who present with later stages of endometrial cancer still tend to have an antecedent history of AUB.
Women should be informed about the symptoms of endometrial cancer and strongly encouraged to report any unexpected bleeding to their doctors.
The suspicion of endometrial neoplasia in a woman presenting to the GP with AUB is further based on age and risk factor profile. For instance, any bleeding, regardless of character or volume, even if spotting or staining, in a post-menopausal woman should prompt referral to the gynaecologist for further evaluation. In premenopausal women, AUB which persists, occurs in the setting of obesity and chronic anovulation, or in women at high risk of endometrial cancer (eg, known case of Lynch syndrome) also warrants gynaecological assessment.
Treating endometrial cancer
Treatment planning is guided by disease factors (eg, cancer stage, histology, and grade) and patient factors (eg, patient’s fitness for surgery, co-existing comorbidities, and preferences).
Surgery alone may be curative for women who are at a low risk of cancer relapse. Women with intermediate- or high-risk disease may benefit from adjuvant therapies. Oncological treatments must be individualized for the patient, and best discussed at a multidisciplinary tumour board with clinicoradiological review.
Surgical staging with total hysterectomy and bilateral salpingo-oophorectomy is the mainstay of management of nonmetastatic endometrial cancer. Options for management of retroperitoneal lymph nodes (in the absence of grossly metastatic disease) include no lymphadenectomy, systematic lymphadenectomy only if the risk of lymph node metastasis exceeds a certain threshold, routine sentinel lymph node sampling following lymphatic mapping, or systematic lymphadenectomy in all patients.
Postoperative treatment is stratified according to cancer recurrence risk, which is influenced by stage, tumour grade, histology, and size, presence of lymphovascular space invasion (LVSI) and lower uterine segment involvement, and patient’s age.
Generally speaking, patients with “low-risk” endometrial cancer have excellent prognosis following surgery so no adjuvant treatment is indicated. Those of “intermediate-risk” are candidates for adjuvant radiation therapy (RT). Some oncologists recommend adjuvant chemotherapy for women with “high-intermediate-risk” disease although this is premised on lower level of evidence. Women with “high-risk” disease often receive adjuvant chemotherapy with or without RT to mitigate their high risk of both distant and locoregional relapse.
The extent and dose of RT corresponds to the risk of cancer relapse. Adjuvant chemotherapy for endometrial cancer is typically platinum-based in combination with either paclitaxel or doxorubicin.
Prognosis is poor for patients with stage IV or relapsed endometrial cancer. There may be a role in selected stage IV cases for debulking surgery or palliative RT if not operable. Otherwise, the role of systemic therapy in inoperable recurrent/metastatic endometrial cancer remains palliative; treatment choice depends on hormone receptor status, tumour grade, prior agents used, and, in some cases, disease-free interval. Hormone therapy is the preferred front-line systemic therapy for patients with hormone receptor positive, grade 1–2 tumours without rapidly progressive disease. While platinum-containing doublets are widely accepted as first-line regimens for metastatic or relapsed endometrial cancer, there are no standard second-line therapies. Responses to each successive treatment line are generally poor and short-lived.
Presently, no approved targeted therapies are available for endometrial cancer. In the MITO END-2 trial, the addition of bevacizumab to carboplatin-paclitaxel chemotherapy backbone to treat stage III–IV or recurrent endometrial cancer after receipt of 0–1 prior lines of chemotherapy was associated with an improvement in progression-free survival (PFS) of 13 vs 8.7 months. [J Clin Oncol 2015;33(May 2015):5502] Another trial comparing letrozole plus everolimus (experimental arm) with alternating medroxyprogesterone acetate plus tamoxifen (control arm) as first- or second-line treatment for advanced, recurrent, or persistent endometrial cancer demonstrated an objective response rate (ORR) in the intent-to-treat population of 24 percent vs 22 percent. [Annual Meeting of Society of Gynecologic Oncology 2018, Opening Scientific Plenary I]
Treatment challenges
It has been 12 years since the Cancer Genome Atlas (TCGA) Research Network contributed to our understanding of the molecular landscape of endometrial cancer, introducing four molecular subtypes, namely: (1) POLE (ultra-mutated) tumours, (2) microsatellite unstable tumours, (3) copy-number high tumours with mostly TP53 mutations, and (4) remaining group without these alterations. [Mod Pathol 2006;19:1091-1100] Risk stratification of adjuvant treatment has not yet incorporated the use of molecular biomarkers but trials are ongoing to investigate the role of an integrated clinicopathological and molecular risk profile.
The outlook of recurrent/metastatic endometrial cancer is dismal. As the role of adjuvant chemotherapy for endometrial cancer has expanded, options for advanced disease have shifted or even narrowed in the event of relapse. Common single agents used today based on ORR in the order of 20–30 percent include platinums, taxanes, anthracyclines, ifosfamide, and topotecan, with PFS ranging from 5 to 12 months. Antiangiogenic drugs, such as bevacizumab and sunitinib, as monotherapy have resulted in ORRs of 12–15 percent. [J Clin Oncol 2011;29:2259-2265; Gynecol Oncol 2014;134:274-280] Research has focused on elucidating the molecular underpinnings of endometrial cancer and discovering potential targeted agents. There are also several active and planned trials of immunotherapy as monotherapy or combined therapy in recurrent/metastatic endometrial cancer.
It is hoped that rationally designed clinical trials can help answer unanswered questions and improve outcomes in endometrial cancer.
Side effect management
Patients with endometrial cancer may present with infective complications while on chemotherapy. Most times, these patients are not neutropenic from their chemotherapy, unless heavily pretreated, and can be managed in the community if clinically stable.
Acute gastrointestinal side effects of external beam RT include nausea, vomiting, and diarrhoea which can be managed symptomatically. Acute RT-related cystitis can manifest as irritative voiding symptoms (dysuria, frequency, urgency, and nocturia) and bladder spasms. These symptoms typically resolve shortly post-RT. If a patient previously treated for endometrial cancer with RT presents to the GP for gross haematuria, she should be referred back to the radiation oncologist and/or the urologist for evaluation and treatment.
A possible side effect of taxane/platinum chemotherapy is peripheral neuropathy, which can occasionally be severe and/or long-lasting even after treatment cessation and may impair patients’ function and mobility. Oncologists can work with rehabilitation medicine physicians to help ameliorate such neuropathy.
Conclusion
GPs should refer patients presenting with AUB early to a gynaecologist for evaluation, to exclude uterine malignancy. As there is no approved targeted or anti-angiogenic agent to treat endometrial cancer, oncologists should consider referral for clinical trial participation after failure of standard first-line treatment for recurrent/metastatic disease.
Online resources
Singapore Cancer Network (SCAN) guidelines for the systemic therapy of endometrial (uterine) cancer [Ann Acad Med Singapore 2015;44:434-439]
Management of endometrial cancer in Asia [Lancet Oncol 2009;10:1119-1127]
US National Comprehensive Cancer Network
https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf
European Society for Medical Oncology (ESMO), European Society for Radiotherapy & Oncology (ESTRO), and European Society of Gynaecological Oncology (ESGO)
Royal College of Obstetricians and Gynaecologists
Society of Gynecologic Oncology