Endometrial cancer

doi:10.1016/S0140-6736(15)00130-0

The Lancet

Volume 387, Issue 10023, 12–18 March 2016, Pages 1094-1108

https://doi.org/10.1016/S0140-6736(15)00130-0 Get rights and content

Summary

Endometrial cancer is the most common gynaecological tumour in developed countries, and its incidence is increasing. The most frequently occurring histological subtype is endometrioid adenocarcinoma. Patients are often diagnosed when the disease is still confined to the uterus. Standard treatment consists of primary hysterectomy and bilateral salpingo-oophorectomy, often using minimally invasive approaches (laparoscopic or robotic). Lymph node surgical strategy is contingent on histological factors (subtype, tumour grade, involvement of lymphovascular space), disease stage (including myometrial invasion), patients' characteristics (age and comorbidities), and national and international guidelines. Adjuvant treatment is tailored according to histology and stage. Various classifications are used to assess the risks of recurrence and to determine optimum postoperative management. 5 year overall survival ranges from 74% to 91% in patients without metastatic disease. Trials are ongoing in patients at high risk of recurrence (including chemotherapy, chemoradiation therapy, and molecular targeted therapies) to assess the modalities that best balance optimisation of survival with the lowest adverse effects on quality of life.

Introduction

Endometrial cancer—a tumour originating in the endometrium—is the most common gynaecological tumour in developed countries, and its prevalence is increasing.¹ As the disease is frequently symptomatic at an early stage, endometrial cancer is often diagnosed at stage I. Historically, standard treatment consisted of hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node dissection followed by adjuvant therapy tailored on the basis of final histology.

Management of endometrial cancer has become more complex during the past 5–10 years for several reasons: changes in histological classification that affect surgical management, adjuvant therapies, and prognosis; changes in the indications and modalities of lymphadenectomy; de-escalation of adjuvant therapy based on data from randomised trials; and discrepancies between the various classifications used to characterise recurrence risk factors.

These modifications have led national scientific societies to review the emerging data and unanswered questions, and to publish specific recommendations for endometrial cancer.2, 3, 4

This Seminar focuses on the epidemiology and the histological and molecular classification of endometrial cancer. We also describe current practice and trials of surgery, adjuvant treatment, and novel targeted therapies.

Section snippets

Epidemiology and risk factors

In 2012, around 320 000 new cases of endometrial cancer were diagnosed worldwide. Endometrial cancer is the fifth most common cancer in women (4·8% of cancers in women), who have a cumulative risk of 1% of developing the disease by age 75 years.¹ It is the 14th cancer in terms of mortality (76 000 deaths); cumulative risk of death by age 75 years is 0·2%.¹ The highest incidences in 2012 are estimated in the USA and Canada (19·1/100 000) and northern (12·9/100 000) and western Europe

Pathogenesis and histological or molecular classifications

In the past 30 years, endometrial cancer has been broadly classified into two subtypes on the basis of histological characteristics, hormone receptor expression, and grade (table 1).²³ The most common subtype is low-grade, endometrioid, diploid, hormone-receptor-positive endometrial cancer, which has a good prognosis. Type II endometrial cancers are described as non-endometrioid, high grade, aneuploid, TP53-mutated, hormone-receptor-negative tumours that are associated with a higher risk of

Clinical presentation and diagnostic assessment

Abnormal uterine bleeding—sometimes associated with vaginal discharge and pyometra—is the most frequent symptom of endometrial cancer and is noted in about 90% of patients (usually during menopause). Patients with advanced disease might have symptoms similar to those of advanced ovarian cancer, such as abdominal or pelvic pain and abdominal distension. Disease can easily be diagnosed on the basis of office-based pipelle sampling or other techniques.34, 35 The histological information provided

Survival

Estimated cumulative risk of endometrial cancer is 0·96%; the corresponding mortality risk is 0·23% and mortality-to-incidence ratio is 0·24—lower than that of breast cancer (0·32), ovarian cancer (0·63), and uterine cervical cancer (0·55).1, 62 Most endometrial cancers (75%) are diagnosed at an early stage (FIGO stages I or II): 5 year overall survival ranges from 74% to 91%;5, 63 for FIGO stage III, 5 year overall survival is 57–66%, and for FIGO stage IV disease is 20–26%.5, 63 5 year

Principles of surgical treatment

Total hysterectomy and removal of both tubes and ovaries is the standard treatment for apparent stage I endometrial cancer and is effective in most cases. Alternatives to primary hysterectomy in women who want to preserve their fertility have been comprehensively reviewed.⁷¹ Hysterectomy and adnexectomy can be done with minimally invasive techniques (laparoscopy or robot-assisted surgery), vaginally, or laparotomically. The safety of laparoscopy has been shown in randomised clinical trials72, 73

Radiotherapy

Around 55% of patients with endometrial cancer have uterine-confined disease with low-risk features, and are treated with surgery only, which is associated with a 95% probability of relapse-free survival at 5 years (appendix).72, 76, 77 Four randomised trials and a Cochrane meta-analysis have assessed the role of external-beam pelvic radiation therapy (EBRT) in stage I endometrial cancer (appendix).55, 56, 98, 99, 100, 101, 102, 103, 104 In a Norwegian trial, 540 patients with clinical stage I

Management of metastatic or recurrent disease

Surgery or other local treatment (radiation therapy in a non-irradiated area) are options in patients with metastatic or recurrent disease—mainly in patients with an isolated centropelvic recurrence or a single metastatic site.¹¹⁵ 5 year overall survival after exenteration for pelvic recurrence ranges from 20% to 40%.115, 116 Results of studies suggest that management of endometrial cancer with peritoneal spread could be similar to that of ovarian cancer, which emphasises the importance of

Targeted therapies

No approved targeted therapies are available for endometrial cancer. The PI3K/AKT/mammalian target of the rapamycin (mTOR) pathway is the most commonly deregulated pathway in endometrial cancer but results of trials with mTOR inhibitors showed response rates of less than 10% (table 5).125, 126, 127, 128, 129, 130, 131, 132 Several hypotheses have been put forward to explain the ineffectiveness of mTOR inhibitors in endometrial cancer: first, a preponderant cytostatic effect; second, limited

Genetic counselling

5–25% of endometrial cancers are related to high-risk germline mutations, which are characterised by early onset of disease—ie, before age 40 years.¹⁴⁶ Genetic testing and counselling should be considered for women with endometrial cancer who are younger than 50 years, and those with a clinically significant family history of endometrial or colorectal cancer.¹⁴⁷

Women with Lynch syndrome or hereditary non-polyposis colon cancer are at increased risk of endometrial, colon, and ovarian cancer

Screening

In the general population, evidence to support screening for endometrial cancer is insufficient. However, women—particularly those who are overweight—should be informed by their family doctor about the risks of endometrial cancer, and encouraged to consult their physician immediately in cases of uterine bleeding or spotting during the perimenopausal period.

No screening strategy has proven efficacy for women with hereditary non-polyposis colon cancer or Lynch syndrome. In view of the frequency

Management of comorbidities

Patients with comorbidities are more likely to be suboptimally managed, particularly in terms of lymph node dissection and adjuvant therapy. In a review of 12 studies,¹⁵⁴ obesity did not seem to affect either progression-free or disease-specific survival. However, Arem and colleagues¹⁵⁵ reported that patients with poorly differentiated endometrial cancer had a specific mortality hazard ratio of 1·39 (95% CI 1·04–1·85) per five-unit increase in BMI, whereas no differences were detected for well

Controversies and outstanding research questions

Recently completed and ongoing trials are focusing on the role of chemotherapy, radiation therapy, or a combination of both in patients with high-risk and advanced endometrial cancer (appendix). In the international PORTEC 3 trial, patients with high-risk endometrial cancer have been randomly assigned to EBRT alone or to a combination of EBRT and chemotherapy. In the GOG-258 trial, adjuvant chemotherapy alone is being compared with chemotherapy combined with radiotherapy (schedule as used in

Search strategy and selection criteria

We searched MEDLINE, Current Contents, and PubMed with the terms “endometrial cancer”, “hysterectomy”, “lymphadenectomy”, “sentinel node”, “chemotherapy”, “radiation therapy”, “targeted therapy”, “fertility sparing management”, “ovarian preservation”, and “molecular classification” for articles published in English between Jan 1, 1990, and Jan 1, 2015. We also reviewed the reference lists of articles identified by this search. We focused our search strategy on systematic reviews, meta-analyses,

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