Description of the condition

Endometrial cancer encompasses a group of tumours affecting the lining of the womb (or uterus), known as the endometrium. Worldwide it is the seventh most common cancer in women (Ferlay 2004).

Endometrial cancer occurs predominately in postmenopausal women (91% of cases in women over 50 years old (Parkin 2005)). Global incidences vary due to differences in risk factors, a higher risk being associated with a 'western' lifestyle; the age‐standardised incidence is 13.6 per 100,000 women per year in more developed countries, compared with 3.0 per 100,000 per year in less developed countries (Ferlay 2004). One of the main risk factors for endometrial cancer is unopposed oestrogen. This may come from outside the body (exogenous), such as oestrogen‐only hormone replacement therapy (HRT), or be produced within the body (endogenous), as with polycystic ovarian syndrome or an oestrogen‐producing tumour. Adipose tissue is an important source of endogenous oestrogen in postmenopausal women, and obesity is associated with an increased risk of endometrial cancer (Calle 2003; Quinn 2001 ).

Most women will present to their physician with symptoms of abnormal vaginal bleeding. This is typically post‐menopausal bleeding due to the ages of highest prevalence, although younger women may present with intermenstrual bleeding, menorrhagia or a change in bleeding pattern; current guidelines form the Royal College of Obstetricians and Gynaecologists recommend endometrial sampling in all women over 40 years old with abnormal vaginal bleeding. Less common symptoms are those of low pelvic pain or vaginal discharge. Most women (75 to 80%) with post‐menopausal bleeding present with early disease (International Federation of Gynaecology and Obstetrics (FIGO) stage I), where the disease is confined to the womb (Shepherd 1989 ‐Table 1), (Jemal 2008 ‐ Figure 1). FIGO staging describes how far the cancer has spread, giving information about the chance of curing the cancer and what treatments are recommended.

Figure 1

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Distribution of stage of endometrial cancer at presentation, USA 1996‐2003 (all races). Adapted from Jemal 2008.

Most endometrial cancers are endometrioid adenocarcinomas. Other histological types tend to have a poorer prognosis, since they are more aggressive (high grade = G3) and present at a more advanced FIGO stage. These include adenosquamous, clear cell and papillary serous carcinomas.

Endometrial cancer spreads directly into surrounding tissues, most commonly into the muscle of the womb, (myometrium) and into the neck of the womb (cervix). Disease spread also occurs via lymphatic vessels. Lymph is tissue fluid which drains from tissues via small lymphatic vessels to lymph nodes (or glands), which contain cells of the immune system. The lymph nodes filter and monitor lymph for signs of infection or inflammation and also trap particles, including cancer cells within them. Lymphatic drainage of the womb is primarily via the pelvic lymph nodes, which surround the external and common iliac vessels (the major blood vessels which drain blood from the lower limbs and pelvis), and then on to the para‐aortic lymph nodes. Results of histopathological studies demonstrated spread to pelvic and para‐aortic lymph nodes in up to 10% of cases of early stage disease (Creasman 1987). Metastasis to more distant organs is via the blood stream (haematological spread).

Description of the intervention

Standard treatment for endometrial cancer is the surgical removal of the womb, tubes and ovaries: a total hysterectomy and bilateral salpingo‐oophorectomy (BSO) and washings. This may be performed via an incision in the abdomen (laparotomy) or by a laparoscopic approach (key‐hole surgery). For patients with a more advanced FIGO stage, adjuvant radiotherapy (and increasingly chemotherapy) is administered to treat extra‐uterine spread, including spread to the lymphatic system and blood vessels (lymphovascular space involvement)

In early stage disease (FIGO 1B, or IC without G3 disease or without evidence of invasion into lymphatic or blood vessels in the womb ‐ for FIGO staging see Table 1), RCTs have demonstrated that adjuvant radiotherapy does not improve overall survival, although it does reduce the number of pelvic recurrences (Kong 2007; Kong 2007a). The reason that reducing the number of pelvic recurrences does not affect survival rates is because pelvic recurrences can usually be successfully treated with radiotherapy in patients who have not previously received any pelvic radiotherapy.

Lymphadenectomy is the removal of lymph nodes. This can be the clearance of all lymph nodes from an anatomical area, or sampling of a few lymph nodes from an area. Lymphadenectomy can be used for the treatment of cancers which spread to the lymph nodes draining the site of the cancer, e.g. in breast surgery. Lymphadenectomy often refers to the systematic removal of all lymph nodes within a defined area, as opposed to lymph node sampling, which refers either to removal of a few representative lymph nodes, or removal of suspiciously enlarged nodes.

How the intervention might work

Knowledge of cancer spread gives prognostic information and guides the need for adjuvant treatment, in the form of radiotherapy, or possibly chemotherapy. There is also the possibility that lymphadenectomy is directly therapeutic; surgery removes involved lymph nodes, which may be the source of pelvic recurrences. However, lymph node involvement is rare if the tumour is of low grade (G1) or confined to the inner half of the myometrium. Hence, surgical staging involving a lymphadenectomy may only be recommended to women who are more at risk of pelvic lymph node involvement: i.e. those with higher grade tumours (G2 or G3, identified by biopsy) or those with evidence of spread to the outer half of the myometrium on pre‐operative imaging (Kim 1993).

Nevertheless, lymphadenectomy is not without serious short‐ and long‐term morbidity. Many women with endometrial cancer are elderly or obese, with serious co‐morbidities, and the prolonged operative time required to perform a full lymphadenectomy may increase the risks of surgery and anaesthesia. Complications from lymphadenectomy include: damage to blood vessels during the operation; development of a blood clot in the veins of the legs or the lungs (deep vein thrombosis or pulmonary embolus) in the post operative period; lymphoedema (swelling of the legs due to poor lymphatic drainage) and/or pelvic lymphocyst formation (collections of lymphatic fluid). These complications can be severe and disabling, and lymphoedema and lymphocyst formation may be under‐reported or under‐recognised in studies.

Why it is important to do this review

There is ongoing debate regarding lymphadenectomy for the treatment of endometrial cancer. The extent of disease, as assessed by pre‐operative imaging (such as MRI) and the grade of tumour (as identified through biopsies), may influence the decision to undertake lymphadenectomy or not. Lymphadenectomy may not routinely be performed and if it is, the extent of lymphadenectomy can range from taking a few lymph nodes for sampling to complete dissection of pelvic and para‐aortic lymphatic tissue (pelvic and para‐aortic lymphadenectomy) depending on the experience, training and opinion of the surgeon.

Evidence from one retrospective non‐randomised study suggested that patients with multiple site lymph node sampling may have increased survival compared to those who did not have lymph node sampling (Kilgore 1995). In this retrospective review of 649 patients with endometrial cancer, women who had multiple site lymph node sampling had an improved 5 year survival (extrapolated from survival curves) compared to women who had no pelvic node sampling (5‐year survival ˜90% versus ˜75%; P= 0.002). Furthermore, one study found that patients who undergo extensive lymph node sampling may have an increased survival as compared with those who have fewer lymph nodes removed (Chan 2006).  This retrospective analysis of 12,333 patients with endometrioid endometrial cancer demonstrated that patients with high risk disease (stage IB, grade 3  or greater) appeared to have improved 5 year survival rates following extensive lymph node removal (75.3% with one node removed versus 86.8% with ≧20 nodes removed; P= 0.001) However, lymphadenectomy, similar to pelvic radiotherapy (Kong 2007), may not be beneficial, since most women with endometrial cancer present at an early stage, and are therefore unlikely to have lymph node involvement. Therefore the additional surgery would make no difference to their chance of cure, or need for further treatment, and would benefit only a small minority of women, to the detriment of the majority, who would be cured by hysterectomy and BSO alone. A previous systematic review found that a survival advantage had not yet been demonstrated by an RCT, although lymph node status gave prognostic information and reduced the need for adjuvant radiotherapy in women found to have negative lymph nodes (Look 2004). A large, population‐based, study of 9185 women with stage I and 881 women with stage II endometrial cancer compared outcomes stratified by whether lymph node sampling had been performed (Trimble 1998). Overall there was no significant difference in 5‐year survival for women with either stage I and II disease for women who did or did not undergo lymph node sampling. In contrast, a recent retrospective study of 63 women with stage III endometrial cancer did demonstrate an improvement in disease‐related survival for women who had para‐aortic lymphadenectomy performed in addition to pelvic lymphadenectomy (Fujimoto 2007).

As these data demonstrate, there is scientific and clinical controversy about the role of lymphadenectomy in endometrial cancer. It is a procedure that carries significant long‐term morbidity for a large minority of patients and should therefore only be performed if there is good evidence from RCTs, demonstrating improvements in survival and QOL, to support its role.

This review will address the value of removing the lymph nodes to which the endometrial cancer cells may spread. This will include routine removal of all of the pelvic lymph nodes (pelvic lymphadenectomy) and also the effect of routinely removing para‐aortic lymph nodes. The review will also assess the value of removing clinically suspicious (enlarged) lymph nodes.