Introduction

Worldwide, approximately 200,000 women are diagnosed with endometrial cancer each year (Ferlay et al 2004). Of these, more than two-thirds arise in developed countries where age-standardized incidence is four times higher than in developing countries (Ferlay et al 2007). Endometrial cancer is now the most common gynaecological malignancy in Western Europe and North America, with an annual incidence of 81,500 women in the European Union and 40,100 women in North America. In the UK, the incidence of endometrial cancer increased by 29.3% between 1993 and 2005, with an incidence of 6891 women in 2005 (Office for National Statistics 2008). This increase is attributable to an increase in obesity, tamoxifen use for breast cancer and increased life expectancy (Reich 1992, Kitchener 2008). Given the anticipated increase in obesity, it is likely that this trend will continue.

Endometrial cancer has traditionally been believed to have a relatively good outcome. Whilst commonly believed to be a curable cancer in contrast to other gynaecological malignancies, the overall 5-year survival rate is disappointing considering that 75% of patients present with early (stage I) disease. Relative survival at both 1 and 5 years after diagnosis has risen steadily from 85% and 72%, respectively, in the late 1980s to 88% and 76% in the late 1990s (Cooper et al 2008). However, there is a significant gap in survival between the most affluent and the most deprived groups of approximately 4% based on data from England and Wales, with survival lagging 2–6% behind Europe (Sant et al 2003, Cooper et al 2008). This deprivation gap may be best explained by comorbidities such as obesity, hypertension and cardiovascular disease, which are more common in deprived communities (Kitchener 2008). In addition, survival in advanced-stage endometrial cancer and poor prognostic types of endometrial cancer continues to be poor.

With the implementation of improving outcomes guidance in endometrial cancer, women with higher grade and poor prognostic types of endometrial cancer should be managed in gynaecological oncology centres, thus centralizing resources and experience, and facilitating trials that investigate new therapies for these patients (Department of Health 1999).

Epidemiology

Most studies focus on the epidemiology of endometrioid cancers, as the epidemiology for non-endometrioid histotypes is less clear (Box 42.1).

Obesity

Body mass index (BMI) plays an important role with a strong linear increase in risk with increasing BMI. There is a six-fold increase in women with a BMI greater than 40 kg/m² compared with those with a normal BMI (20–24 kg/m²), whereas women with a BMI under 20 kg/m² have half the risk (Lindemann et al 2008). The fact that obesity increases risk has been attributed to changes in concentrations of endogenous hormones in obese women. Oestrogens produced in adipose tissue have a direct mitogenic effect on endometrial cells. In postmenopausal women, oestrogens derived from peripheral adipose tissue are the primary source of endogenous oestrogen, and the rate of production is related to the size of the adipose depots. In younger premenopausal women, obesity can also be associated with anovulatory cycles, resulting in the absence of counterbalancing progesterone. Oligo- and amenorrhoeic women with polycystic ovary syndrome can develop endometrial hyperplasia and later carcinoma. There is a weight-related increase in insulin and insulin-like growth factor-I, both of which are endometrial growth factors. Cytokines produced in fat tissue (leptin and adiponectin) may play a direct role in endometrial carcinogenesis, as well as transcription factors that can modulate both cellular lipid metabolism and tumorigenesis. There is also a strongly increased risk of endometrial cancer in diabetics, possibly because of shared underlying mechanisms.

Tamoxifen

Tamoxifen improves the survival of postmenopausal women with hormone-receptor-positive breast cancer. Breast and endometrial cancer share several risk factors including age of menopause, unopposed oestrogen use and obesity, and breast cancer patients have an increased rate of endometrial cancer regardless of endocrine therapy. The risk of endometrial cancer rises with both the use of higher doses and increasing duration of tamoxifen use. Treatment beyond 5 years increases the risk at least four fold. However, the absolute risk of endometrial cancer is still very small in tamoxifen-treated women (Early Breast Cancer Trialists’ Collaborative Group 1998). The use of aromatase inhibitors for postoperative adjuvant therapy instead of tamoxifen significantly reduces the risk of adverse gynaecological events (Duffy et al 2009). Switching from tamoxifen to an aromatase inhibitor may reduce the risk of endometrial cancer, but needs to be balanced against the side-effects and costs of therapy.

Hereditary non-polyposis colorectal cancer

Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common cancer family syndromes. The estimated lifetime risk of developing endometrial cancer in women carrying these mutations is approximately 42–60%. HNPCC results from germline mutations in DNA mismatch repair genes and is autosomal dominant in inheritance (Froggatt et al 1996). As well as an increased risk of malignancies in the colon, cancers of the endometrium, ovary, biliary tract, stomach, small intestine and renal tract occur more commonly in these women (Box 42.2). Endometrial cancer is the most common and usually occurs in the premenopausal period. The majority of mismatch repair gene defects involve the genes MSH2 and MLH1, with defects in PMS1 and PMS2 being less common (Papadopoulos and Lindblom 1997). A good family history will help to identify women who may carry these mutations. If such a mutation is found or if the woman is thought to be at high risk, there may be a role for prophylactic hysterectomy and bilateral salpingo-oophorectomy. Screening may be offered to those who do not wish to have surgery but with the caveat that there is no evidence that it is effective. There may also be a role for prophylactic progesterone in these women, and studies are currently investigating the role of the Mirena™ intrauterine system for prophylaxis.

Hormones

The combined oral contraceptive pill has a large protective effect that lasts for at least 20 years after cessation. Older hormone replacement therapy (HRT) regimens that utilized unopposed oestrogen in women with an intact uterus increase the relative risk of endometrial carcinoma approximately six fold after 5 years of use (Weiderpass et al 1999). It is strongly recommended that women with intact uteri should not be started on regimes containing oestrogen alone, and should be offered endometrial protection by regimes with either 10–12 days of cyclical progestogens or continuous combined regimens (Lethaby et al 2004).

Pathology

There is a growing consensus that endometrial cancers can be classified into two types based on clinical and molecular characteristics. Type I endometrial cancers (80%) are oestrogen dependent, usually arise in a background of endometrial hyperplasia, have well to moderately differentiated endometrioid histology, tend to be biologically indolent and have a good prognosis (Bokhman 1983). Type II cancers are not oestrogen driven, have a higher grade, occur in a background of atrophic endometrium and have a poorer prognosis (Bokhman 1983). Uterine papillary serous carcinomas and clear cell carcinomas are considered to be type II endometrial cancers. These cancers, and uterine serous papillary cancer in particular, are characterized by early metastasis, resistance to therapy and a high mortality rate. Within the type II cancer histological subtypes, Creasman et al (2004) found 5-year survival of 81% for surgically staged stage I clear cell cancer and 72% for uterine papillary serous cancer. This is in comparison with over 95% for well to moderately differentiated stage IA endometrioid cancers. Although unusual cancers only account for 10% of endometrial cancers, they account for more than 50% of recurrences and deaths (Acharya et al 2005).

The morphological and clinical differences are paralleled by genetic distinctions (Hecht and Mutter 2006). Type I cancers are associated with mutations in the K-ras2 oncogene, loss of the PTEN tumour suppressor gene, defects in DNA mismatch repair and near-diploid karyotype, whereas type II cancers are associated with mutations in TP 53 and ERBB-2 expression, and most are non-diploid. A dualistic model of endometrial tumorigenesis has been proposed which could explain the very different clinical outcomes in these groups of patients (Table 42.1, Figure 42.1). An understanding of the molecular heterogeneity of various histological types of endometrial cancer has the potential to lead to better individualization of treatment in the future (Maxwell et al 2005).

Table 42.1 Clinicopathological characteristics and genetic abnormalities in type I and type II endometrial carcinomas

Source: From Doll A, Abal M, Rigau M, Monge M, Gonzalez M, Demajo S, et al. Novel molecular profiles of endometrial cancer-new light through old windows. J Steroid Biochem Mol Biol 2008;108(3–5):221–9.

Figure 42.1 A dualistic model of endometrial tumorigenesis. EEC, oestrogen-dependent endometrial cancer; NEEC, non-oestrogen-dependent endometrial cancer; ER, oestrogen receptor; PR, progesterone receptor.

Source: Doll A, Abal M, Rigau M et al 2008 Journal of Steroid Biochemistry and Molecular Biology 108: 221–229.

Malignancy may develop in either the glands or the stroma of the endometrium. Endometrial adenocarcinoma, derived from the endometrial glandular cells, is overwhelmingly the most common malignant tumour arising in the body of the uterus; the stroma is the origin of the much less common endometrial stromal sarcoma. Carcinosarcoma or malignant mixed Müllerian tumour comprises both glandular and stromal elements; however, carcinosarcomas are monoclonal and epithelial in origin, contrary to popular belief.

Histopathology

Endometrial carcinoma is usually seen as a raised, rough, perhaps papillary area occupying at least half of the endometrium. It often arises in the fundal region of the uterus; the internal os is rarely involved early in the disease (Figure 42.2). Myometrial invasion may be obvious to the naked eye. There seems to be no correlation between the degree of exophytic growth of the tumour within the uterine cavity and the presence of myometrial invasion.

Figure 42.2 Macroscopic pathology of endometrial cancer.

There are several different histological subtypes of endometrial carcinoma (Table 42.2).

Table 42.2 Classification of endometrial carcinomas

Endometrioid (usual) carcinoma (includes glandular and villoglandular patterns)

Secretory

Ciliated cell

With squamous differentiation (includes adenoacanthoma and adenosquamous carcinoma)

Special variant carcinomas

Papillary serous adenocarcinoma

Clear cell carcinoma

Mucinous carcinoma

Pure squamous cell carcinoma

Mixed

Undifferentiated

Carcinosarcoma

Microscopically, approximately 80% of malignant endometrial epithelial tumours are conventional adenocarcinomas which can be graded into well (grade 1, 50%), moderately (grade 2, 35%) and poorly differentiated (grade 3, 15%). The International Confederation of Gynecology and Obstetrics (FIGO) grading takes into account the relative proportion of glandular and solid areas, as well as nuclear atypia. Approximately one-quarter of well-differentiated tumours have a papillary or villoglandular component. Such tumours need to be distinguished from serous papillary adenocarcinomas, which also show a papillary pattern but belong to the non-endometrioid, poorly differentiated type. Numerous morphological forms of endometrial adenocarcinomas exist, but while adenoacanthoma, adenosquamous carcinoma, secretory carcinoma and ciliated carcinoma are variants of ordinary endometrioid adenocarcinoma, papillary serous carcinoma, clear cell carcinoma and mucinous carcinoma are considered to be non-endometrioid.

Endometrioid adenocarcinoma

The most common endometrial carcinoma is referred to as endometrioid adenocarcinoma, the glandular pattern of which generally resembles that of normal proliferative-phase endometrium, although sometimes showing extreme complexity of the glands and cribriform pattern (Figure 42.3). Multilayering of the epithelial cells is nearly always seen. The secretory and ciliated cell variants are rare and well differentiated by definition. Secretory adenocarcinoma is a well-differentiated adenocarcinoma characterized by neoplastic glands with a subnuclear vacuolization resembling normal 17-day secretory endometrium. Mucinous adenocarcinoma is a low-grade neoplasm in which most of the cells contain prominent intracytoplasmic mucin, and should be distinguished from otherwise typical endometrioid carcinomas with abundant extracellular mucin but no intracellular mucin.

Figure 42.3 A well-differentiated (grade 1) endometrial carcinoma of endometrioid pattern. Haematoxylin and eosin ×170.

Endometrial adenocarcinoma with squamous metaplasia (adenoacanthoma)

Up to 25% of endometrioid-pattern endometrial adenocarcinomas contain areas of squamous metaplasia. Those tumours in which the squamous component is morphologically benign are commonly termed ‘adenoacanthomas’. The squamous change is seen as islands of typical squamous epithelium, very often situated within the gland lumina or as surface or diffuse squamous metaplasia (Figure 42.4).

Figure 42.4 Adenocarcinoma with benign squamous metaplasia (adenoacanthoma). Haematoxylin and eosin ×195.

Papillary serous and clear cell adenocarcinomas

These are less common histological subtypes, both associated with a poor prognosis. Clear cell carcinoma is composed of large, clear cells containing glycogen, often forming papillary structures lined by ‘hobnail’ cells (Figure 42.5). Papillary serous carcinoma closely resembles ovarian papillary serous carcinoma, featuring severe atypia, a complex papillary pattern, high mitotic index, prominent myometrial invasion and psammoma bodies (Figure 42.6). Most patients are postmenopausal.

Figure 42.5 Clear cell endometrial carcinoma with (A) acinar pattern and (B) papillary pattern.

Figure 42.6 Uterine papillary serous carcinoma.

Histopathological reporting

It is essential not only to recognize specific subtypes and to grade carcinomas accurately, but also to record the extent of myometrial invasion. The maximum depth of myometrial invasion, overall thickness of the myometrium, and minimum distance of the tumour from the serosal surface should be recorded. The presence of lymphovascular invasion should be noted. The cervical stroma, fallopian tubes and ovaries should all be examined carefully for tumour. Histopathological examination of the omentum would be valuable in uterine papillary serous carcinoma and clear cell carcinoma. The number of lymph nodes removed, the number of lymph nodes positive for malignancy, extracapsular spread and the extent of lymphatic spread (e.g. node replaced with malignancy or not) should also be reported. There is no convincing evidence for routine ultrastaging or special immunohistochemical analysis of surgically removed lymph nodes (Figure 42.7).

Figure 42.7 Lymph node involvement in clinical stage I endometrial carcinoma

Source: Ayhan et al 1994 Surgical pathological spread patterns of endometrial cancer: A Gynecologic Oncology Group Study. Cancer 60: 2035–2041.

The national minimum dataset published by the Royal College of Pathologists provides a useful tool for both gynaecologists and histopathologists. Serous carcinoma, clear cell carcinoma, and squamous and undifferentiated carcinoma are not graded, these tumours being highly malignant neoplasia. Sarcomas are also highly malignant neoplasms (Figures 42.8–42.11). The architectural grade, nuclear grade and FIGO grade of tumours can be used to separate patients into groups with significantly different rates of progression of disease and relative survival.

Figure 42.8 A low-grade endometrial stromal sarcoma with prominent lymphatic channel involvement. Haematoxylin and eosin ×64.

Figure 42.9 A high-grade endometrial stromal sarcoma. Nuclear crowding and pleomorphism are apparent and although mitotic figures (arrowed) are not conspicuous, this tumour contains more than 10 mitotic figures per 10 high-power fields. Haematoxylin and eosin ×650.

Figure 42.10 Malignant mixed Müllerian tumour. Malignant papillary epithelium and malignant cartilage are both present in this illustration. Haematoxylin and eosin ×195.

Figure 42.11 Leiomyosarcoma. Although a few cells are spindled, most are poorly differentiated and show marked nuclear pleomorphism. Haematoxylin and eosin ×720.

Spread of Disease

Endometrial carcinoma spreads by invading the myometrium. In some cases, it extends over the endometrial surface before penetrating the muscle layer. The more deeply it invades, the greater the likelihood of lymphatic or, less commonly, vascular involvement. Usually, initial lymphatic spread occurs to the external iliac, internal iliac and obturator group of lymph nodes. Further involvement of common iliac lymph nodes and para-aortic nodes can also occur. In approximately 5% of cases, para-aortic lymph nodes are involved without obvious histological involvement of the pelvic lymph nodes. Lymphatic spread may rarely include the supraclavicular or the inguinal nodes. Spread to the cervix may occur by extension along the surface (implants). This does not affect the prognosis, unlike infiltration of the cervical stroma. This is difficult to assess clinically (see below). Direct infiltration into the parametria is uncommon except when the cervix is involved.

In women with metastatic disease, spread to the ovaries is common. In 5% of cases (Gynecologic Oncology Group 2001), a synchronous primary ovarian cancer is noted. Transperitoneal spread occurs either when myometrial invasion reaches the serosal surface or via the fallopian tubes. This will involve the peritoneal surfaces and omentum in the same way as ovarian carcinoma. Clear cell and papillary serous carcinomas have a propensity to spread in this way, often without deep myometrial invasion.

The current FIGO staging criteria are shown in Box 42.3.

FIGO Staging

The FIGO surgical staging system is based on histopathological findings including myometrial invasion, and is important in determining prognosis and treatment post hysterectomy. This staging system is based on findings in the uterus. As deep myometrial invasion or serosal involvement cannot always be visualized grossly, it is imperative that the pathologist samples the uterine corpus and cervix adequately for microscopic examination. Indicators of poor prognosis include high histological grade, deep myometrial invasion, unfavourable histological subtypes, lower uterine segment involvement by tumour, and myometrial vascular space invasion. The presence or absence of endometrial hyperplasia should be included in the report as aggressive carcinoma types are not associated with hyperplasia.

Depth of myometrial penetration is a more important guide to the likelihood of nodal metastases than tumour grade (Table 42.3; Creasman et al 1987). Serous papillary and clear cell cancers have the highest risk of spread to para-aortic nodes. Only 10% of cases subsequently proven to have nodal spread had clinically enlarged nodes but, on the other hand, enlarged lymph nodes are not necessarily involved with metastatic disease. Serous papillary carcinoma of the endometrium, histologically similar to serous papillary cancer of the ovary, has a very poor prognosis and a pattern of spread akin to ovarian malignancy.

Positive peritoneal washings are present in approximately 12–15% of all cases of endometrial cancer, with half of these having no histological evidence of extrauterine spread. The Gynaecological Cancer Intergroup have proposed changes to the FIGO staging which have been incorporated into the revised FIGO staging for endometrial cancer (Box 42.3). They recommend that the grading of tumours is added to stage I tumours as this carries a direct clinical relevance. They also recommend removing the upgrading to stage IIIC on the basis of positive peritoneal washings, as these are very likely due to handling at the time of surgery and do not have independent prognostic significance; and that metastasis to positive inguinal lymph nodes is considered stage IIIC rather than stage IV. Although not part of FIGO staging, some centres perform a serum CA125 in women with endometrial cancer as reports suggest that an elevated serum CA125 at diagnosis indicates a high risk of subsequent recurrence but is less effective at predicting myometrial invasion than ultrasound.

Diagnosis of Endometrial Cancer

Investigations and Diagnosis of Endometrial Cancer

Patients with suspicious symptoms should initially be investigated with a transvaginal ultrasound to investigate the endometrial cavity. Transvaginal ultrasound is useful in the investigation of women with postmenopausal bleeding because it helps to identify those at higher risk of endometrial cancer who require further investigation, and is also an effective means of excluding endometrial cancer. Transvaginal ultrasound measurement of endometrial thickness of less than 5 mm can be a good diagnostic index (Scottish Intercollegiate Guidelines Network 2002). The pooled sensitivity and specificity of endovaginal ultrasound in the detection of endometrial cancer if a cut-off of 5 mm was used were 96% [95% confidence interval (CI) 94–98%] and 61% (95% CI 59–63%), respectively. Sensitivity decreased and specificity increased with increasing thresholds. Thin (<5 mm) endometrial measurement on endovaginal ultrasound can exclude endometrial disease in the majority of postmenopausal women with vaginal bleeding, regardless of hormone replacement use (Smith-Bindman et al 1998).

The mean endometrial thickness in women on sequential HRT with postmenopausal bleeding is greater than that in women with postmenopausal bleeding who are not on sequential HRT. Thus, an abnormal endometrial thickness in women with postmenopausal bleeding who are not using sequential HRT represents a greater probability of endometrial disease than in women taking HRT (Gupta et al 2002). Women presenting with postmenopausal bleeding and taking tamoxifen have a higher probability of malignancy (substantially >10%). In these cases, the ultrasound image is more difficult to interpret. Therefore, it is advisable to sample the endometrium initially and examine the cavity hysteroscopically.

Screening for Endometrial Cancer

As most patients with endometrial carcinomas present early, it is unlikely, based on current technology, that a population screening programme would be of any value. Routine screening in asymptomatic women for endometrial carcinomas is currently not justified. Women at risk, including those on tamoxifen and families with hereditary non-polyposis colon cancer, have a higher risk of endometrial cancer and should report any bleeding or spotting. Ultrasound screening is not recommended for women on tamoxifen. Whilst a Pap smear is not a screening test for endometrial cancer, the incidental finding of endometrial cells on a Pap smear in a postmenopausal woman requires investigation.

Preoperative Evaluation

A transvaginal ultrasound report should also include an assessment of ovarian morphology as synchronous primary ovarian cancers, oestrogen-producing tumours or endometrial cancer metastasis can be identified in this way. Some centres also perform magnetic resonance imaging (MRI) in order to plan management such as reserving pelvic lymphadenectomy for deeply invasive lesions. Computed tomography (CT) scan of the abdomen and pelvis in uterine papillary serous cancer is advisable to detect upper abdominal disease. A CT of the chest is advisable in women with carcinosarcoma to exclude pulmonary metastasis. If the diagnosis of endometrial carcinoma is confirmed, a chest X-ray is essential. A full blood count, urea, creatinine and electrolyte estimations are required, as is urinalysis for sugar and protein.

If preoperative radiological assessment is undertaken, it seems that MRI is the most accurate for assessing local spread to the cervix and through the myometrium. Neither CT nor MRI is sufficiently sensitive to detect small, involved lymph nodes. Many patients also require medical optimization as these patients are frequently elderly with multiple comorbidities. Assessment by an anaesthetist may be helpful in determining fitness for surgery.

Treatment

Non-surgical management of endometrial carcinoma

Non-surgical management of endometrial carcinoma involves radiotherapy, chemotherapy and hormonal therapy.

Radiotherapy

After surgery, radiotherapy is the most common modality of treatment used in endometrial cancer. It has a role in most stages of this disease. The use of radiotherapy began empirically, but, more recently, randomized trials have confirmed its benefits. The most important role is as adjuvant therapy following surgery in early-stage disease, but it also provides good palliation in advanced-stage disease. In circumstances where surgery may be very high risk, definitive treatment with radiotherapy alone can be considered. The following discussions will present evidence for adjuvant radiotherapy as per the old FIGO staging for endometrial cancer.

Stages IA and IB, grades 1 and 2

For the usual histological type of endometrioid adenocarcinoma which is well differentiated (grade 1) or moderately differentiated (grade 2), there is usually no indication for any adjuvant treatments. This is because the risk of local recurrence is very low (0–9%) (GOG 33) and radiotherapy is unlikely to be of significant benefit, especially when the majority of recurrences are salvageable by further treatment.

Stages IA and IB, grade 3 or high-risk histology

Poorly differentiated endometrioid adenocarcinoma, clear cell carcinoma and papillary serous carcinoma pose a higher risk of not only locoregional but also systemic recurrence. This is evident from their poorer relapse-free survival (RFS) and overall survival (OS) compared with grades 2 and 3 endometrioid adenocarcinomas (Creasman et al 2004). Five-year survival rates for papillary serous carcinoma, grade 3 endometrioid carcinoma and clear cell carcinoma are 72%, 76% and 80%, respectively. Almost half of those perceived to have early-stage uterine papillary serous carcinoma are found to have advanced-stage disease at surgery or in the definitive pathology. OS and progression-free survival (PFS) slip down to 80% and 68%, respectively, for stage I uterine papillary serous carcinoma. Recurrence rates were as high as 29% for stage IB–IC uterine papillary serous carcinoma (Havrilesky et al 2007a). While systemic management of this particular category is still evolving, radiotherapy has been in use for decades to at least reduce the risk of locoregional recurrence. Historically, this has been achieved mainly by external beam radiotherapy as this would encompass most pelvic lymph nodes including obturator, internal iliac, external iliac and common iliac, which are the main lymph node groups to which endometrial cancer would metastasize (Table 42.4).

Table 42.4 Trials of adjuvant radiotherapy in endometrial cancer

In the largest postoperative radiotherapy trial in endometrial cancer (PORTEC 1), 715 patients with FIGO stage IC, grades 2 and 3, stage IB, any grade and stage IA, grade 3 endometrioid carcinoma, serous papillary carcinoma and clear cell carcinoma were randomized to receive either external beam radiotherapy or no adjuvant radiotherapy following total abdominal hysterectomy, bilateral salpingo-oophorectomy and washings (Creutzberg et al 2000). Adjuvant radiotherapy reduced the risk of locoregional recurrence from 13.7% to 4.2%, which was statistically significant. The distant metastasis rate (7.9% vs 7%, respectively) and death due to distant metastases (6.4% vs 4.5%, respectively) at 5 years were similar in the radiotherapy and observation arms. There was no significant difference in survival between the treated and non-treated groups. Higher age of the patient (≥60 vs <60, hazard ratio 3.1, P = 0.02) and poor differentiation of the tumour (grade 3 vs grade 2, hazard ratio 4.9, P = 0.0008) were significant risk factors for cancer-related deaths. The risk of gastrointestinal toxicity was increased from 1% to 17% (P = 0.0001) in the treated group. PORTEC 1 registered 99 patients with FIGO stage IC, grade 3 endometrial carcinoma for analysis purposes only as they all received radiotherapy (Creutzberg et al 2004). Five-year distant metastasis rate was higher for FIGO stage IC, grade 3 compared with FIGO stage IC, grade 2 endometrial carcinoma (31% vs 20%, respectively) in patients treated with adjuvant radiotherapy. Five-year survival was 74% vs 58% for stages IB and IC, respectively.

Another study by the GOG looked at the value of adjuvant radiotherapy following definitive surgery that involved selective pelvic lymph node dissection (Keys et al 2004). Three hundred and ninety-two patients with intermediate risk of recurrence (FIGO stages IB, IC, IIA and IIB) who underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, selective pelvic lymphadenectomy and selective para-aortic lymph node dissection were randomized to either adjuvant radiotherapy to the pelvis or no further adjuvant treatment. Based on GOG 33 trial, three factors were considered as risk factors: grade 2–3, involvement of outer third of myometrium and lymphovascular space invasion. Patients were considered to be at high–intermediate risk of recurrence if they were aged 70 years or more with one risk factor, 50 years or more with two risk factors, or any age with all three risk factors. It is interesting to note that one-third of stage I patients meet this criteria and that two-thirds of recurrences occur in this group. Risk of recurrence in patients at high–intermediate risk was reduced to 6% with radiotherapy compared with 26% when no adjuvant radiotherapy was given. At 4 years, there was a trend towards better survival with radiotherapy (92% vs 86%), although this was not statistically significant. The trial, however, was not powered to detect a survival advantage.

Two trials have evaluated the usefulness of brachytherapy without external beam radiotherapy, also labelled as ‘teletherapy’. The first of these studies was a prospective non-randomized study (Fanning 2001). Two hundred and sixty-five patients underwent complete surgical staging with full lymphadenectomy up to the duodenum, undertaken by one surgeon. Sixty-six patients were identified to have intermediate-risk disease on the basis of grade 3, involvement of outer myometrium (FIGO stage IC) or involvement of cervix (FIGO stage IIA–B), and all received adjuvant brachytherapy but no external beam radiotherapy. Five-year survival was reported to be 84% and PFS was 97%. Although one should avoid comparing the results of two different trials, it was noted with interest that this PFS was comparable with the PFS observed in GOG 99 trial for a similar group of patients who received teletherapy. The second pivotal randomized trial of adjuvant brachytherapy compared with external beam radiotherapy was planned on the basis of similar observations in phase II trials (PORTEC 2). Patients at high–intermediate risk (on the basis of PORTEC 1 results) were randomized to receive either external beam radiotherapy or brachytherapy. The primary endpoint was vaginal recurrence rate, and secondary endpoints were quality of life, OS and locoregional recurrence. The analysis was by intention to treat. A total of 427 patients were randomized into the two treatment groups. Three-year vaginal recurrence rate was 1.9% (P = 0.97 in both groups). Three-year pelvic nodal recurrence rate was 0.6% in the external beam radiotherapy group compared with 3.5% in the brachytherapy alone arm (P = 0.03). Three-year OS and RFS rates were 90.4% and 90.8% (P = 0.55) and 89.5 and 89.1 (P = 0.38), respectively. The distant recurrence rates were similar in both groups.

ASTEC is a large phase III, randomized trial which addressed two issues, namely the role of lymphadenectomy and adjuvant radiotherapy in early-stage endometrial cancer (Kitchener et al 2009). Although the results of the lymphadenectomy part of the trial have recently been published, the results of the radiotherapy part are not yet in the public domain.

Usually, a dose between 40 and 50 grays (Gy) is given in 20–28 fractions over 4–5.5 weeks using megavoltage (MV) photons of higher energy (typically between 8 and 15 MV). The side-effects of radiotherapy are described as early (usually temporary and appearing during treatment and up to 3 months after) or late (usually permanent and typically occurring more than 3 months after radiation therapy). Early side-effects include tiredness, diarrhoea, local soreness of skin/vagina, local hair loss and radiation cystitis. Delayed toxicity includes the risk of chronic proctitis or a weak bladder leading to poor control, urinary urgency and occasionally incontinence, but most importantly the risk of a fistula (involving bowel, vagina or urinary bladder) or narrowing of the bowel which may require colostomy. Obviously, this risk is directly proportional to the dose of radiotherapy and the amount of bowel in the radiation field. The risk is less than 5% over 5 years at the doses mentioned above (Milano et al 2007). Comorbidity, especially previous pelvic operations and inflammatory bowel disease, increase this risk significantly and therefore are relative contraindications to radiotherapy to the pelvis. Similarly, hereditary conditions including ataxia telangiectasia and xeroderma pigmentosum markedly increase radiation sensitivity, and are absolute contraindications to adjuvant radiotherapy.

Stages IC, IIA and IIB

Involvement of the outer half of the myometrium and cervical stroma are well known to increase the risk of local recurrence as well as regional lymph node spread. As many as one-third of patients with apparent stage IC, grade 2 tumours may have pelvic nodes involved, and one-quarter may have para-aortic nodes involved. There has been a definite role for radiotherapy in these stages following surgery to reduce that risk. The modality of radiotherapy, the dose and the extent of the area radiated have not been without controversy. While preliminary results of the largest phase III randomized trial of adjuvant radiotherapy in the UK do not show any advantage for external beam radiotherapy for stage IC disease, the fact that some centres were allowed to use brachytherapy in accordance with their local guidelines has made interpretation difficult. In fact, most radiation/clinical oncologists continue to offer radiotherapy to this group of patients, and were reluctant to recruit these patients into any trials of adjuvant radiotherapy or not. For these reasons, the PORTEC 1 trial excluded stage IC, grade 3 patients from randomization although they were registered in the trial to follow their progress (Creutzberg et al 2004).

With the adoption of pelvic lymphadenectomy, the use of external beam radiotherapy in early-stage cancer is being replaced by localized brachytherapy, eliminating the need for radiating a large pelvic volume including pelvic nodes. While the issue of pelvic node surgery in early endometrial cancer has been controversial and open to debate, patients who do undergo this type of surgery and who are node negative may be eligible for brachytherapy alone. The PORTEC 2 trial has shown no differences in vaginal vault recurrence rates between patients who had external beam radiotherapy or brachytherapy. However, the recent ASTEC publication discouraged the routine use of pelvic lymphadenectomy outside of a clinical trial (Kitchener et al 2009). This is unfortunate as it would lead to inadequate staging of endometrial cancer patients and hence deny adjuvant treatments to those with higher stage disease. Obviously, there are also significant implications of this in terms of acute and long-term toxicity of radiotherapy. There is a definite need for more evidence to finally resolve this issue. Detailed discussion on this subject is outwith the scope of this chapter.

If the cervix is involved, external beam radiotherapy is usually followed by brachytherapy. Brachytherapy is administered by a remote afterloading system. The intention is to boost the vaginal vault with a higher dose of radiotherapy without giving an excessive dose to the small bowel. In brachytherapy, sources of radiation are placed near the area of interest so that the area nearest to the source receives a higher dose, and the normal tissues (organs at risk) away from the source receive a much smaller dose, thereby reducing the risk of serious morbidity.

Stages IIIA, IIIB and IIIC

Locally advanced endometrial cancer has a lower OS rate but there is also a significant risk of local recurrence. While the prognosis is usually determined by distant recurrence, local relapse can be distressing and uncomfortable, with intractable symptoms such as pain, bleeding, discharge, and fistulation into the vagina, bladder and rectum. Involvement of ureters or bladder usually leads to renal impairment, compromising further cytotoxic therapy. If patients are suitable for chemotherapy, they usually receive this first, followed by radiotherapy.

Stage IVA

An attempt should be made to deliver a radical dose of radiotherapy in otherwise fit patients. This may include external beam radiotherapy as well as brachytherapy. The aim in the first place is to control the local disease, and hence the local symptoms, but a small number of patients may be salvaged. They may go on to live for many years (Churn and Jones 1999). For the majority, a palliative dose of radiation is given to help local symptoms.

Stage IVB

The aim of radiotherapy is almost always palliation in this situation. Virtually any part of the body can receive a palliative dose, but, for obvious reasons, the most common site to be treated is the pelvis. Either external beam radiotherapy or brachytherapy can be used. This aims to help symptoms such as pain, bleeding and spinal cord compression, but also those that arise from the mass effect of raised intracranial pressure from brain metastases. The total dose and number of fractions depend on the site, extent, tempo of the disease and fitness of the patient. Most commonly used doses are 8 Gy in a single fraction, 20 Gy in five fractions over 1 week, and 30 Gy in 10 fractions over 2 weeks.

Radiotherapy technique

The quality of planning and delivery of radiotherapy has improved remarkably over the last few years in line with the improvements in computer and technological advances (Figure 42.12). The latest state-of-the-art multi-leaf-collimator-equipped linear accelerators with ability to deliver gated, conformal MV radiotherapy are in stark contrast with the old orthovoltage (KV) machines with limited planning techniques. For external beam radiotherapy, the patient first undergoes a planning scan which is usually a CT scan, although MR scans are likely to replace CT for this purpose. Work is also ongoing to explore the usefulness of PET-CT and PET-MRI in radiotherapy planning (Figure 42.13). After the planning CT, patients are marked with tattoos (usually pin head size) to ensure reproducibility of the treatment position during each fraction of radiotherapy. Clinical or radiation oncologists then draw the target volume, i.e. the area to be treated (Figures 42.14 and 42.15). Most patients are treated using a four-field plan (brick technique) to reduce the dose of radiation to normal tissues around the target volume (Figures 42.16 and 42.17). Once the physicist has planned the treatment and it is approved by the oncologist, treatment can be started. There are many quality assurance and safety nets at different stages to ensure safe radiation exposure in line with the local radiation protection laws. One treatment is given per day, Monday to Friday, with no treatment over the weekend. Patients can be treated over the weekend or even twice a day depending upon the availability of resources and staff. If treated twice a day, there has to be a minimum gap of 6 h between treatments to allow the normal tissue repair to take place. Patients are reviewed weekly to assess for any side-effects.

Figure 42.12 Linear accelerator; delivery of megavoltage external beam radiotherapy.

Figure 42.13 Computed tomography/positron emission tomography image fusion.

Figure 42.14 Superior, inferior and lateral limits of anterior and posterior beams of external beam radiotherapy for endometrial cancer. Note lead shielding at all four corners.

Figure 42.15 Superior, inferior, anterior and posterior borders of right and left lateral fields of four-field external beam radiotherapy plan for endometrial cancer. Top anterior and posterior corners are shielded.

Figure 42.16 Axial slice of four-field external beam radiotherapy plan showing isodose distribution including planning target volume (red line) and shielding anteriorly (grey bands)

Figure 42.17 Isodose distribution on coronal section. Lead shielding at all four corners of anterior and posterior radiation fields. Red line represents 90% isodose (planning target volume).

Where needed, brachytherapy is delivered using afterloading devices. In recent years, there has been a gradual move from low- (LDR) to medium-dose-rate (MDR) brachytherapy (dose rates <1200 cGy/min) and now to high-dose-rate (HDR) brachytherapy (dose rates >1200 cGy/min), meaning that the treatment can now be given in a few minutes rather than many hours. The results of HDR brachytherapy in cervical cancer confirm its efficacy at no significant additional toxicity (Lertsanguansinchai et al 2004). LDR and MDR brachytherapy require a single insertion, while HDR brachytherapy requires two to four treatments depending on the dose needed. Also, the total dose required is less for HDR systems.

Depending upon the dose required and the aim of treatment, one to three applicators are placed vaginally to treat the uterus, vaginal vault or both. This is usually done under general or spinal anaesthetic, but can be carried out under local or even no anaesthetic, especially in postoperative cases where only vault radiation is required. Patients are treated in isolation rooms for radiation protection. The applicators are connected to the tubes from the radiation delivery machine holding radiation sources. Once all planning is complete and rechecked and all staff have left the room, the machine can be switched on. Patients should be able to lie on their backs and keep their legs straight for many hours for LDR and MDR brachytherapy, although they can be treated while under anaesthetic for HDR brachytherapy.

Radiotherapy for recurrent disease

Proponents of radiotherapy claim that many of the recurrences are not localized, while advocates of no adjuvant radiotherapy for early disease stress that the majority of recurrences (although not all) are localized and therefore are salvageable, the so-called ‘Alabama approach’ (Barnes and Kilgore 2000). This approach, although not widely popular, is being adopted by some in view of no survival advantage of adjuvant radiotherapy and a definite, although small, risk of late serious toxicity of radiotherapy. Recurrent, localized disease at the vault can be treated with radiotherapy or surgery, and success rates are high (Creutzberg et al 2003). If radiotherapy is used, the doses required are high and the risk of toxicity is proportionally high. Nevertheless, any patient with localized recurrence should be viewed as potentially curable.

Chemotherapy

The role of chemotherapy is less well established. There are many reasons for this, but mainly the comorbidities of typical endometrial cancer patients such as hypertension, diabetes mellitus, obesity and related problems, combined with the myth that early endometrial cancer has excellent survival, have discouraged oncologists from exploring this avenue in the past. However, improvements in general health care, refinements of cytotoxic agents, the use of granulocyte colony-stimulating factor and 24-h medical/nursing support for such patients has resulted in a refreshed interest in assessing the role of chemotherapy.

Early-stage localized disease has excellent survival after surgery and it would be difficult to demonstrate any benefit from adjuvant chemotherapy. In high-risk early-stage disease, the risk of systemic relapse is high and so is the 5-year disease-specific mortality rate. Papillary serous carcinoma, clear cell carcinoma and poorly differentiated endometrioid carcinoma infiltrating the outer half of the myometrium are particularly associated with poor OS (5-year OS 70–80%) (Murphy et al 2003). These high-risk scenarios may benefit from adjuvant chemotherapy. Until recently, there were no convincing phase III data to show a survival benefit for the use of chemotherapy; based on retrospective data, many oncologists were considering fitter patients for adjuvant chemotherapy, especially if they had serous carcinoma or even elements of clear cell carcinoma. Evidence is now gradually accumulating to support this approach. Most oncologists now agree that serous papillary carcinoma should be treated as ovarian carcinoma with adjuvant chemotherapy. A recently published systematic review (Table 42.5) evaluated data collected from 2288 patients recruited into 11 trials of chemotherapy for advanced disease.

Table 42.5 Systematic reviews of chemotherapy in advanced endometrial carcinoma

A GOG study showed better OS of 15.3 vs 12.3 months, PFS of 8.3 vs 5.3 months and overall response rate of 57 vs 34% in favour of the addition of paclitaxel to the combination of doxorubicin and cisplatin, but at the cost of much higher toxicity (Fleming et al 2004). Combinations of an anthracycline and platinum are still probably the most commonly used regimes in endometrial carcinoma.

The Japanese GOG study showed that early-stage high-risk patients, including stages IC, grade 3, II and IIIA, had higher PFS (83.8% vs 66.2%, P = 0.024) and OS (89.7% vs 73.6%, P = 0.006) when treated with combination chemotherapy comprising cyclophosphamide, adriamycin and cisplatin compared with treatment with pelvic radiotherapy alone (Susumu et al 2008). A phase II feasibility study by the Radiation Therapy Oncology Group used concurrent chemotherapy (cisplatin 50 mg/m² on days 1 and 28) during external beam radiotherapy of 45 Gy in 25 fractions followed by four cycles of adjuvant combination chemotherapy with cisplatin 50 mg/m² and paclitaxel 175 mg/m² four weekly (Greven et al 2006). Forty-six patients with grade 2 or 3 endometrial adenocarcinoma with FIGO stages between IC, IIB and IIIB were treated and followed-up to a median of 4.3 years. At 4 years, pelvic, regional and distant recurrence rates were observed to be 2%, 2% and 19%, respectively. Four-year DFS and OS were 81% and 85%, respectively. Grade 2 and 4 late toxicity was seen in 21% of cases and grade 1 and 2 in 57% of cases. The inferences drawn were that this was a feasible regime with acceptable toxicity showing excellent locoregional control, and should be tested in a randomized controlled trial. It has become the basis of the PORTEC 3 trial.

There seems to be a stronger view in favour of adjuvant chemotherapy in locally advanced disease as the risk of distant spread and resultant mortality is high. The response rates to different chemotherapeutic agents used alone range between 4% and 77%. A systematic review of chemotherapy in advanced endometrial carcinoma by Humber et al reported an improvement in OS to 15 months from 6.9 months for best supportive care (Humber et al 2007). Median PFS improved from 3.2 months to 8.3 months. Overall response rates ranged between 17% and 34% for single agents, but between 30% and 69% for combination chemotherapy. Unfortunately, randomized evidence is lacking but retrospective data have shown some improvement in RFS but not OS. A randomized trial of adjuvant chemotherapy with cisplatin and adriamycin has been completed by the European Organization for Research and Treatment of Cancer, and the results are encouraging (Aapro et al 2003). Many oncologists feel uncomfortable not giving adjuvant chemotherapy to this group of patients (FIGO stage IIIA onwards), and treat them with platinum +/− anthracycline/taxane.

Metastatic endometrial cancer carries a very poor prognosis. Palliative treatments range from radiotherapy to hormonal therapy to chemotherapy depending on the symptoms of the patients, comorbidities and their wishes. Cytotoxic options include platinum +/− anthracycline/taxane.

Hormonal therapy

A proportion (11–25%) of endometrial carcinomas express ER and/or PR. Published data do not support the routine use of adjuvant hormones in early-stage disease. This is because of a high rate of recurrence following endocrine treatment in spite of very significant initial complete response rates (Ushijima et al 2007). However, in exceptional circumstances where, due to extreme comorbidities or patient choice, surgery or radiotherapy cannot be used, consideration may be given to the use of hormone treatment. For advanced endometrial carcinomas, especially those that are well differentiated, showing strong progesterone positivity and metastatic to the lungs, hormone therapy is a reasonable choice and should always be considered (Bouros et al 1996, Thigpen et al 1999). Long-term responses have been documented. The most commonly used agent is medroxyprogesterone in high doses such as 200 mg two to three times a day. Fluid retention and heart failure are recognized complications. Other hormonal agents such as aromatase inhibitors have been used with some efficacy (Rose et al 2000).

Uterine Sarcomas

The uterus is not an uncommon site for the development of sarcomas. The principles of management are very similar to those for endometrial carcinomas and soft tissue sarcomas at other sites. The mainstay of treatment is surgery for early and localized disease. Radical radiotherapy can be considered for surgically unfit patients. The common perception of these tumours being radioresistant is only true for leiomyosarcomas.

The indications for adjuvant treatment are somewhat variable but mainly depend on the type of sarcoma, size and degree of surgical clearance. For small (≤5 cm) low-grade sarcomas with complete microscopic clearance, radiotherapy is unnecessary as the risk of local recurrence is low. Similarly, there is insufficient evidence to suggest that radiotherapy is beneficial in cases of endometrial stromal sarcomas. Tumours larger than 5 cm, of higher grade and malignant mixed Müllerian tumours, also known as ‘carcinosarcomas’, should be considered for adjuvant radiotherapy. Incomplete surgical clearance usually requires higher doses of radiotherapy. Previous history of radiotherapy to the pelvis is very important as this may be a causative factor in some pelvic sarcomas (Nakanishi et al 2001).

Retrospective data suggest no definite survival benefit with adjuvant radiotherapy for early disease, but a significant reduction in the risk of local recurrence. The Royal Marsden experience shows local recurrence rates as high as 70% without radiotherapy. With external beam radiotherapy, the rate of local recurrence fell to 40%, and, with the addition of brachytherapy, fell as low as 23%. Local DFS improved to 70% from 55% with the use of radiotherapy in stage I disease. In stage II and III disease, the best results are achieved with external beam radiotherapy and brachytherapy combined.

Since publication of the meta-analysis of adjuvant chemotherapy in soft tissue sarcoma and the small associated benefit, many oncologists have extrapolated the data to include uterine sarcomas of high grade, especially leiomyosarcomas (Sarcoma Meta-analysis Collaboration 2000). More recent updates have only shown a marginal benefit against significant toxicity (Pervaiz et al 2008). Doxorubicin and ifosfamide are given as a three-weekly cycle to a total of six. Common side-effects include nausea and vomiting, hair loss, cardiotoxicity, confusion and neutropenic sepsis. Another challenge is the management of malignant mixed Müllerian tumours. The prognosis of this aggressive subtype remains very poor, with 3-year OS of approximately 22%. The only randomized trial of cisplatin and ifosfamide that showed some benefit also revealed that the toxicity was quite significant (Sutton et al 2000, 2005). Although the use of adjuvant chemotherapy is gradually increasing, there is, as yet, no set standard. The relatively low incidence of these tumour types and frailty of many patients makes it difficult to plan randomized trials.

Recurrent disease might be localized in a small proportion of cases. The history of previous treatments, relapse-free interval, distribution of the disease and comorbidities determine further management which may include localized surgery to exenterative surgery to radical radiotherapy or only palliative measures. For metastatic disease, the goal is palliation at the outset. Radiotherapy for localized symptoms, chemotherapy for more widespread disease, occasionally surgery for intractable local symptoms, and even hormonal treatment with progestogens for low-grade endometrial stromal sarcomas have a place.

Prognosis

The aura of good prognosis surrounding endometrial cancer may just be a reflection of diagnosis and prompt treatment at an early stage. The prognosis for advanced-stage disease is quite poor, with the exception of metastatic disease responsive to progestogens. In this situation, years of control can sometimes be achieved with very significant improvement of symptoms. Although hormone-resistant disease may respond to chemotherapy, the responses are short-lived. Aggressive/high-risk histologies also carry a poorer prognosis (Table 42.6).

Table 42.6 Five-year overall survival by International Federation of Gynecologists and Obstetricians (FIGO) stage

Source: Creasman WT, Carcinoma of the corpus uteri; Int J Gynecol Obstet 2003;83:79, with permission of Elsevier.

Stage IC poorly differentiated endometrioid, papillary serous and clear cell tumours have 5-year survival rates of 50–70% (Murphy et al 2003, Havrilesky et al 2007b). Uterine sarcomas are also aggressive histiotypes, but the prognosis ranges from approximately 30% OS for malignant mixed Müllerian tumours (Callister et al 2004) to 50–90% for endometrial stromal sarcomas (Chan et al 2008). Leiomyosarcomas probably fall in the middle, with a 5-year survival rate of 40% (Kahanpaa et al 1986) (Box 42.4).

Targeted Therapies

Currently, approximately 250 clinical trials involving endometrial cancer are registered internationally. Fifty-nine of these include some form of targeted therapy. These studies focus almost exclusively on recurrent or persistent disease. Agents are used as monotherapy or in combination with chemo- or radiotherapy, and also with other targeting agents.

Forty-six trials cover three groups of agents: tyrosine kinase receptor inhibitors or antibodies (n = 23), mTOR (mammaliam target of rapamycin) inhibitors (n = 14) and oestrogen inhibitors (selective ER modulators, aromatase inhibitors) (n = 9). The remaining 13 trials include agents such as cell cycle inhibitors, mitogen-activated protein kinase inhibition, gonadotrophin-releasing hormone agonism, folic acid analogism, histone deacetylase inhibition, the monoclonal antibody RAV12, CALAA-01 (RNA interference), UCN-01 (protein kinase C inhibition) and cyclo-oxygenase II inhibition.

Amongst these, the most widely researched molecules are the epidermal growth factor receptor and the vascular endothelial growth factor (VEGF) receptor families. The growth and progression of tumours is unequivocally angiogenesis dependent. The main proangiogenic factor, namely VEGF, also known as ‘vascular permeability factor’, is a potent angiogenic cytokine that induces mitosis and also regulates the permeability of endothelial cells. VEGF is an endothelial-cell-specific growth factor and the principal regulator of angiogenesis under normal and pathological conditions in most organs. Increased levels of VEGF and angiogenic markers are associated with poor outcome in endometrioid endometrial cancer patients (Kamat et al 2007).

The human epidermal growth factor receptor-2 (HER-2 protein), which is also known as c-erbB-2 or neu, is a member of subclass 1 of the superfamily of receptor tyrosine kinases. HER-2 is an independent prognostic factor in endometrial cancer and an important oncogene in high grade and stage endometrial cancer (Morrison et al 2006). Overexpression of HER-2/neu was associated with an overall worse prognosis in uterine papillary serous cancer (Slomovitz et al 2004). Inhibition of the epidermal growth factor receptor in poor prognostic types of endometrial cancer may be of benefit. There is limited research into new therapies for endometrial cancer, despite the increasing incidence. Identification of new drugs and targeted therapies for poor prognostic types of endometrial cancer will benefit treatment at initial presentation and relapse.

Follow-Up in Endometrial Cancer

Recurrence from endometrioid endometrial cancer tends to be pelvic and frequently occurs at the vaginal vault, usually within the first 2 years after diagnosis. In patients who have received adjuvant radiotherapy, recurrences can be sited outside the radiotherapy field. Recurrence in sarcomas can be distant and occur in the chest. Vaginal bleeding and discharge is the most common presentation at relapse. During follow-up, symptoms such as vaginal bleeding and/or discharge, and any urinary or gastrointestinal disturbance should raise the suspicion of relapse and prompt appropriate investigation. The history should also aim to identify morbidity associated with radiotherapy, such as troublesome diarrhoea which can be managed with the use of codeine or over-the-counter medication. Vaginal dilators are also beneficial to preserve vaginal capacity after radiotherapy in patients keen to preserve vaginal capacity, and also to aid clinical examination at follow-up. An abdominal examination and vaginal examination to detect vaginal/pelvic masses is of value. Patients with early-stage endometrial cancer stage IA with grade 1 endometrioid cancer can be discharged safely. All patients with poor prognostic types of histology and patients who have received adjuvant radio-/chemotherapy should be seen at regular intervals for the first 2 years and then less frequently in the subsequent 3 years after diagnosis. The value of clinician-led follow-up compared with patient-initiated follow-up in the presence of symptoms for early-stage endometrial cancer has never been proven. However, it remains conventional practice to institute a regime of follow-up for patients at greatest risk of recurrence. HRT can be safely instituted in symptomatic young women with adequately staged and treated stage I endometrial cancer.

Challenges and Future Directions

The rising incidence in endometrial cancer is likely to continue and this will impact on current resources. Laparoscopic surgery will become more established in the management of this disease, as will tailoring adjuvant therapy for those at greatest risk of recurrence. Results of trials of targeted therapies in poor prognostic types of endometrial cancer are eagerly awaited, and may pave the way for individualization of treatment in the future.