Endometrial carcinomas

Endometrial carcinomas present at a mean age of 63 years, however 4% of women with endometrial carcinoma are younger than 40, which has significant quality of life implications associated with childbearing and premature menopause related to treatment.

Classification of endometrial carcinomas

In 1983, Bokhman classified carcinoma of the endometrium into two distinct groups (3). The first group described a group of tumours that originated in women with metabolic disturbances that include obesity, varying degrees of glucose intolerance, hyperoestrogenism and hyperlipidaemia. These tumours developed in a hyperplastic endometrium, were well to moderately differentiated, were less aggressive, and usually had a favourable prognosis. Tumours in Bokhmans second group were noted to be more aggressive, to have a greater chance of lymphatic spread, have higher recurrence rates, and the prognosis was less favourable than the first group. This di­chotomous model has definite limitations due to heterogeneity within the two groups. Fortunately, advances in histological and immunohistochemical assessment of endometrial carcinomas have allowed these tumours to be more appropriately classified into high- risk and low-risk histological subtypes (Table 63.2).

The low-risk group incorporates tumours that have progressed through a stage of intraepithelial neoplasia (atypical endometrial hyperplasia) and so have maintained some degree of similarity to the parent tissue exhibiting varying degrees of endometrial gland for­mation and are thus described as endometrioid. The International Federation of Gynecology and Obstetrics (FIGO) provided a grading system of endometrioid carcinomas in 1988 that classified them into well (grade 1), moderately (grade 2), and poorly (grade 3) differenti­ated tumours, based on the progressive loss of glandular architecture leading to increasing solid growth patterns, as well as the degree of nuclear atypia.

The high-risk groups of tumours, while still originating from glandular epithelium, usually develop in an atrophic endometrium and display morphology that is structurally different from endo­metrial tissue. This group includes serous carcinomas and clear cell carcinomas. Both these exhibit TP53 gene mutations and chromo­somal instability (4). Two additions to the high-r isk group in­clude poorly differentiated (grade 3) endometrioid carcinoma and carcinosarcoma. Carcinosarcoma, which was previously classified

Figure 63.1 Uterine cancer.

as a uterine sarcoma, is now regarded as a carcinoma that has undergone metaplastic sarcomatous differentiation. It is a highly aggressive tumour with its carcinomatous component usually con­tributing to metastatic spread and is thus included in the high-risk group (5).

The majority of women with endometrial carcinoma have grade 1 and 2 endometrioid tumours and frequently present with early- stage disease and have excellent outcomes. The remaining 10-20% who are diagnosed with carcinomas of high-risk histology usually present in the late sixth and seventh decades. They often have more advanced disease and in over 50% of cases the disease has spread be­yond the uterine corpus at the time of diagnosis.

Risk factors

Risk factors for developing endometrial cancer can be divided into lifestyle factors, medical conditions, and hereditary factors. Medical conditions which are associated with the development of endomet­rial cancers are often sequelae of lifestyle factors, which are now becoming more evident in developing countries. Extreme body mass index, diabetes mellitus, hypertension, polycystic ovarian syn­drome, early menarche, late menopause, infertility or nulliparity, unopposed oestrogen therapy, postmenopausal use of tamoxifen, oestrogen-secreting tumours, and HNPCC are all associated with

Table 63.1 Uterine malignancies

an increased risk. The highest lifestyle-related risk is obesity (relative risk 2.54; 95% confidence interval 2.11-3.06) (6). Women who have inherited a HNPCC gene mutation have a 40-60% lifetime risk of developing endometrial carcinoma and a 9-12% risk of developing ovarian carcinoma due to defects in the DNA mismatch repair genes MLH1, MSH2, MSH6, and PMS2 (7).

Screening for endometrial cancer

Evidence does not support screening for endometrial cancer in a low-risk population as most cases cannot be avoided. There is no standard screening test. Ultrasonographic measurement of the endometrial thickness in low-risk asymptomatic women, may re­sult in unnecessary interventions to sample the endometrium with potential procedure related complications and patient anxiety. To decrease the incidence of disease in the low-risk population, health professionals should rather focus on promoting healthy lifestyle choices, diagnosing and managing manifestations of the metabolic syndrome, and educating patients on the importance of having ab­normal uterine or postmenopausal bleeding assessed.

Where tamoxifen is prescribed to postmenopausal women as part of breast cancer treatment, women should be counselled about the risk of endometrial polyps, hyperplasia, and endometrial cancer and that they should report any abnormal bleeding immediately. Tamoxifen has been reported to cause endometrial abnormalities in as many as 39% of women (9). The Mirena intrauterine system (IUS) has been used for endometrial protection. Although studies have not shown significant progesterone-associated risks of breast cancer development and carcinogenesis in breast cancer survivors with the use of Mirena, there are still concerns about oncogenic ef­fects of any progestogens (10-12). Results from a small (n= 94) ran­domized controlled trial by Wong et al. could not demonstrate increased rates of recurrences nor breast cancer-related deaths amongst patients who were offered levonorgestrel as prophylaxis compared to non-users (13).

Women who are deemed high risk for developing endometrial cancer include carriers of the HNPCC mutation, women from fam­ilies where there is a known mutation or where there is a strong

• Annual surveillance of the endometrium by gynaecological exam­ination, transvaginal ultrasound, and aspiration biopsy starting at 35 years and should continue annually.

• Consider insertion of a levonorgestrel-releasing IUS.

• Prophylactic surgery using a minimally invasive approach should be discussed at the age of 40 years to prevent endometrial and ovarian cancer. The complications associated with surgical pro­cedures as well as the uncertainty about the gains of prophylactic surgery should be discussed with honesty (15).

Endometrial hyperplasia

Endometrial hyperplasia is an abnormal proliferation of the endo­metrium and is driven by excessive levels of oestrogen, whether ex­ogenous such as unopposed hormone therapy or endogenous from cyclical aromatization of androgens to oestrogens in excessive per­ipheral adipose tissue found in overweight women. A body mass index greater than 40 kg/m² has been shown to increase the risk of atypical endometrial hyperplasia by 13- fold (9). Abnormal or uterine bleeding is the hallmark of presentation because of an unstable, pro­liferative endometrial lining. Endometrial sampling should be per­formed in women who present with abnormal bleeding over the age of 40 years, and in women younger than 40 with significant risk fac­tors for endometrial cancer, including obesity and any suggestion or evidence of a hereditary mutation.

Histologically, endometrial hyperplasia is assessed architectur­ally as simple (ordered) or complex (disordered), and cytologically as being atypical or not. The most significant finding in the histo­logical report is the presence of atypical cells, irrespective of the architecture as complex atypical hyperplasia is the immediate pre­cursor lesion of endometrial carcinoma.

Endometrial hyperplasia can be managed medically or with sur­gery. The choice of method is based on age, comorbid status, desire to retain fertility, and the presence of atypia. It is important to ad­dress potential sources of excessive oestrogen including obesity and to exclude oestrogen-secreting ovarian tumours in the management of endometrial hyperplasia.

Management of hyperplasia

Medical treatment

Endometrial hyperplasia without atypia can be managed medic­ally using systemic or local progestins. Oral medroxyprogesterone acetate (10-20 mg daily) or megestrol acetate (160—320 mg daily) can be prescribed in either continuous or cyclical regimes. Response rates with medical therapy are good with positive responses seen after 3 months of treatment and complete response rates usually by 6 months to 1 year. Side effects of progestin therapy include weight gain, oedema, headaches, dizziness, and lack of libido are less common with local progestin therapy. The levonorgestrel-releasing IUS has been proven effective, and even superior, to oral medica­tion in managing hyperplasia with and without atypia (17). Where there is no response to therapy after 6 months, progression to atyp­ical hyperplasia, or unacceptable side effects, surgery should be considered.

Surgical management

In patients who are not medically fit to undergo surgery, progestin therapy must be prescribed (9). Endometrial hyperplasia where atypia is present is best managed by simple hysterectomy using minimally invasive techniques where possible. Bilateral salpingo- oophorectomy should be considered in postmenopausal women. Endometrial ablation and resection may be considered in women with complex non-atypical hyperplasia where medical therapy has failed and hysterectomy carries excessive risk or is against the patient's wishes. However, where atypical hyperplasia is present, ab­lative techniques are not recommended.

Clinical features of endometrial carcinoma

The most common symptom of endometrial carcinoma is abnormal uterine bleeding. The bleeding may be postmenopausal or in pre- and perimenopausal women it may be intermenstrual or prolonged bleeding. A thorough history, which includes a detailed menstrual history, recent cervical smear results, past and current use of hor­mone therapy, medical conditions, and family history of cancer and hereditary cancer syndromes must be taken. A full clinical examin­ation should be performed which includes assessment of peripheral lymph node groups, examination of the breasts, abdominal exam­ination, external and speculum examination of the lower genital tract, plus bimanual examination of the upper genital tract. Careful assessment of adnexal masses, uterine size and mobility, nodularity or masses in the pouch of Douglas, and parametrial disease are im­portant to assess possible extrauterine spread and resectability.

Where no obvious cause of bleeding is detected on physical exam­ination, the upper genital tract must be assessed using pelvic ultra­sound scanning. Premenopausal women with significant risk factors for endometrial cancer and women over the age of 40 years must undergo histological endometrial assessment. There is no defined upper limit of endometrial thickness in premenopausal women, thus screening using sonographic endometrial thickness is not recom­mended. However, in premenopausal woman suspicion for hyper­plasia or malignancy is increased when the endometrial thickness is greater than 12 mm. Office sampling using a flexible plastic endo­metrial sampler is adequate. A meta-analysis of sampling devices concluded that the Pipelle was the most sensitive device in detecting endometrial cancer (91—99%) and highly specific (98%) (18). In patients where office sampling is not successful, hysteroscopy is an excellent alternative and offers both visualization of the entire endo­metrial cavity and allows directed biopsy of any suspicious lesions.

In postmenopausal women, where bleeding is associated with an endometrial thickness greater than 5 mm, endometrial sam­pling must be performed. In women reporting a single episode of postmenopausal bleeding without significant risk factors, with a normal clinical examination and normal cervical cytology and an endometrial thickness less than 5 mm, sampling is not indicated (19). Studies have investigated the relationship between endometrial thickness and the risk of malignancy. Overall, using a cut-off value of 5 mm to perform endometrial sampling would offer satisfactory sensitivity with a false-negative rate of less than 1% (19). However, repeated episodes of postmenopausal bleeding, even where the endometrial thickness is less than 5 mm, must be histologically as­sessed as high-risk histological carcinomas develop in an atrophic endometrium (20). In such cases hysteroscopy may better assess an atrophic cavity. One study by Chandavarker et al. reported a diag­nosis of either type 1 or type 2 endometrial cancer in 90 out of a total of 250 (36%) patients diagnosed with endometrial cancer, who had a prior endometrial stripe with a thickness not more than 4 mm (21).

Other less common presenting symptoms may include a pelvic mass, lower abdominal pain, and manifestations of metastatic dis­ease including vaginal or vulval tumours or respiratory complaints. Not too infrequently, women may present to other disciplines with venous thromboembolic phenomena and on further investigation an endometrial malignancy may be diagnosed.

Cervical smears that report the presence of atypical glandular cells in an otherwise asymptomatic woman necessitate careful pelvic, colposcopic, and endometrial assessment. The presence of endo­metrial cells on a cervical smear in asymptomatic postmenopausal women also warrants investigation.

Further investigations following a diagnosis of endometrial cancer

Histological specimens reporting endometrial cancers or atypical hyperplastic endometrium, where possible, should be evaluated by an experienced gynaepathologist. Subtle differences in the con­tinuum between atypical hyperplasia and endometrial cancer as well as the assessment of the grade of differentiation may not always be clear. Appropriate immunohistochemical staining techniques may also be required to differentiate between primary endocervical adenocarcinomas and endometrial adenocarcinomas and between uterine and ovarian serous carcinomas.

Biochemical and radiological preoperative investigations include the following:

• Full blood count.

• Liver function tests, specifically alkaline phosphatase and gamma­glutamyl transferase.

• Urea, electrolytes, and renal function tests.

• Random blood glucose (to exclude undiagnosed diabetes mellitus).

• CA125 (has been shown to correlate with extrauterine spread in high-grade tumour but a consensus opinion is that there is no evi­dence to support the use of serum tumour markers in endometrial cancer) (14, 22).

• Imaging (dependent on local resources, institutional indications for staging lymphadenectomy, and whether fertility preservation is a treatment goal):

■ Pelvic ultrasound to determine tumour size, assess adnexa, cervical involvement, and depth of tumour invasion into the myometrium.

■ Pelvic magnetic resonance imaging (MRI) to size tumour and assess pelvic spread, myometrial invasion, cervical involve­ment, and pelvic lymphadenopathy

■ Computed tomography (CT) scan of chest, abdomen, and pelvis to investigate distant metastases to lung and liver, ex­clude hydronephrosis, assess peritoneal spread, and pelvic, para-aortic, mediastinal, and hilar lymphadenopathy.

■ In low-income countries, a chest X-ray and abdominal ultra­sound are often the only available and affordable options.

■ CT-positron emission tomography, where available, has a high specificity but low sensitivity in excluding lymph node disease.

2009 FIGO staging of endometrial carcinoma

Endometrial cancer is staged surgically. In 2009, the Gynecological Oncology Group of FIGO published a revision of the 1988 staging system of endometrial carcinoma. This new system is felt to be a more accurate staging instrument and thus a better prognostic tool than its predecessor (Table 63.3) (23).

Surgical staging includes removal of the uterus and adnexae. A systematic pelvic with or without para-aortic lymphadenectomy should be performed in patients with high-risk tumour features such as grade 3 differentiation, non- endometrioid histology, cervical stromal invasion, lymphovascular system space invasion (LVSI), and where the tumour invades more than 50% of the myometrial thickness.

Cytological examination of peritoneal washings or free abdom­inal fluid is reported separately and does not upstage the woman. Malignant cells in peritoneal fluid have not been shown to be of prognostic significance (24).

Treatment of endometrioid endometrial cancer

The primary management of endometrial cancer is surgery.

Surgery

Surgery in endometrial cancer aims to remove the primary tumour, to perform comprehensive staging, and, in advanced abdominal dis­ease, to achieve optimal cytoreduction where feasible. Surgery with curative intent may not always be possible where:

• there are patient-related factors such as extreme cachexia, extreme obesity, severe cardiorespiratory compromise, or recent acute pul­monary embolism or venous thromboembolism

• there is unequivocal (cytological or histological) evidence of parenchymal liver or lung metastases as well as lymph node involvement

• clinical or radiological examination suggests that pelvic or ab­dominal disease is not resectable.

Prior to implementing any form of treatment, each patient must be individualized:

• Fertility desires and surgical menopause in women under the age of 40 years must be discussed (see ‘Fertility-sparing options').

• Suitability for surgery must be assessed. Elderly, frail women and women with severe comorbidities may require assessment and op­timization by a physician, geriatrician, and anaesthetist.

• The need for systematic lymphadenectomy must be deter­mined. This may be determined by preoperative factors or by intraoperative assessment of the tumour (see ‘Lymphadenectomy in endometrial cancer').

Source data from 2009 FIGO staging of endometrial carcinoma.

• The extent ofsurgery must be tailored to each woman. Laparoscopic and vaginal routes may need to be considered. A shorter surgical time and less morbid surgical route may be necessitated by co- morbid disease or cardiorespiratory compromise. Intraoperative limitations in access or visibility due to visceral and abdominal wall adipose tissue may also make the procedure unnecessarily challenging. In certain cases, systematic lymphadenectomy, though indicated, may need to be abandoned.

Conventional surgery should include:

• a midline abdominal incision for non-endometrioid subtypes or where preoperative investigations suggest upper abdominal disease

• careful and bloodless entry to the peritoneal cavity

• peritoneal washings or sampling of free fluid

• abdominal survey exploring the entire peritoneal cavity in a systematic manner looking for tumour deposits and enlarged lymph nodes

• extrafascial hysterectomy with or without a vaginal cuff

• bilateral salpingo-oophorectomy

• removal of all suspicious or enlarged pelvic and para-aortic nodes

• infracolic omentectomy, to be considered in cases with serous histology (14)

• systematic lymphadenectomy, where indicated by institutional policy, based either on preoperative or intraoperative tumour assessment

• a maximal effort at cytoreduction (where feasible) has been shown to improve progression-free and overall survival rates (25).

Further surgical considerations include the following:

• Obesity is a major risk factor for endometrial cancer and a lower transverse incision is more suited to patients with clinically early- stage, low-grade disease. This group of patients seldom require systematic lymphadenectomy and rarely have extrapelvic disease. Wound complications, incisional hernias, and complications re­lated to impaired mobility are less.

• Laparoscopic surgery: laparoscopy offers great benefit to obese women. It has been extensively researched and is widely used to manage endometrial cancer. For laparoscopy to be an effective al­ternative, it needs to be as safe and have equivalent oncological out­comes to open surgery. The Gynecologic Oncology Group (GOG) LAP2 trial showed that intraoperative surgical complication rates were similar between the patients who had laparotomy and those who had the laparoscopic approach. The laparoscopic group had significantly less minor postoperative complications and most women were discharged 2 days after surgery (26). A follow-up study of the LAP2 trial and a 2009 meta-analysis of trials com­paring open and laparoscopic surgery found that the laparoscopic route did not significantly disadvantage oncological outcomes (27, 28). Retrospective studies have shown robotic surgery to have equivalent oncological outcomes to a laparoscopic approach (29).

• Routine radical hysterectomy for overt stage II tumours is not of survival benefit and increases intraoperative and postoperative complications (14). Women with stage II disease will receive adju­vant local radiation and any residual microscopic parametrial dis­ease will be sterilized. Removal of the parametrium should only be considered when there is palpable parametrial spread and radical surgery will achieve clear margins.

• Synchronous ovarian tumours are a rare occurrence and more common in younger women. They are frequently of endometrioid histology and to decide whether they are metastatic spread from a primary endometrial tumour or a de novo ovarian carcinoma is challenging. In a study of17 women under 45 years with endomet­rial cancer, 29.4% had synchronous ovarian tumours compared to 4.6% in women over 45 years (30). In these cases, ovarian preser­vation is not appropriate. Each tumour site needs to be viewed as an independent cancer and managed with the appropriate surgical and adjuvant therapies.

• A vaginal approach should be offered in women fit for anaes­thesia, but where abdominal surgery is not safe or achievable. Hysterectomy and bilateral adnexectomy should be possible using this route.

• Oophorectomy in young women: there is significant morbidity and mortality associated with removal of ovaries in young women. Not performing bilateral oophorectomy in those under 45 years without a significant hereditary risk and with grade 1 early-stage endometrial disease has not been shown to impact overall sur­vival. Salpingectomy should still be performed (14).

• Palliative hysterectomy should be considered, where safe and feas­ible, in advanced disease to alleviate vaginal bleeding, offensive discharge, and pain. Patients with carcinosarcoma frequently present with distant metastases but also have a rapidly enlarging uterus often with a fungating and necrotic tumour mass pro­truding through the cervix. In selected patients, quality of life can certainly be improved by removing the uterus.

Lymphadenectomy

The main purpose of lymphadenectomy in endometrial cancer is surgical staging and should be considered in women with inter­mediate (stage I low-grade tumours with >50% invasion or grade 3 tumours with <50% invasion) or high-risk factors. However, lymphadenectomy also provides important prognostic information and is essential in evaluating the need for adjuvant therapy.

As with all gynaecological cancers, suspicious or enlarged lymph nodes detected at surgery should be removed, or at least sampled if removal is deemed unsafe (i.e. a node densely adherent to a major vessel). Systematic lymphadenectomy is probably the most contro­versial topic in the management of endometrial cancer. There has been much debate in terms of the indications, extent, and thera­peutic and survival benefits of systematic lymphadenectomy.

As the majority of women with endometrial cancer present with early-stage low-grade disease, hysterectomy and bilateral salpingo- oophorectomy is sufficient treatment to achieve cure. Two ran­domized trials have shown that performing a routine systematic lymphadenectomy on these women offers no survival (31, 32). Such practice is unnecessary and increases intra- and postoperative com­plication rates. A 2015 European Consensus Conference strongly recommends against performing systematic lymphadenectomy in these women (14). However, the studies on which the current ra­tionale for lymphadenectomy is based have been criticized for a number of reasons including:

• low node yields

• not including or only sampling the para-aortic nodes

• most study participants had early-stage low-risk cancers where lymphadenectomy would not have been of benefit

• a heterogeneous population in terms of tumour characteristics combining endometrioid and non-endometrioid subtypes and grade 1 and 2 with grade 3 tumours

• women were randomized to adjuvant radiotherapy regardless of the results of the lymphadenectomy.

Indications for a lymph node dissection

Systematic lymphadenectomy is performed based on specific in­dications. These indications try to exclude early-stage low-risk tumours where lymphadenectomy would be of no benefit. The in­dications have been determined using the results of various trials on endometrial cancer and they may be based on both preopera­tive and intraoperative factors. Exact indications for systematic lymphadenectomy are often institution dependent and are deter­mined by resources and personal interpretation of controversial and contradicting data (Table 63.4).

Certain intraoperative factors are established using frozen section. This requires the presence of a gynaepathologist in theatre which

Table 63.4 Indicators for systematic lymphadenectomy

may not always be possible, especially in developing countries. As an alternative, intraoperative sectioning of the uterus (preferably in the coronal plane) with visual assessment of the depth of myometrial invasion has been shown to be up to 87% accurate in grade 1 tu­mours and 65% accurate in grade 2 tumours (33, 34). Where the intraoperative tumour diameter is less than 2 cm, nodal metastases are unlikely (35). This practice may be of benefit where assessing the need for systematic lymphadenectomy via preoperative imaging or frozen section is not always available.

Extent of lymphadenectomy

In women where lymphadenectomy is indicated, there is no doubt of the need for complete resection of all pelvic nodes up to and in­cluding the common iliac nodes; however, the need for and extent of para-aortic dissection is controversial.

Complete para-aortic lymphadenectomy significantly increases surgical time, blood loss, surgical incision size, and postoperative complications including a 20% risk of lower limb lymphoedema (36). Women may be obese, frail, and often have significant comorbid conditions and the risk-benefit profile of such extensive surgery needs to be carefully assessed. The single factor that seems most pre­dictive of para-aortic nodal involvement is confirmed pelvic node metastases. Both a Japanese study and one conducted by the Mayo Clinic (United States) have shown nearly 50% of patients with posi­tive pelvic nodes have positive para-aortic nodes, whereas over 95% of patients had negative para-aortic nodes when the pelvic nodes were negative (37, 38). There may be uterine lymph channels that drain directly to the para- aortic nodes at the level of the renal vessels. This is explained by the collateral uterine-ovarian lymphovascular supply and accounts for the small group of women (1.6%) who have para-aortic metastases with negative pelvic nodes, where these posi­tive nodes would be missed by pelvic lymphadenectomy alone (39).

Sentinel node biopsy in endometrial cancer

Following the success of sentinel node biopsy in breast and vulval cancers, sentinel node studies have been performed in endomet­rial cancer. This practice has the potential to afford every case of endometrial cancer a nodal assessment independent of risk fac­tors. Performing sentinel node biopsy has been shown to detect lymph node metastases in 10% of women who would not usually have undergone systematic lymphadenectomy based on tumour factors (40). Its benefits include less surgical morbidity, specifically lymphoedema, while still providing essential information to stage the disease and tailor adjuvant therapy. There is some controversy about where the dye or fluorescent stain should be injected in endo­metrial cancer: be it at the cervix, as done when mapping sentinel nodes in early-stage cervical cancer, or via hysteroscopy into the uterine fundus or into the tumour.

Radiotherapy in the management of endometrial cancer

Radiation can be used for a number of indications in endometrial cancer including:

• adjuvant therapy for intermediate or high-risk disease

• primary treatment where surgery is not suitable

• treatment of recurrent disease

• palliation of symptoms including bleeding or symptomatic metastases.

While adjuvant radiotherapy has no significant effect on overall survival it has been shown to increase progression-free survival by reducing pelvic recurrences (32, 41, 42). The need for adjuvant radiotherapy in endometrial cancer is based on specific risk fac­tors in stage I disease but is always indicated in stage II disease and greater.

Adjuvant radiation can be delivered in four forms: vault brachy­therapy, external beam pelvic radiation, extended field radiation (to expand the irradiated field to include para-aortic nodes below the renal arteries), and whole abdominal radiation. The vagina is the most common site of recurrence. Vault tumours are difficult to manage surgically but vault brachytherapy and external pelvic ra­diation are effective and well tolerated adjuvant interventions (41, 43). Whole pelvis irradiation has been shown to be as effective as vaginal vault brachytherapy in reducing tumour recurrence at the vault; however, vaginal brachytherapy is preferred as the total radi­ation dose is smaller thus reducing radiation-mediated toxicity (42).

Surgery followed by adjuvant pelvic radiation was shown in the ASTEC study to reduce recurrence in the pelvis and at the vault in early-s tage disease but demonstrated no improvement in overall survival (32). The findings of the ASTEC study were mirrored in the PORTEC-1 study; however, both studies received much criti­cism (41). ASTEC had major design faults and the PORTEC-1 study included participants who were considered at low risk of developing recurrent disease.

PORTEC-2 randomized patients with an intermediate-risk pro­file for local recurrence to either vault brachytherapy or whole pelvis irradiation. No significant difference in vaginal vault recurrence or overall survival was seen in either arm; however, external beam treatment increased long-term morbidity (42). The findings of both PORTEC studies were criticized as lymphadenectomy was not per­formed in either trial, both were underpowered, and included large numbers of low-risk tumours that had minimal risk of pelvic nodal involvement and recurrence.

In early-stage low-risk tumours (stage I, grade 1-2, <50% myometrial invasion, LVSI negative) vault recurrence is not common and adjuvant radiotherapy is not indicated (14). In stage I disease with high- to intermediate-risk factors (grade 3 endometrioid with <50% myometrial invasion, or grade 1-2 with extensive LVSI) or high-risk factors (grade 3 endometrioid with ≥50% myometrial invasion regardless of LVSI) there is unanimous support in the lit­erature that such cases require adjuvant radiation to decrease local recurrence; this was further supported by the GOG-99 study (44). In stage II disease where the tumour has invaded the cervical stromal tissue, a vaginal brachytherapy boost is often prescribed in addition to external beam radiation. In cases of high-intermediate-risk dis­ease where the nodal status is unknown, adjuvant external beam therapy should be chosen above vault brachytherapy where there is unequivocal LVSI (14).

Primary treatment of endometrial cancer using radiotherapy is reserved for patients not suited to surgery. Radiation is delivered to the uterus using intracavity brachytherapy via a rod or Hayman's pack that is inserted transvaginally into the cavity. Intracavity therapy is usually combined with external beam radiotherapy, how­ever, external radiotherapy may prove problematic as the weight and abdominal girth of certain patients may exceed the limits of the ex­ternal beam radiation machine.

Chemotherapy in endometrial cancer

Chemotherapy in early-stage endometrial cancer

The role of chemotherapy in early-stage endometrioid endometrial cancer has not been established, however, chemotherapy may be beneficial in patients with early- stage carcinosarcoma. The toxicity of combination chemotherapy and only a marginal increase in overall survival may not justify use of these drugs (45, 46). Ifosfamide-based combination treatment, especially when combined with paclitaxel, has shown more activity in the treatment of advanced stage or recur­rent carcinosarcoma (47).

Chemotherapy in advanced-stage disease

The combination of postoperative radiation and chemotherapy seems to give better progression-free and overall survival out­comes compared to either chemotherapy or radiation given as stand-alone treatments (48). Although multiagent chemotherapy is more effective, the cumulative toxicity is not well tolerated (49). In a GOG study, by Randall et al., chemotherapy seemed to offer better progression-free survival in stage III patients, with gross residual disease and endometrioid histology compared to whole abdominal irradiation (50).

Role of targeted therapies

Phosphotidylinositol-3 kinase (PI3K) is mutated in both type 1 and 2 uterine cancers. Current treatments aim at inhibiting this pathway (51).

Targeted therapies such as PI3K/AKTZmammalianZmechanistic target of rapamycin (mTOR) and vascular endothelial growth factor inhibitors are considered in oncological practice to:

• act synergistically with current chemotherapeutic agents

• reduce resistance to chemotherapy

• increase progesterone receptor expression in patients with advanced-stage or recurrent uterine carcinoma resistant to progestogens (52).

Most of these target-based treatments are being tested in phase II studies.

Metformin in endometrial cancer

Metformin is a biguanide that not only counteracts insulin resist­ance, but has been found to counter proliferative, invasive, and metastatic activity in patients with type 1 endometrial cancer. The antitumour effect of metformin is believed to inhibit the mTOR pro­tein kinase (53).

Fertility-sparing management in endometrial cancer

Increasingly, more women under the age of 40 years are diagnosed with endometrial cancer. Fertility is sometimes a concern at the time of diagnosis. Most of these women are diagnosed with low-risk carcinomas or endometrial hyperplasia, though high-grade (grade 3) endometrioid carcinoma may be found in about 8% of young women (54). A high-stage endometrial cancer diagnosis is also not uncommon. The depth of tumour invasion should be considered before conservative treatment is considered. Dynamic MRI with contrast is more sensitive in assessing depth of tumour infiltration (55). Hormonal therapy has been used with reasonable resolution of disease. There have also been reports of successful pregnancies after hormonal treatment for endometrial cancer (56). Progression of dis­ease has been observed in 47% of these women. Physicians should have a thorough discussion of possible risks and benefits of the con­servative management before embarking on this approach.