Unresolved Issues in the Management of Endometrial Cancer

Cathrine Holland

Disclosures

Expert Rev Anticancer Ther. 2011;11(1):57-69. 

In This Article

Fertility-sparing Treatment

The treatment of endometrial cancer in very young women can present a particular challenge. A minority of women develop endometrial cancer before the age of 40 years but as the incidence of endometrial cancer is projected to increase, the number of young women with the disease can be expected to rise. Most cases are endometrioid-type cancers and there is often coexisting atypical hyperplasia, a precursor lesion. Because of the association of infertility and nulliparity with this type of cancer, it is not surprising that a significant proportion of premenopausal women are childless at the time of diagnosis. For some of these, the possibility of fertility-sparing treatment is a consideration. Endometrioid tumors typically express progesterone receptors and many respond to hormonal treatment.[6] A number of studies have been published reporting the use of progestogens as a treatment for atypical hyperplasia or grade 1 endometrioid tumors that appear to be confined to the endometrium. The use of the levonorgestrel intrauterine system with histological response is described in single-institution studies[7] but numbers are very small. Gonadotropin-releasing hormone analogs have been investigated as treatment for advanced endometrial malignancy, but to date there are no significant data to support their use in the conservative management of early disease. Most studies report on the use of oral progestogens, typically high dose. A review of 99 women treated within nine different studies reported an overall complete response rate of 54% with a total of 37 live births.[8] More recently, response rates of 55–63% have been reported with the use of high-dose progestogens.[9,10] Even higher responses of up to 82% are reported for atypical hyperplasia.[9] Pregnancy rates for women with a complete histological response are encouraging with rates of 43–83%, although fertility treatment may be required.[10–12] In a series of 21 women with either grade 1 endometrial cancer or atypical hyperplasia, the use of a cyclical regime of low-dose progestogen appeared effective with all women alive at 98 months of follow-up.[11] However, up to 47% of women treated with progestogens suffer a relapse, emphasizing the need for caution.[9] In addition, whilst more accurate than CT, the limitations of MRI in detecting myometrial invasion must be appreciated.[13] In one institutional review of endometrial cancer cases in women younger than 35 years old, the disease was either upstaged or upgraded following hysterectomy in 20% of cases.[14] In total, 30% of tumors were found to be at an advanced stage and 24% of women had high-grade tumors.[14] Another study of 301 women with stage I endometrial cancer reported that the negative predictive value of MRI for myometrial invasion was only 49.2%, further emphasizing that caution is required when selecting women for conservative treatment.[15] It is clear that fertility-sparing treatment is a realistic option for some women with stage I disease (Table 1) but there are a number of unanswered questions that remain. Currently, the optimum preparation and dose of progestogen is unknown as these differ widely between studies. However, based upon these, the most effective regimes appear to be either medroxyprogesterone acetate 200–600 mg daily or megestrol acetate 160 mg daily. Hysteroscopy and sampling for endometrial response is typically undertaken at 3–6 monthly intervals, the optimum frequency being based upon time to response in a relatively limited number of studies. Women with a pre-existing history of infertility will usually need fertility treatment and there is no guidance regarding the length of time for which this is safe before hysterectomy should be considered. In addition, there is no robust evidence to guide the clinician regarding the need for hysterectomy after a successful pregnancy has been achieved. There are a number of case reports in the literature detailing the consequences of failed conservative management or loss of patients to follow-up.[16–18] This is a subject that requires further evidence from prospective randomized multicenter trials. At the present time, fertility-sparing treatment should be undertaken only after fully informing the woman and her partner of the risks and the limitations in current knowledge and the proven high success rate of standard treatment. In addition, a clear plan for regular histological surveillance of the endometrium is required and a time frame for the continuation or cessation of conservative management should be agreed.

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